Acta Haematol 2014;132:383–390 DOI: 10.1159/000360202
Published online: September 10, 2014
Survivorship in Adolescents and Young Adults Ashwin Kishtagari Montreh Tavakkoli Jae H. Park Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, N.Y., USA
Abstract In the USA, approximately 26,000 adolescents and young adults (AYAs) aged 15–29 years are diagnosed with cancer every year. The cure rate among this population exceeds 80%, resulting in a growing number of AYA cancer survivors. AYA cancer survivors suffer from a wide range of long-term treatment-related toxicities that adversely affect quality of life and increase the risk of premature death. Therefore, it is important to recognize the unique medical needs of the AYA cancer survivors and develop a cost-effective and systemic approach to screen and prevent cancer treatment-related sequelae and the adverse health outcomes. © 2014 S. Karger AG, Basel
Introduction
In the USA, about 26,000 adolescents and young adults (AYAs) aged 15–29 years are diagnosed with cancer every year [1], and the cure rate of AYA cancers now exceeds 80% [2], resulting in a growing and large number of AYA cancer survivors with unique medical needs and an excess risk of chronic health conditions [3–5]. Much of our understanding of long-term health status, morbidity and © 2014 S. Karger AG, Basel 0001–5792/14/1324–0383$39.50/0 E-Mail [email protected] www.karger.com/aha
mortality after cancer in AYAs has emanated from the Childhood Cancer Survivor Study (CCSS) due to the limited number of studies and lack of a cohort in North America that is solely focused on the AYA population. Chronic disease in AYA cancer survivors can involve multiple organ systems and may not become clinically evident for many years. Late mortality in childhood cancer survivors is significantly increased (standardized mortality ratio, SMR = 19.4), mainly from subsequent cancers (SMR = 9.2), pulmonary (SMR = 8.8) and cardiac (SMR = 7.0) diseases [6]. Oeffinger et al. [3] subsequently reported the cumulative incidence of 73.4 and 42.4% for a chronic health condition and severe, disabling or lifethreatening conditions, respectively, 30 years after the cancer diagnosis in childhood cancer survivors (mean age 26.6, range 18–48 years). Survivors exposed to radiation therapy (RT), chemotherapy or combination therapy (chemotherapy + RT) were all found to have elevated risks of severe or life-threatening conditions, and the incidence increased over time, suggesting that the cohort continues to face new-onset morbidity as they age and even 20–25 years after their treatment. In this section of the review series on AYAs, we describe secondary malignancies and chronic health conditions that often complicate the management of AYA survivors of hematological malignancies.
A.K. and M.T. contributed equally to this work.
Jae H. Park Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10065 (USA) E-Mail parkj6 @ mskcc.org
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Key Words Adolescents and young adults · Chronic health conditions · Secondary malignancies · Survivorship
Treatment modalities for hematological malignancies commonly include high doses of chemotherapy, RT or a combinatorial modality of chemotherapy and RT. While these agents have improved overall survival from primary malignancies, the potential to introduce mutations at sublethal doses in healthy cells may lead to the development of secondary cancers (SCs). Furthermore, AYAs have a greater life expectancy following treatment for their primary cancer [7], and are at a higher risk of developing SCs than the general population and their adult counterparts [8, 9]. In a registry-based report of a Nordic cohort of 47,697 childhood cancer survivors, the overall risk of SCs was 2.3-fold higher compared to the general population [10]. Two other large registry-based studies of a US cohort of 14,581 and a UK cohort of 16,541 childhood cancer survivors reported a 6.4-fold and 5.8-fold greater risk of SCs than that in the general population [11, 12]. The risk and type of SC depend on the type of primary cancer, the therapeutic regimen and the cumulative doses of chemotherapy and/or RT [8]. The use of chemotherapy is frequently associated with the development of myelodysplasia and acute myeloid leukemia, and RT tends to increase the risk of solid SCs. Chemotherapy-induced myelodysplasia and acute myeloid leukemia have a shorter latency and are associated with alkylating agents or topoisomerase II inhibitors. Radiation-induced solid tumors usually have a latency period longer than 10 years and account for the largest burden of SCs [13]. Hodgkin’s Lymphoma In a British cohort of 6,798 patients diagnosed with Hodgkin’s lymphoma (HL) between 15 and 34 years of age, the 20-year cumulative risk of developing SCs was 13% for patients treated with chemotherapy alone and 18% for patients treated with chemotherapy + RT [14]. In another study performed on 1,641 patients diagnosed with HL at ages ≤20, the cumulative risk of SCs was 1.9% at 10 years, 6.9% at 20 years and 18% at 30 years [15]. A Dutch cohort study of 1,253 patients diagnosed with HL at ages 20 Gy conformal RT in addition to any spinal RT [74]. Issues regarding gonadal dysfunction and fertility are discussed in more detail elsewhere in this issue.
