The cancer is over, now what?

Understanding risk, changing outcomes

Authors

  • Kevin C. Oeffinger MD,

    Corresponding author
    1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
    2. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New YorkThe articles in this supplement represent presentations and discussions at the “International Workshop on Adolescents and Young Adults with Cancer: Toward Better Outcomes in Canada” that was held in Toronto, Ontario, March 11-13, 2010.
    • Memorial Sloan-Kettering Cancer Center, 600 East 66th Street, New York, NY 10065
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    • Fax: (646) 888-4923

  • Emily S. Tonorezos MD, MPH

    1. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New YorkThe articles in this supplement represent presentations and discussions at the “International Workshop on Adolescents and Young Adults with Cancer: Toward Better Outcomes in Canada” that was held in Toronto, Ontario, March 11-13, 2010.
    Search for more papers by this author

Abstract

About 26,000 adolescents and young adults ages 15 to 29 years are diagnosed with invasive cancer each year. Although >80% will survive beyond 5 years from their cancer diagnosis, many will develop serious morbidity or die prematurely secondary to health problems in part related to their cancer therapy. This article provides a brief overview of mortality, morbidity, and health status among long-term survivors of adolescent and young adult (AYA) cancer. Four examples were used to illustrate the potential of risk-reducing strategies: breast cancer after chest irradiation, coronary artery disease after chest irradiation, cardiovascular disease in testicular cancer survivors, and the multitude of health problems faced by survivors receiving an allogeneic hematopoietic stem cell transplant. A conceptual model for risk-based health care was presented and future directions of the delivery of care for AYA cancer survivors discussed. Cancer 2011;117(10 suppl):2250–7. © 2011 American Cancer Society.

In Canada and the United States, about 26,000 adolescents and young adults (AYA) ages 15 to 29 years are diagnosed with invasive cancer every year.1, 2 With a 5-year survival rate for adolescent and young adult (AYA) cancers now exceeding 80%,1, 2 there is a growing number of AYA cancer survivors with unique and special healthcare needs.

To date, much of our understanding of long-term outcomes after cancer in AYA has emanated from the Childhood Cancer Survivor Study (CCSS), a 26-institution retrospective cohort study following more than 14,000 long-term survivors of cancer in childhood and adolescence from the United States and Canada who were diagnosed from 1970 to 1986.3 For this workshop, outcomes among those diagnosed between the ages of 15 and 20 years are particularly relevant. However, extrapolations from those diagnosed during their childhood are also meaningful to our understanding of AYA survivorship and so will be discussed within context. In British Columbia, McBride et al have assembled a cohort of all 5-year survivors of cancer diagnosed before age 25 years from 1970 to 1995 through the Childhood/Adolescent/ Young Adult Cancer Survivors (CAYACS) Research Program. Population sample comparison groups were drawn from provincial registries, and these records have been linked to provincial administrative data sets.4 A similar effort to link multiple administrative databases is underway by the Pediatric Oncology Group of Ontario (POGO). Several single-cancer studies have assessed long-term outcomes among Hodgkin lymphoma (HL) and testicular cancer survivors across the AYA age range. Notably, however, there is not a cohort, in North America or internationally, that spans the age range of the AYA population (15 to 29 years) and includes survivors of different cancer groups.

