Addressing Areas of Public Health Emphasis

Cancer Survivorship: Improving Treatment Outcomes and Quality of Life

The Opportunity

Entering the new millennium armed with new insights into biology, including information from the sequencing of the human genome, we are beginning to see the fruits of the "War on Cancer" launched in 1971. Once almost uniformly fatal, cancer has become for many, a chronic illness, and for growing numbers, a curable disease. There are an estimated 8.9 million cancer survivors in the United States today. This estimate represents individuals currently alive who had a diagnosis of cancer other than non-melanoma skin cancer or in situ disease at some point in their lives. An impressive 14 percent of these individuals were originally diagnosed over 20 years ago.

Cancer survival has risen steadily over the past three decades for all cancers combined. In the absence of other competing causes of death, current figures indicate that for adults diagnosed today, 60 percent can expect to be alive five years later. The relative 5-year survival rate for those diagnosed as children - defined as those under the age of 19 - is even higher. Almost 75 percent of childhood cancer survivors will be alive 5 years later and 10-year survival is approaching 70 percent. As past and future advances in cancer detection, treatment, and care diffuse into clinical practice, the number of survivors can be expected to increase. Fewer deaths from cardiovascular disease and the aging of the population will contribute to this trend.

While cancer survivors are living longer, we have limited knowledge and many questions about the health status, functioning, and quality of life for most of those who are post-treatment.

• What are the most common late effects of treatment?
• Who is at risk and can they be protected?
• Can treatment-related injury to normal tissue be prevented or reversed?
• What proportion of survivors will experience recurrent or second malignancies?
• Who should be following these survivors to detect disease recurrence?
• What constitutes "optimal surveillance" and what is the cost of such follow-up care?
• Do medical, psychosocial or behavioral interventions reduce morbidity in these populations?

What is clear is that most of our current treatments, although benefiting the patient overall, will produce some measure of adversity. In some cases, these effects can have a profound impact on survivors' health and quality of life. For example:

• A quarter of deaths among childhood cancer survivors are due to late consequences of treatment (e.g., second malignancies, cardiac failure). However, as many as a quarter of childhood cancer survivors may not know what treatment they received, and a small number may be unaware that they even had cancer. In one large study, 46 percent did not believe that their treatment could have put them at later risk for a serious health problem. This knowledge gap has implications for optimal care.
• Breast and lymphoma patients exposed to systemic chemotherapy are at increased risk for problems with cognitive functioning (e.g., memory, concentration, executive capacity) and some may be genetically more susceptible to this chronic effect of treatment.
• Between a quarter to a third of patients undergoing bone marrow or stem cell transplant suffer from symptoms of post-traumatic stress disorder (PTSD). Similar numbers of parents (especially mothers) of children treated for cancer also experience PTSD symptoms, even years after their children were treated.
• Female brain cancer survivors are eight times more likely to experience separation or divorce than male survivors.

The adverse effects of cancer treatment remain poorly documented and understood. As presently configured, our surveillance databases (e.g., SEER and other tumor registries) often cannot identify a patient's current health status and phase of survivorship - whether in active treatment, disease free, or dying of cancer. Although more than 60 percent of cancer survivors are age 65 and older, and the median age of cancer diagnosis is 67-68, only a small proportion of NCI's funded research focuses on the effect of cancer on older Americans, many of whom also are affected by co-morbid health conditions such as hypertension, diabetes, heart disease, and arthritis.

In addition, most survivorship research to date has been conducted among breast cancer survivors. While prostate cancer survivors are just now being studied, efforts to describe or address outcomes for the significant number of colorectal, gynecologic, hematologic, and other cancer survivors are rare. Few studies have been conducted among those who are poor, elderly, of low education, living in rural areas, or come from ethnically diverse backgrounds. Thus, more research is needed to address issues of survivorship for specific cancers as well as for populations that have been under-represented in previous research, such as the elderly.

Cancer survivors and their family members face unique and uncharted consequences of illness and treatment. Information about our survivorship community is critical if we are to:

• Help patients make decisions now about treatment options that will affect their future.
• Tailor therapies to maximize cure while minimizing adverse treatment-related effects.
• Develop and disseminate evidence-based interventions that reduce cancer morbidity as well as mortality and facilitate optimal coping and adaptation among cancer survivors.
• Improve the quality of care, control costs, and equip the next generation of physicians, nurses, and other healthcare professionals to provide not just the science but also the art of comprehensive cancer medicine.

A number of recent reports have identified the need for funding cancer survivorship research that will lead to increased length and quality of life for those diagnosed with cancer. These include elements articulated in several Institute of Medicine reports, highlighted in each of the Progress Review Group summaries, and included in previous NCI bypass budgets. A proactive health investment calls for time critical research to address the needs identified in these reports.

