The last 50 years have witnessed significant progress in antineoplastic drug development, radiation technology, diagnostic imaging, and cancer biology that has resulted in the development of curative therapy for many types of cancer. Prevention and screening programs have increased survival after cancer further by facilitating the detection of occult malignancies at earlier, more treatable stages. Consequently, 64% of adults with cancer, almost 9 million individuals, are surviving 5 years from diagnosis.1 Likewise, contemporary therapy cures almost 80% of children and adolescents with the disease. In the United States, this translates into > 270,000 childhood cancer survivors and represents 1 in 1000 adults younger than age 45 years and 1 in 570 adults ages 20–34 years.1, 2 It is anticipated that ongoing cancer research will produce increasing numbers of long-term cancer survivors who may have special needs as a result of their cancer experience.
Numerous studies have confirmed the vulnerability of this growing population to specific cancer-related sequelae. Complications after chemotherapy and radiation therapy are common and may be identified early during treatment or follow-up, then resolve or persist. In children, some cancer-related complications do not become apparent until many years after cancer treatment, when growth and pubertal development are completed. In adults, complications predisposed by cancer therapy may be exacerbated further by organ dysfunction associated with aging. Cancer-related sequelae that persist or develop 5 years after cancer diagnosis are termed “late effects.” Late effects include adverse effects on organ function as well as psychosocial complications related to the cancer experience, both of which influence the long-term survivor's quality of life. Whereas one or more late effects commonly are experienced by childhood cancer survivors, severe or life-threatening late effects are reported in only approximately 25%.3–6 Studies of global assessments in long-term survivors of adult malignancies have not been reported.
Late effects can be divided into four broad categories, including complications that affect growth and development, vital organ function, fertility and reproduction, and secondary carcinogenesis. Adverse effects on growth and development are particularly problematic for younger cancer patients. These include effects on linear growth, skeletal maturation, intellectual function, as well as emotional and sexual maturation and sexual development. Detrimental effects on vital organs initially may be asymptomatic, only to be manifest after the completion of growth or during aging. Fertility and reproductive outcomes often are priority concerns of young adult cancer survivors. Finally, the development of another malignancy represents one of the most distressing late complications for both clinicians and survivors.
Late effects predispose survivors to cancer-related morbidity and early mortality through their impact on general health, functional status, mental health, quality of life, and long-term survival. The long-term survivor's general health may be affected not only by cancer-related medical sequelae but also by their mental health, which may be influenced by general anxiety and fears related to their cancer experience. Chronic pain related to cancer or its therapy may be associated with activity limitations that compromise functional status. All of these factors adversely may affect the survivor's quality of life and long-term survival. This has been demonstrated readily by several investigations that have indicated a higher risk of early mortality in childhood cancer survivors compared with healthy age-matched and gender-matched control populations.7–10 After death from primary cancer, late effects, including vital organ dysfunction and secondary malignancy, are the most common cause of early mortality in these cohorts. The desire to prevent cancer-related morbidity and mortality has motivated numerous therapeutic changes over the last several decades. Integral to this effort is the identification of factors that predispose survivors to adverse health outcomes.
The objective of the current article was to describe a model for healthcare across the cancer continuum. To provide the foundation for such a model, three important aspects are discussed: 1) factors that contribute to cancer-related morbidity, 2) primary interventions in the care continuum, and 3) secondary interventions in the care continuum. Hodgkin disease, a pediatric malignancy with established curative therapy for more than 30 years, is provided as an example to illustrate the paradigm of primary and secondary interventions in the care continuum.
Factors that Contribute to Cancer-Related Morbidity
A multitude of factors contribute to cancer-related morbidity (Fig. 1). Among these are host-related factors, such as patient age at diagnosis, gender, race, and health problems antedating cancer diagnosis; and genetic factors, such as cancer-predisposing genetic mutations or genetic polymorphisms that affect drug metabolism and DNA repair. Cancer-related factors include tumor histology, site, and biologic features, which often determine tumor responsiveness and the intensity and type(s) of antineoplastic therapy. Treatment and genetic factors influence the risk of treatment toxicity and persistent or chronic effects, which, in turn, may influence the progression of diseases associated with aging. Finally, health behaviors also may modify health risks predisposed by cancer and often represent the primary method of risk reduction available to the survivor.