Late Mortality, Serious Morbidity, and Diminished Health Status

Mertens et al5 has published updated data from the CCSS describing the cause-specific mortality among 5-year survivors of cancer in childhood (Fig. 1). The estimated probability of survival 30 years from diagnosis was 82%. The overall standardized mortality ratio (SMR) was 8.4. Increases in cause-specific mortality were seen for deaths due to subsequent malignancy (SMR = 15.2) and cardiac (SMR = 7.0), pulmonary (SMR = 8.8), and other medical (SMR = 2.6) causes. At 20 years of follow-up (25 years after first cancer diagnosis), the death rate due to a subsequent malignancy exceeded that due to all other causes. To illustrate these rates in another way, consider an individual diagnosed with HL in 1982 at age 18 years. The 5-year survival rate at that time was 82% for all stages of disease.6 So, if we overlay the CCSS mortality on this estimate, the 30-year survival rate (by age 48 years) would be 61%, with much of this excess mortality due to therapy-related problems. Exemplifying this late mortality related to the cancer diagnostic evaluation, a 15-year-old diagnosed with stage IIIA HL who had a staging laparotomy and splenectomy in 1986 died of overwhelming pneumococcal sepsis at the age of 35. As an illustration of late mortality secondary to cancer therapy, an adolescent diagnosed with stage IA HL in 1979, after being told that he was lucky to have the “good cancer,” was treated with 45-Gy mantle irradiation and died 26 years later from “sudden death syndrome.” At the time of death, he had high-grade 3-vessel coronary artery disease, severe aortic insufficiency, severe esophageal strictures, and severe restrictive lung disease.

Figure 1.

Overall survival according to sex in the Childhood Cancer Survivor Study cohort and expected survival based on age-, year-, and sex-matched US population mortality rates are shown. (Adapted from Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100:1368-1379; used with permission.)

Not surprisingly, long-term survivors of cancer in childhood and adolescence have an excess risk of chronic health conditions. We reported in the CCSS cohort that, by 30 years after the cancer diagnosis, the cumulative incidence of a chronic health condition was 73.4%, with a cumulative incidence of 42.4% for severe, disabling, or life-threatening conditions or death (Fig. 2).7 Survivors had an 8-fold increased relative risk of a serious chronic health condition compared with siblings who had not had cancer. Two of the more common cancer groups affecting adolescents and young adults, HL and bone tumors, were among the 3 highest-risk groups, with more than a 10-fold increased risk of serious morbidity. The most common treatment exposure associated with a poor outcome was chest irradiation, primarily mantle irradiation. Survivors who were treated with chest irradiation and an anthracycline or bleomycin had a 13-fold increased risk of a serious outcome compared with siblings.

Figure 2.

Cumulative incidence of chronic health conditions among 10,397 adult survivors of childhood and adolescent cancer is shown. (Adapted from Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572-1582; used with permission.)

Lastly, it is important to realize that this frequent occurrence of morbidity affects the daily lives of survivors. Hudson et al8 assessed the health status of CCSS survivors upon time of enrollment into the cohort. Six domains of health status were assessed: general health, mental health, functional impairment, activity limitations, pain, and fears/sense of uncertainty. The prevalences of moderately to extremely adverse outcomes for each of these domains ranged from 10.2% to 17.2% of the cohort. Notably, 43.6% of the survivors had at least 1 moderately to extremely adverse health status domain.

Generally, around this time in a talk, someone will raise his hand and say that such data reflect historical therapy and that the outcomes for AYA cancer patients treated with contemporary therapy will be significantly better. That hypothesis remains to be proven. As an anecdotal example, take a mother and daughter who we follow at Memorial Sloan-Kettering. The mother was diagnosed in 1975 at the age of 20 with stage IIB HL and was treated with mantle and inverted-Y field irradiation. Since that time, she has had thyroid and breast cancer, a 2-vessel coronary artery bypass graft, multiple basal cell carcinomas, restrictive lung disease, diabetes, nonalcoholic steatosis, and musculoskeletal problems—all related, in part, to her previous therapy. Her daughter was diagnosed in 2002 with stage IIIB HL at the age of 14. She was treated with 21-Gy involved-field irradiation, 21-Gy irradiation to the para-aortic lymph nodes, and BEACOPP chemotherapy. Within a year after her HL diagnosis, she developed myelodysplastic syndrome/t-acute myeloid leukemia and underwent an allogeneic stem cell transplant after preconditioning with busulfan, melphalan, and fludarabine. Since then, she has developed osteonecrosis of the hips, ovarian failure, hypothyroidism, insulin resistance, dyslipidemia, and iron overload/hemochromatosis. Obviously one should be cautious when using anecdotal experience to draw inferences. A recent small study of HL survivors treated with low-dose involved-field irradiation provides troubling support for the contention that the reduction in the incidence of late effects may not be as great as we hoped.9 Although we are striving to move from a historic era associated with much toxicity of therapy to one of improved long-term outcomes, the simple fact remains that many cancers in AYA require intensive therapy to be cured. Or, as poignantly stated by one of our survivors, “Late effects are the luxury of having survived the cancer.”