AYA Screening and Surveillance Recommendations
AYA cancer survivors suffer from a wide risk of late and long-term treatment-related toxicities that adversely affect quality of life and increase the risk of premature death. Therefore, it is important to anticipate and screen for late treatment effects and apply timely interventions in order to prevent or ameliorate cancer treatment-related sequelae and the adverse health outcomes. To this end, the Children’s Oncology Group developed risk-based, exposure-related long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. Implementation of these guidelines is intended to standardize and enhance follow-up care childhood and AYA cancer survivors. The entire guidelines can be downloaded at www.survivorshipguidelines.org. While recommendations for the active surveillance and follow-up of AYA survivors of hematological malignancies are of importance from a clinical standpoint, it is also critical to address the issue from a more practical perspective to ensure adherence to these guidelines. For instance, cancer centers experience a significant loss to follow-up of AYA cancer survivors, and AYAs, like other healthy individuals, receive a majority of their care through primary care practitioners [77–79]. However, primary Acta Haematol 2014;132:383–390 DOI: 10.1159/000360202
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3.1) [62]. The risk of stroke also appears to be dependent on a cumulative radiation dose, with the highest possible risk associated with cranial irradiation of ≥50 Gy and less so with ≥30 Gy [63]. While high-dose systemic chemotherapy is associated with only subtle long-term neurocognitive deficits (attention, executive functioning), its use increases the risk of peripheral neuropathy, psychiatric conditions and neuroendocrine changes. In a cross-sectional study performed on 80 survivors of ALL between 5 and 18 years of age with a 3-year follow-up, 34% had developed neuropathy, most commonly symmetric motor axonal polyneuropathy seen in 24% of the children [64]. In a study on 5,736 survivors of childhood leukemia, HL and NHL, patients frequently reported depression and somatic distress that was added by intensive chemotherapy [65]. Similarly, the CCSS reported an increased risk of psychiatric conditions among patients treated for ALL and NHL, with a significant increase in depression and somatic distress relative to sibling controls [66]. Lastly, cranial irradiation, hematopoietic stem cell transplantation and chemotherapy are associated with changes in the neuroendocrine system that seem to play a role in physical inactivity, obesity, visceral adiposity, insulin resistance, dyslipidemia and poor cardiopulmonary fitness seen in childhood survivors of hematological malignancies. While this finding is significantly elevated with cranial radiation, it is attenuated and associated with a later onset among those who have been treated with chemotherapy alone [67].
care physicians may be unfamiliar with the long-term toxicities and appropriate surveillance measures necessitated for the early detection and prevention of chronic illness among AYA cancer survivors [69]. One study conducted on 1,174 family practitioners found that 84% of primary care physicians had cared for ≤2 childhood cancer survivors within the past 5 years. Of these, 48% never, or almost never, received a treatment summary from the patients’ referring cancer center. Furthermore, only 33 and 27% were comfortable caring for survivors of HL and ALL. However, their most important discovery was in the failure of 84–90% of primary care physicians to identify the appropriate follow-up care for a case presentation of childhood HL [80]. Similarly, a lower than anticipated rate of compliance with the breast cancer surveillance guideline was reported in female childhood cancer survivors at high risk of developing secondary breast cancer [63.5% of those aged 25–39 years and 23.5% of those aged 40–50 years, 81], largely attributed to the lack of training among providers in posttransitional health care and the loss of communication among providers and their patients. One solution to this problem may lie in the development of a personalized 1-page survivorship guide that is created by the patients’ oncologist at the completion of treatment, and is directly mailed to survivors in an automated fashion on an annual or biannual basis. The survi-
vorship guide would include the recommended screens based on the treatment regimens and cumulative doses provided for the treatment of the AYA malignancy, and provide age-specific screening guidelines based on the anticipated long-term toxicities. Support for the utilization of such a program stems from the recent findings of Oeffinger et al. [82]. According to this study, 72 survivors of HL who were diagnosed between 27 and 55 years of age and at a high risk of developing secondary breast cancer and cardiomyopathy, and who had not been screened with mammography or echocardiograms for ≥2 years, were sent a 1-page survivorship care plan with recommendations for surveillance. At a 6-month follow-up, 41% of the patients were screened with mammography and 20% had been screened with an echocardiogram. The 9 physicians enrolled in the study failed to use the resources provided, but were responsive to patients’ requests for the screens. While additional studies are required to determine the effectiveness of such an approach over consecutive years, the 1-page Cancer Treatment Summary and Survivorship Care Plan may overcome multiple issues in the transition of survivorship care to their primary health care providers and provide a cost-effective means towards minimizing loss to follow-up and improving surveillance among AYA cancer survivors.