Studying Adverse Long-Term or Late Effects of Cancer and Its Treatment

As children and adults with a history of cancer are living longer and data from NCI research studies are maturing, the nature and extent of long-term and late effects are being documented and reported: neurocognitive problems, premature menopause, gastrointestinal system dysfunction, cardiorespiratory system dysfunction, sexual impairment, infertility, chronic fatigue and pain syndromes, second malignancies, and others. The biological mechanisms for these late normal tissue effects are not yet well understood. Identification of patients at increased risk for complications of treatment and information on interventions to reduce those risks will help patients, their families, and their providers negotiate critical decisions.

In addition, adverse effects are not limited to physical and functional problems. Research shows that many survivors and their families experience significant psychosocial outcomes: fear of recurrence, sense of isolation, anxiety and depression; employment and insurance discrimination; altered body image; and relationship difficulties. For example, individuals from ethnic minority and lower educational backgrounds are less likely to return to work after cancer. It is clear that for those who have finished treatment, being disease free does not necessarily mean being free of their disease.

Monitoring Outcomes

There is widespread acceptance that population based surveillance systems are key mechanisms for tracking and monitoring outcomes among survivors. With NCI's recent expansion of the Surveillance, Epidemiology and End Results (SEER) and National Clinical Trials Programs, our ability to track and monitor disease and care-related outcomes among survivors through these types of surveillance mechanisms is developing. But to take advantage of these programs, we need to add components such as infrastructure support, data elements, and consent processes that will permit us to follow survivors' outcomes over the years.

Understanding the Role of Behavioral and Socio-Cultural Factors in Patient Outcomes

There is growing appreciation of the role that socio-cultural and behavioral factors play in patient outcomes, from decision making, to adherence to treatments, to surveillance and health maintenance behaviors post-treatment. While we know that human behavior can have a profound impact on how cancer is managed and may also affect disease-free or overall survival, we are not currently using this information in the systematic delivery of care. For example, it is estimated that 23-35 percent of head and neck cancer patients and 13-20 percent of lung cancer patients who smoked prior to illness continue to do so after treatment.

Two published reports that integrated data from a number of studies revealed that psychosocial or behavioral interventions improved patients' health-related quality of life, functioning, and even medical status. Despite this, we know little about the best delivery of interventions and the resulting economic impact on individuals and society. Nor do we understand cancer's consequences for millions of family members affected by this illness, many of whom may themselves be at increased risk for cancer due to shared cancer-causing genes, life-style, and/or toxic exposures. As cancer care increasingly is pushed into the outpatient setting, the economic, physical, and emotional burden on family members is increasing. We have, to date, failed to fully appreciate this additional at-risk population or taken advantage of the opportunity to provide these vital caregivers with supportive or health-promoting interventions as part of standard cancer care.

Understanding Genetic Risk and Treatment

It is expected that with the decoding of the human genome, our ability to identify hereditary cancer risk patterns and genes associated with susceptibility to treatment-related late effects will accelerate. What impact these genetic characteristics have on treatment and subsequent patient outcomes remains a question. Using tissue and blood samples from survivors to track outcomes holds the promise of helping us to better understand how cancer-causing genes operate and what therapies may be effective in controlling their effects. It will also permit us to understand which therapies work best and for whom they are successful. An increasing number of cohort studies are focusing on cancer survivors.

Training Researchers and Disseminating Research Findings

In the last decade, NCI and the Office of Cancer Survivorship have supported the emergence of a number of training programs and researchers committed to studying the long-term and late effects of cancer. These programs and the number of scientists in the field, nevertheless, remain small and need to be leveraged for growth. In addition, it is critical to disseminate the resulting research findings across disciplines so that clinicians and researchers, experts from the biomedical and social sciences, ethicists, statisticians, epidemiologists, economists, health policy experts and consumers can use the new knowledge for further research, intervention development, trend analysis, and advocacy.

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The Plan - Cancer Survivorship: Improving Treatment Outcomes and Quality of Life

Goal
Reduce the adverse effects of cancer diagnosis and treatment and optimize outcomes for cancer survivors and their families.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