Can We Reduce the Risk of Premature Nonrelapse Mortality and Serious Morbidity?

Following are four examples illustrating the potential of risk-reducing strategies: breast cancer after chest irradiation, coronary artery disease after chest irradiation, cardiovascular disease in testicular cancer survivors, and the multitude of health problems faced by survivors receiving an allogeneic hematopoietic stem cell transplant. With these examples, we highlight 4 key points: age at exposure has varying influences on outcomes; these are common, not rare, outcomes; there is often a prolonged window of time in which the disease process is asymptomatic but can be detected with available technology; and the role of prevention, surveillance, and early intervention is substantive.

Breast cancer after chest radiation

Breast cancer is one of the major factors contributing to premature, nonrelapse mortality among women treated with chest irradiation. Bhatia et al10 reported that, by age 45 years, 20% of women treated for HL with mantle irradiation were diagnosed with breast cancer. The risk of breast cancer is strongly associated with age at radiation, as described by Dores et al11 in a large international population-based cohort study. The relative risk of breast cancer for women treated younger than age 21 years, 21 to 30 years, and 31 to 40 years was 14.2, 3.7, and 1.2, respectively. Similar trends were seen for the absolute excess risk of breast cancer. The incidence of breast cancer begins to increase 8 to 10 years after radiation with a median age at breast cancer diagnosis in the early 30s. Characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population; women diagnosed at an early stage generally have excellent outcomes. There are some notable limitations in therapy for women diagnosed with breast cancer after chest irradiation. Further breast irradiation after a lumpectomy is often not an option due to the previous high dose of irradiation delivered to the overlying skin and the potential for skin necrosis. Similarly, previous anthracycline chemotherapy used in the treatment for the original cancer often precludes the use of doxorubicin for node-positive women, which may result in poorer outcomes among this subset.12 In a recent systematic review from the Children's Oncology Group (COG), Henderson et al13 described the known and potential benefits and harms associated with breast cancer surveillance and provided the COG recommendations to begin annual mammography and breast magnetic resonance imaging (MRI) at age 25 years or 8 years after the radiation, whichever occurs last. We recently reported that almost 50% of women in the US and Canada aged 25 to 39 years who were treated with chest irradiation had never had a mammogram or MRI, and barely half of women aged 40 to 50 years were having regular screening mammograms (and rare MRI).14 The strongest predictor of breast cancer screening among these women was a physician recommendation, regardless of specialty or setting.

Coronary artery disease (CAD) after chest irradiation

Although the volume of radiotherapy administered in the treatment of HL has substantially decreased from the mantle field to involved-field or involved-node irradiation,15 the proximal coronary arteries remain in the field. Consequently, radiation-induced or accelerated CAD, predominantly affecting the left main and left anterior descending arteries, is common. By 20 years after mediastinal irradiation, the cumulative incidence of symptomatic CAD is 21%;16 by 30 years, the cumulative incidence of a myocardial infarction is 13%.17 In a large cohort study, Swerdlow et al18 reported that the standardized mortality ratio from a myocardial infarction was 3-fold higher in subjects who were treated with chest irradiation than in the general population. This finding emphasizes that not only is the risk of CAD increased, but also when an HL survivor has a myocardial infarction it often involves the major coronary arteries with dire consequences. Mulrooney et al19 reported a dose-response relationship between cardiac radiation and risk of myocardial infarction, congestive heart failure, and valvular heart disease. Younger age at radiation is associated with an increased risk of myocardial infarction-related mortality18 and congestive heart failure.17 Traditional cardiovascular risk factors, such as smoking, dyslipidemia, and diabetes, further increase the risk of radiation-associated CAD.17 Thus, it is imperative in follow-up of survivors of HL to screen for and aggressively manage cardiovascular risk factors, such as dyslipidemia20 and to counsel regarding smoking cessation and appropriate levels of physical activity. Some, including our group, also recommend low-dose aspirin therapy. With the increased risk of death from a myocardial infarction, is it also important to consider methods to screen for CAD. Stress echocardiography is an excellent functional method of screening AYA survivors treated with chest irradiation.21 We recently reported on our experience using CT coronary angiography to detect obstructive and nonobstructive CAD.22 Further research is needed to determine who should be screened, with what test(s), at what frequency, and the potential benefits and harms of statins and low-dose aspirin therapy among this high-risk population.