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Published online: September 10, 2014
Survivorship in Adolescents and Young Adults Ashwin Kishtagari Montreh Tavakkoli Jae H. Park Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, N.Y., USA
Abstract In the USA, approximately 26,000 adolescents and young adults (AYAs) aged 15–29 years are diagnosed with cancer every year. The cure rate among this population exceeds 80%, resulting in a growing number of AYA cancer survivors. AYA cancer survivors suffer from a wide range of long-term treatment-related toxicities that adversely affect quality of life and increase the risk of premature death. Therefore, it is important to recognize the unique medical needs of the AYA cancer survivors and develop a cost-effective and systemic approach to screen and prevent cancer treatment-related sequelae and the adverse health outcomes. © 2014 S. Karger AG, Basel
Introduction
In the USA, about 26,000 adolescents and young adults (AYAs) aged 15–29 years are diagnosed with cancer every year [1], and the cure rate of AYA cancers now exceeds 80% [2], resulting in a growing and large number of AYA cancer survivors with unique medical needs and an excess risk of chronic health conditions [3–5]. Much of our understanding of long-term health status, morbidity and © 2014 S. Karger AG, Basel 0001–5792/14/1324–0383$39.50/0 E-Mail [email protected] www.karger.com/aha
mortality after cancer in AYAs has emanated from the Childhood Cancer Survivor Study (CCSS) due to the limited number of studies and lack of a cohort in North America that is solely focused on the AYA population. Chronic disease in AYA cancer survivors can involve multiple organ systems and may not become clinically evident for many years. Late mortality in childhood cancer survivors is significantly increased (standardized mortality ratio, SMR = 19.4), mainly from subsequent cancers (SMR = 9.2), pulmonary (SMR = 8.8) and cardiac (SMR = 7.0) diseases [6]. Oeffinger et al. [3] subsequently reported the cumulative incidence of 73.4 and 42.4% for a chronic health condition and severe, disabling or lifethreatening conditions, respectively, 30 years after the cancer diagnosis in childhood cancer survivors (mean age 26.6, range 18–48 years). Survivors exposed to radiation therapy (RT), chemotherapy or combination therapy (chemotherapy + RT) were all found to have elevated risks of severe or life-threatening conditions, and the incidence increased over time, suggesting that the cohort continues to face new-onset morbidity as they age and even 20–25 years after their treatment. In this section of the review series on AYAs, we describe secondary malignancies and chronic health conditions that often complicate the management of AYA survivors of hematological malignancies.
A.K. and M.T. contributed equally to this work.
Jae H. Park Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10065 (USA) E-Mail parkj6 @ mskcc.org
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Key Words Adolescents and young adults · Chronic health conditions · Secondary malignancies · Survivorship
Treatment modalities for hematological malignancies commonly include high doses of chemotherapy, RT or a combinatorial modality of chemotherapy and RT. While these agents have improved overall survival from primary malignancies, the potential to introduce mutations at sublethal doses in healthy cells may lead to the development of secondary cancers (SCs). Furthermore, AYAs have a greater life expectancy following treatment for their primary cancer [7], and are at a higher risk of developing SCs than the general population and their adult counterparts [8, 9]. In a registry-based report of a Nordic cohort of 47,697 childhood cancer survivors, the overall risk of SCs was 2.3-fold higher compared to the general population [10]. Two other large registry-based studies of a US cohort of 14,581 and a UK cohort of 16,541 childhood cancer survivors reported a 6.4-fold and 5.8-fold greater risk of SCs than that in the general population [11, 12]. The risk and type of SC depend on the type of primary cancer, the therapeutic regimen and the cumulative doses of chemotherapy and/or RT [8]. The use of chemotherapy is frequently associated with the development of myelodysplasia and acute myeloid leukemia, and RT tends to increase the risk of solid SCs. Chemotherapy-induced myelodysplasia and acute myeloid leukemia have a shorter latency and are associated with alkylating agents or topoisomerase II inhibitors. Radiation-induced solid tumors usually have a latency period longer than 10 years and account for the largest burden of SCs [13]. Hodgkin’s Lymphoma In a British cohort of 6,798 patients diagnosed with Hodgkin’s lymphoma (HL) between 15 and 34 years of age, the 20-year cumulative risk of developing SCs was 13% for patients treated with chemotherapy alone and 18% for patients treated with chemotherapy + RT [14]. In another study performed on 1,641 patients diagnosed with HL at ages ≤20, the cumulative risk of SCs was 1.9% at 10 years, 6.9% at 20 years and 18% at 30 years [15]. A Dutch cohort study of 1,253 patients diagnosed with HL at ages 20 Gy conformal RT in addition to any spinal RT [74]. Issues regarding gonadal dysfunction and fertility are discussed in more detail elsewhere in this issue.