Care across the cancer continuum implies longitudinal care from cancer diagnosis until death, regardless of the patient's age. This type of care would require the clinician to consider the long-term consequences of treatment decisions on an aging cancer survivor. A diagnosis of cancer during infancy, childhood, adolescence, or adulthood may increase vulnerability to specific treatment toxicities. Clinicians who want to optimize the opportunity for cancer cure and reduce the risk of severe treatment effects will take these vulnerabilities into consideration. For example, intensively treated infants have high risks of neurocognitive injury, growth delay, musculoskeletal defects, and vital organ dysfunction because of the immaturity of these organ systems and tissues. These same concerns are true for older children who, based on their cognitive maturity and psychosocial support, may be more vulnerable to emotional problems and deficits in social maturation. These concerns continue in adolescence and can be complicated further by disruption of sexual development. In young adults, treatment effects on reproductive health are considered more frequently during treatment planning; whereas, in more senior adults, maintaining vital organ function is prioritized to avoid trading one life-threatening disease for another.
In newly diagnosed patients, clinicians provide primary interventions with various treatment modalities guided by a desire to control and hopefully eradicate disease with a minimum of health morbidity. After effective therapy is developed and acute and late toxicities are identified, the risks and benefits of specific treatment modalities can be considered more accurately. The identification of factors that predispose survivors to toxicity is possible only through continued monitoring after cancer treatment. Modification of treatment modalities based on an understanding of host-related and cancer-related factors that predispose individuals to adverse health outcomes represents another method of primary intervention in newly diagnosed cancer patients. After long-term survival is achieved, secondary interventions may be directed to survivors who are at high risk of cancer-related morbidity, with the objective of promoting health and resilience by preventing adverse health outcomes.
Primary Interventions in the Care Continuum
The paradigm at treatment planning, which is the first stage in the continuum of care, should consider patient characteristics, such as age, gender, race, and genetic features, as well as tumor characteristics, such as histopathology, tumor site, and tumor genetics, and how these factors influence tumor responsiveness and the risk of acute and late treatment complications. For example, monitoring long-term survivors of Hodgkin disease has permitted identification of the clinical features of patients most predisposed to late treatment complications. Younger age at treatment and higher radiation doses, for instance, increase the risk of growth inhibition.11 Higher doses of alkylating agent chemotherapy and abdominal-pelvic radiation predispose patients to infertility and early menopause.12 Cervical radiation, particularly at higher doses, increases the risk of thyroid dysfunction.13 Life-threatening cardiac events, such as pericarditis and myocardial infarction, have been observed in patients who were treated with anteriorly weighted, high-dose chest radiation, particularly those who were younger at diagnosis.14 Cardiomyopathy has been observed in patients who were treated with higher cumulative doses of anthracycline chemotherapy, again, with increased risks in younger patients.15, 16 Pulmonary fibrosis has been observed as a dose-related complication of bleomycin therapy and chest/lung radiation.17 The risk of secondary acute myelogenous leukemia is related to the cumulative dose of alkylating agents or treatment exposures, including topoisomerase II inhibitors, like epipodophyllotoxins and anthracyclines, whereas secondary solid tumors appear to be associated largely with radiation therapy; concurrent alkylating agent chemotherapy may increase the risk of secondary pulmonary and gastrointestinal tumors.17–26 Finally, breast cancer risk after Hodgkin disease has been observed almost exclusively in female survivors.20–26 Treatment with higher cumulative radiation doses and treatment during puberty enhance this risk.
Recognizing these well established risks, treatment planning for patients with Hodgkin disease considers disease characteristics (such as tumor bulk and stage) as well as gender-related and age-related late effects risks.27 High-dose radiation therapy as a single modality largely has been abandoned at pediatric centers because of the concern about cardiovascular disease and second malignancies. Chemotherapy alone often is preferred for young children, in whom growth inhibition will be more severe, and for girls, in whom the risk of breast cancer is significant. For patients with more aggressive disease features, combined-modality therapy is preferred as a means to reduce specific treatment exposures with dose-related toxicity and to improve disease control. Thus, the evolution of pediatric Hodgkin therapy has been guided largely by information obtained from long-term monitoring of childhood cancer survivors.
Secondary Interventions in the Care Continuum
The growing long-term cancer survivor population would benefit from secondary intervention measures that reduce the risk of adverse health outcomes. Thus, maintaining health and resilience after cancer represents the second stage in the care continuum. In this stage, the objectives are to maintain cancer-free survival and to prevent cancer-related morbidity, particularly events that predispose survivors to early mortality. Health after cancer can be maintained by providing an intervention that reduces morbidity or an intervention that facilitates the detection of cancer-related complications at early, more easily treated stages. To implement secondary intervention measures, factors must be identified that predispose survivors to cancer-related morbidity and that modify cancer-related health risks, and interventions must be provided to prevent or ameliorate cancer-related morbidity.