Cardiovascular disease (CVD) among testicular cancer survivors

Men surviving testicular cancer have an increase risk of circulatory deaths23 and CVD.24-26 Notably, the magnitude of risk of CVD with cisplatin-based chemotherapy appears equivalent to that associated with smoking.24 Risk appears to be associated with the total dose of cisplatin; survivors treated with 850 mg or more having a 3.4-fold increased risk of CVD compared with those treated with surgery alone.26 Men treated for testicular cancer may also have an increased risk of systolic and diastolic hypertension, microalbuminuria, obesity, and metabolic syndrome.27-31 Further research to ascertain the potential role of cisplatin (and other therapies used to treat germ cell tumors) in the development of CVD is warranted. Regardless, periodic screening for CVD risk factors and risk-reducing strategies should be an integral part of follow-up care of testicular cancer survivors.

Allogeneic hematopoietic stem cell transplant recipients

Survivors of AYA cancer who were treated with an allogeneic stem cell transplant often develop multisystem problems, including pulmonary complications,32 cardiomyopathy,33 gonadal dysfunction and other endocrinopathies,34 renal insufficiency,35, 36 insulin resistance and diabetes,37, 38 dyslipidemia, hypertension,37 metabolic syndrome,39 iron overload and hemochromatosis,40, 41 balance and gait abnormalities,42, 43 osteonecrosis,44 osteopenia and osteoporosis,45, 46 cataracts,43 and second malignancies.47, 48 Late complications may occur from pretransplant therapy, myeloablative regimens, or chronic graft-versus-host disease. Care of this population of AYA cancer survivors requires close monitoring, surveillance for late effects, and coordination and communication of care.

Model for Risk-Based Survivorship Healthcare

As described above, AYA survivors of cancer represent a high-risk population with the potential to develop a wide array of late effects. For many late effects, risk does not plateau with aging. There is often a clinically silent period before overt clinical disease, sometimes with intervals as long as 2 to 3 decades. Faced with these risks and challenges, how can the healthcare delivered to AYA cancer survivors be optimized? The incidence of some late effects can be decreased with secondary and tertiary prevention (e.g., smoking avoidance/cessation). Also, many late effects can be diagnosed and curatively treated at an early stage, thus lessening the long-term consequences. For example, among female survivors of pediatric and young adult cancer treated with chest radiation, invasive breast cancer can be diagnosed at an early and treatable stage with the use of recommended breast cancer surveillance with mammography and breast MRI. In the last decade, the model of risk-based healthcare of survivors has evolved. Risk-based survivorship care is lifelong healthcare that integrates the cancer and survivorship experience in the overall healthcare needs of the individual.49, 50 A systematic plan for lifelong screening, surveillance, and prevention that incorporates risks based on the previous cancer, cancer therapy, genetic predispositions, lifestyle behaviors, and comorbid health conditions should be developed for all AYA survivors of cancer. The fundamental tenets of risk-based healthcare are provided in Table 1. Possibly up to a third of this population experience relatively few minor complications and will face minimal long-term risks. It is difficult to fully appreciate risk, however, because the long-term effects of cancer therapies on the aging organ systems will only become evident as the survivor population ages.