AYA Screening and Surveillance Recommendations
AYA cancer survivors suffer from a wide risk of late and long-term treatment-related toxicities that adversely affect quality of life and increase the risk of premature death. Therefore, it is important to anticipate and screen for late treatment effects and apply timely interventions in order to prevent or ameliorate cancer treatment-related sequelae and the adverse health outcomes. To this end, the Children’s Oncology Group developed risk-based, exposure-related long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. Implementation of these guidelines is intended to standardize and enhance follow-up care childhood and AYA cancer survivors. The entire guidelines can be downloaded at www.survivorshipguidelines.org. While recommendations for the active surveillance and follow-up of AYA survivors of hematological malignancies are of importance from a clinical standpoint, it is also critical to address the issue from a more practical perspective to ensure adherence to these guidelines. For instance, cancer centers experience a significant loss to follow-up of AYA cancer survivors, and AYAs, like other healthy individuals, receive a majority of their care through primary care practitioners [77–79]. However, primary Acta Haematol 2014;132:383–390 DOI: 10.1159/000360202
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3.1) [62]. The risk of stroke also appears to be dependent on a cumulative radiation dose, with the highest possible risk associated with cranial irradiation of ≥50 Gy and less so with ≥30 Gy [63]. While high-dose systemic chemotherapy is associated with only subtle long-term neurocognitive deficits (attention, executive functioning), its use increases the risk of peripheral neuropathy, psychiatric conditions and neuroendocrine changes. In a cross-sectional study performed on 80 survivors of ALL between 5 and 18 years of age with a 3-year follow-up, 34% had developed neuropathy, most commonly symmetric motor axonal polyneuropathy seen in 24% of the children [64]. In a study on 5,736 survivors of childhood leukemia, HL and NHL, patients frequently reported depression and somatic distress that was added by intensive chemotherapy [65]. Similarly, the CCSS reported an increased risk of psychiatric conditions among patients treated for ALL and NHL, with a significant increase in depression and somatic distress relative to sibling controls [66]. Lastly, cranial irradiation, hematopoietic stem cell transplantation and chemotherapy are associated with changes in the neuroendocrine system that seem to play a role in physical inactivity, obesity, visceral adiposity, insulin resistance, dyslipidemia and poor cardiopulmonary fitness seen in childhood survivors of hematological malignancies. While this finding is significantly elevated with cranial radiation, it is attenuated and associated with a later onset among those who have been treated with chemotherapy alone [67].
care physicians may be unfamiliar with the long-term toxicities and appropriate surveillance measures necessitated for the early detection and prevention of chronic illness among AYA cancer survivors [69]. One study conducted on 1,174 family practitioners found that 84% of primary care physicians had cared for ≤2 childhood cancer survivors within the past 5 years. Of these, 48% never, or almost never, received a treatment summary from the patients’ referring cancer center. Furthermore, only 33 and 27% were comfortable caring for survivors of HL and ALL. However, their most important discovery was in the failure of 84–90% of primary care physicians to identify the appropriate follow-up care for a case presentation of childhood HL [80]. Similarly, a lower than anticipated rate of compliance with the breast cancer surveillance guideline was reported in female childhood cancer survivors at high risk of developing secondary breast cancer [63.5% of those aged 25–39 years and 23.5% of those aged 40–50 years, 81], largely attributed to the lack of training among providers in posttransitional health care and the loss of communication among providers and their patients. One solution to this problem may lie in the development of a personalized 1-page survivorship guide that is created by the patients’ oncologist at the completion of treatment, and is directly mailed to survivors in an automated fashion on an annual or biannual basis. The survi-
vorship guide would include the recommended screens based on the treatment regimens and cumulative doses provided for the treatment of the AYA malignancy, and provide age-specific screening guidelines based on the anticipated long-term toxicities. Support for the utilization of such a program stems from the recent findings of Oeffinger et al. [82]. According to this study, 72 survivors of HL who were diagnosed between 27 and 55 years of age and at a high risk of developing secondary breast cancer and cardiomyopathy, and who had not been screened with mammography or echocardiograms for ≥2 years, were sent a 1-page survivorship care plan with recommendations for surveillance. At a 6-month follow-up, 41% of the patients were screened with mammography and 20% had been screened with an echocardiogram. The 9 physicians enrolled in the study failed to use the resources provided, but were responsive to patients’ requests for the screens. While additional studies are required to determine the effectiveness of such an approach over consecutive years, the 1-page Cancer Treatment Summary and Survivorship Care Plan may overcome multiple issues in the transition of survivorship care to their primary health care providers and provide a cost-effective means towards minimizing loss to follow-up and improving surveillance among AYA cancer survivors.
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