Pediatric Hodgkin disease can be used again to illustrate the potential benefits of secondary intervention in a group of childhood cancer survivors who are predisposed to a significant, potentially life-threatening, treatment-related complication: secondary breast cancer. The risk of secondary breast cancer in females who are treated for Hodgkin disease ranges from 4% to 35% at 20 years, depending on the series reported. This represents an 8-fold to 75-fold excess risk compared with age-matched control populations.20–26 Established risk factors include chest radiation, which is used commonly to treat involved mediastinal or axillary lymph nodes or lungs, and pubertal status at the time of radiation. The risk of breast cancer becomes elevated 5–9 years after radiation, with most cancers observed among women who were ages 14–25 years at the time of initial therapy.
Potential secondary intervention measures to reduce the morbidity of breast cancer after Hodgkin disease include health education (for survivors and healthcare providers) regarding predisposing cancer treatment; predisposing patient characteristics; modifying lifestyle factors, such as alcohol and diet; and the benefits and methods of early detection. Other secondary intervention measures include early initiation of breast cancer surveillance, including self-examination, clinician examination, and mammography. Potential secondary intervention measures that have not been studied well among pediatric survivors of Hodgkin disease include chemoprevention and surgical prophylaxis. It is noteworthy that research initiatives targeting secondary intervention interventions should be undertaken with the same scientific rigor as that used in therapeutic investigations.
A Model of Care Across the Cancer Continuum
The complete model for care across the cancer continuum uses primary intevention measures, starting from cancer diagnosis, and shifts to secondary intervention measures when long-term survival is achieved (Fig. 2). In patients with pediatric cancer, the model also requires the transition from a pediatric to an adult healthcare setting as survivors complete their growth and development. This model comprises longitudinal care from cancer diagnosis to death; comprehensive care, including intervention measures to reduce cancer-related morbidity and mortality; and continuity of care that is coordinated optimally by a primary care provider who is knowledgeable about cancer-related health risks. The model also provides multiple opportunities to reduce cancer-related morbidity. At the time of diagnosis, primary intervention measures comprise risk-adapted therapy with the treatment intensity required to assure disease control with minimal morbidity. After long-term survival is achieved, secondary interventions are focused on survivors who are at high risk for morbidity. The model cannot be effective without the information obtained from long-term follow-up of cancer survivors.
There are many challenges to providing optimal care across the cancer continuum. Disseminating specific information about cancer-related health risks to primary healthcare providers, particularly those who assume the care of aging childhood cancer survivors, has been difficult because of the evolving cancer therapies and late effects risk profiles. Further complicating follow-up care are the long latency needed to evaluate many of the health outcomes, the multiple factors that influence cancer-related health risks, and the generally unknown effects of aging on treatment sequelae. All of these factors have resulted in a lack of consensus regarding screening and risk-reduction methods that could be used to guide primary care providers and third-party payers.
Nevertheless, our healthcare system requires the transition of long-term survivors from oncology back to primary care. In the case of pediatric patients, at young adulthood, childhood cancer survivors must transition from pediatric to adult medical practices. This is problematic, because many primary care providers lack knowledge about cancer-related health risks and risk reduction methods, resulting in a general discomfort with managing cancer survivor medical care. The healthcare system also does not support cancer survivor care consistently in specialized, long-term follow-up programs staffed by clinicians experienced with late cancer treatment effects.
Clinicians and cancer survivors must work together to overcome the challenges that prevent optimal care across the cancer continuum. Critical to achieving this objective is the development of an infrastructure that facilitates early identification of new and changing late effects. Appropriate infrastructure also would support timely investigations that more accurately define the high-risk survivor profile for secondary interventions. Priority investigations comprise the evaluation of clinical, treatment, genetic, and behavioral factors that influence health risks and that are essential to the development late-effects screening guidelines. The development of education programs for medical students, residency and fellowship trainees, and practicing physicians that specifically address the unique needs and medical management of cancer survivors should be supported to disseminate information about this vulnerable, growing population. Finally, prospective evaluations of secondary interventions for cancer survivors should be pursued with the same standards that are used in controlled randomized trials of antineoplastic therapy to provide survivors with effective, proven opportunities for risk reduction.