Table 1. Basic Tenets of Risk-Based Healthcare of AYA Cancer Survivorsa
  • AYA indicates adolescent and young adult.

  • a

    Adapted from Oeffinger KC. Longitudinal risk-based health care for adult survivors of childhood cancer. Curr Probl Cancer. 2003;27:143-167.

• Longitudinal care that is considered a continuum from cancer diagnosis to eventual death, regardless of age
• Continuity of care consisting of a partnership between the survivor and a single healthcare provider who can coordinate necessary services
• Comprehensive, anticipatory, proactive care that includes a systematic plan of prevention and surveillance
• Multidisciplinary team approach with communication between the primary healthcare provider, specialists of pediatric and adult medicine, and allied/ancillary service providers
• Healthcare of the whole person, not a specific disease or organ system, that includes the individual's family and his cultural and spiritual values
• Sensitivity to the issues of the cancer experience, including expressed and unexpressed fears of the survivor and his/her family/spouse/partner

The COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers were developed to assist the clinician delivering risk-based healthcare for survivors of cancer in childhood and AYA, regardless of the setting.51, 52 Unfortunately, risk-based care appears to be the exception rather than the rule for this high-risk population.53 Cancer centers do not have adequate capacity or resources to care for AYA cancer survivors, and transitioning of survivors to community physicians is often difficult. Thus, partnership with community-based primary care physicians is essential to the shared-care model (Fig. 3).54, 55 With this approach, survivors who are at low risk of therapy-related late effects and recurrence of the primary cancer are transitioned back to the community-based primary care physician with a detailed cancer treatment summary. Survivors with a moderate risk of late effects are transitioned to the institution's long-term follow-up program for targeted education and initiation of screening for late effects (or management of persistent toxicity of therapy) and then transitioned to the primary care physician after some time period. This approach allows an institution to allocate the limited resources and personnel in an appropriate risk-stratified manner and focusing on the healthcare needs of the high-risk population. Integrated through each of these 3 groups is periodic 2-way communication between the cancer center staff and the patient's primary care physician.

Figure 3.

Proposed risk-stratified shared care model for adolescent and young adult (AYA) cancer survivors is shown. The solid line denotes primary responsibility for risk-based care. Risk stratification is based upon determination of the Long-term Follow-Up Clinic (LTFU) staff. CA indicates cancer; DX, diagnosis; Onc, oncologist; PCP, primary care provider; RX, therapy. (Adapted from Oeffinger KC, McCabe MS. Models for delivering survivorship care. J Clin Oncol. 2006;24:5119; used with permission from the American Society of Clinical Oncology.)

Summary

Although AYA survivors are at an increased risk of a wide array of health problems, the frequency and severity of these therapy-related outcomes can often be reduced with risk-based healthcare that incorporates recommendations from the COG Long-Term Follow-Up Guidelines. Further research is warranted to better understand the mechanisms by which specific late effects develop, to develop risk-prediction models for more serious outcomes, and to develop and test risk-reducing interventions.

FUNDING SOURCES

Funding for the national task force on adolescents and young adults with cancer has been made possible by a financial contribution from Health Canada through the Canadian Partnership Against Cancer. Funding for the workshop was provided by C17; the Advisory Board of the Institute for Cancer Research at the Canadian Institutes for Health Research (CIHR); the Public Health Agency of Canada; the Ontario Institute for Cancer Research; the Meetings, Planning and Dissemination Grants program of the CIHR; the Terry Fox Research Institute; LIVESTRONG, formerly the Lance Armstrong Foundation; the Canadian Cancer Society Research Institute; Young Adult Cancer Canada; Hope and Cope; and the Comprehensive Cancer Centre at the Hospital for Sick Children, Toronto, in addition to the support provided by the Canadian Partnership Against Cancer to the Task Force on adolescents and young adults with cancer.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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