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Objective 1: Expand research efforts to understand the biological, physical, psychological, and social mechanisms, and their interactions, that affect a cancer patient's response to disease, treatment, and recovery.
Fund cohort and case control studies that examine the prevalence and incidence of late effects, in particular among survivors five or more years post-diagnosis.	$3.0 M
Fund behavioral and epidemiological studies that examine both negative and positive physiologic and psychosocial effects, and their correlates, of cancer on survivors who are post-treatment.	$5.0 M
Identify the genetic and/or phenotypic markers of susceptibility to treatment-related adverse effects and gene-environment interactions, using molecular epidemiological research. (See the Genes and the Environment Plan, Objective 1.)
Support efforts to synthesize the research, and its implications for future directions, with respect to the role of sociocultural, behavioral, emotional, and spiritual factors in survivor and family outcomes and their willingness to adopt appropriate surveillance and health maintenance behaviors post-treatment.	$1.5 M
Ensure that efforts to expand our knowledge base, with respect to the impact of cancer and its treatment on survivor's outcomes, includes attention to diverse cancer sites and underrepresented groups - e.g. certain ethnic groups, persons diagnosed at 65 or older, older cancer survivors with competing health problems, rural populations, low-income groups or those with limited education.
TOTAL	$9.5 M

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Highlights of Recent Cancer Survivorship Related Research

Tool Enhances Studies on the Long-Term Consequences of Cancer Treatment. Among the critical issues for cancer survivors are the "late effects" of their illness and treatment that sometimes do not show up for a number of years. To better define these consequences, the NCI is funding a program to update the common toxicity scoring system to incorporate the LENT score, Late Effects of Normal Tissues. This scoring system enables investigators to:

• Compare newer treatments with the current regimens for treating all cancers.
• Relate laboratory research to the severity of effects experienced by patients when investigating molecular mechanisms for late tissue damage.
• Facilitate the development, for use in clinical trials, of interventions to prevent, reduce, or possibly reverse "late effects" of cancer treatment.

Adjusting Chemotherapy Dosage Reduces Incidence of Congestive Heart Failure among Cancer Survivors. Treatment with the chemotherapy drug anthracycline, or more specifically its metabolic byproduct doxorubicin, places survivors at risk for congestive heart failure following their cancer treatment. At greatest risk are women, African Americans, and younger patients. The risk of congestive heart failure, diagnosed during longer patient follow-up, increases with higher amounts of anthracycline given over the course of treatment. NCI-funded researchers have discovered that moderately reducing the overall cumulative dosage of anthracycline can reduce the incidence of congestive heart failure from 7 to well under 1 percent.

Growth Hormone Replacement Helps Children Safely Achieve Normal Height following Treatment for Leukemia. Most (70-80 percent) children with Acute Lymphoblastic Leukemia (ALL) are cured with current treatments. However, because of treatment related effects, many of these survivors are short in stature as adults. The specific cause of short stature may be different from patient to patient, but in many of the most severe cases the levels of growth hormone (GH) in the blood are found to be low. Some of these patients have been treated with growth hormone therapy over the years, although the medical community has not been in agreement about the effectiveness or the safety of such treatment. An NCI-sponsored team of investigators recently found that replacing GH in those survivors where it is low, effectively induces "catch-up growth" and most patients reach normal, or near normal, adult heights. This study also examined safety issues, confirming that treatment with GH does not cause relapse of ALL or second cancers. Although further study is warranted, these results suggest that growth hormone therapy is a safe treatment choice that will benefit many adult survivors of ALL.

Lung Cancer Survivors Retain Quality of Life. Although lung cancer is one of the most common cancers in the United States, little is known about the quality of life (QOL) of lung cancer survivors. NCI-supported scientists recently analyzed self-reported indicators from five-year survivors of non-small cell lung cancer (NSLC) for factors (such as other diseases, pulmonary function, depression and anxiety, tobacco use, social and spiritual well-being, and demographics) that have the most effect on QOL. Notably, half of the survivors said their cancer had made a positive change in their life and the majority were "very hopeful." Risk factors for poorer QOL are strongly linked to depression, suggesting potential interventions by health care providers. The number of comorbid conditions (other diseases) experienced by the survivors was a weak indicator of overall QOL, although those with higher income and with few comorbid conditions reported better physical well-being. Nonwhite participants rated greater than whites for overall QOL as well as for mental health. This study, for the first time, highlights the range of QOL experienced by NSLC long-term survivors and provides insights for potential rehabilitation. The complex interactions of QOL by race/ethnicity and socioeconomic status deserve further study.

Social Interventions Can Benefit Breast Cancer Survivors. An NCI-sponsored study of breast cancer survivors over a four-year follow-up period shows that health-related quality of life is influenced by the survivor's availability of social networks. On average, socially isolated women were more adversely affected by breast cancer, scoring lower on "role function," "vitality," and "physical function" compared to the most socially integrated women. The level of a patient's social integration is an important factor and appears to explain more of this variance than differences in treatment or tumor type. The study results suggest that rehabilitation programs should incorporate interventions that address the availability of adequate social support among breast cancer survivors.

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As opposed to invasive tumors, in situ tumors are confined to their site of origin and do not spread. Back.

In a cohort study, the same patient group is studied over a period of time. Back.