Cancer survivorship and comorbidity disease risk after cancer treatment

Childhood patients with cancer

In 2013, there were an estimated 420,000 survivors of childhood cancer in the United States, with the number expected to increase to 500,000 by 2020. More than 80% of children treated for cancer are now surviving more than 5 years posttreatment and multiple medical conditions can develop as long-term and late effects of cancer treatment. Importantly, childhood cancer survivors not only have more extensive morbidities, they also have an increased and premature mortality. In regards to cardiovascular (CV) disease, childhood patients with cancer have a 15 times higher risk of heart failure (HF), a 10 times higher risk of coronary artery disease (CAD), and a 9 times higher risk of stroke than their siblings, for instance. Notably, exposure to 250 mg/m ² or more of doxorubicin or its equivalence increases the relative hazard of heart failure, pericardial disease, and valvular abnormalities by a factor of two to five compared with non-exposure. ^, Cardiac radiation treatment (RT) exposure of 15 Gy has been shown to increase the relative hazard of heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by two- to six-fold compared with no RT exposure. ^,

Notably, these data stem from the premodern radiation therapy era. For currently treated patients, these data may be an overstatement of cardiovascular (CV) risk, but for the large population of survivors of pediatric cancer who continue to age into adulthood, these risk numbers represent their potential for late cardiac disease . The risk of HF after anthracyclines and RT has been said to be dose-dependent. However, no “safe” dose of anthracycline or RT exists to preclude the development of late CV effects and that risk is lifelong.

This risk is further modified by the presence and control of cardiovascular risk factors. As shown from data from the Childhood Cancer Survivor Study, the risk of any cardiac event increased with an increasing number of cardiovascular risk factors. Hypertension, in particular, significantly increases the risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values <.01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond expected values ( Fig. 24.1 ). Hypertension was independently associated with the risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).

Adolescents and young adults with cancer

Cancer survivorship and disease risk in the adolescent and young adult (AYA) subgroup has its own unique challenges for treatment and long-term health and is often overlooked. The AYA group is defined as those diagnosed with cancer between 15 and 39 years of age with a heterogeneous diagnosis of cancer ranging from leukemia, lymphoma, germ cell tumors, sarcomas, breast, and thyroid cancer. Treatment of patients in this subgroup requires an understanding of the interplay between risk behaviors (smoking, binge drinking, obesity, lack of physical activity), socioeconomic vulnerabilities, and chronic conditions (cardiovascular disease [CVD], hypertension, diabetes mellitus, and treatment-related disability). In one retrospective cohort study using the Kaiser Permanente Southern California database, 5673 AYA patients diagnosed with cancer from 1998 to 2009 were compared with 57,617 controls. Chao and colleagues found that AYA cancer survivors had a more than two-fold increased risk of developing CVD (adjusted incidence rate ratio, 2.37; 95% CI, 1.93 to 2.93) when compared with patients without cancer. The highest risk of developing CVD was seen in survivors of leukemia and breast cancer (adjusted incidence rate ratio, 4.23; 95% CI, 1.73 to 10.31; and 3.63; 95% CI, 2.41 to 5.47, respectively). Cancer survivors who developed CVD had an 11-fold higher mortality rate than survivors without CVD. Hypertension was the most common and most potent CVD risk factor.

Another population-based study from the California Cancer Registry and state hospital discharge data of 79,176 AYA patients diagnosed with 14 first primary cancers in the period 1996–2012 demonstrated an approximate 2.8% incidence of developing CVD. Survivors of central nervous system cancer (7.3%), acute lymphoid leukemia (6.9%), acute myeloid leukemia (6.8%), and non-Hodgkin lymphoma (4.1%) had the highest 10-year CVD incidence. Interestingly, in multivariable models, African-Americans (hazard ratio [HR], 1.55; 95% Cl, 1.33 to 1.81; vs. non-Hispanic caucasians), those with public/no health insurance (HR, 1.78; 95% CI, 1.61 to 1.96; vs. private), and those who resided in lower socioeconomic status neighborhoods had a higher CVD risk. These sociodemographic differences in CVD incidence were apparent across most cancer sites. The mortality rate was ≥ eight-fold among AYAs who developed CVD. These studies highlight the nuances between both risk/sociodemographic and inherent cardiovascular effects.

Adult patients with cancer

Anthracycline-induced cardiac dysfunction and heart failure is now a well-recognized long-term effect of cancer therapy. Anthracycline chemotherapy (e.g., doxorubicin, epirubicin, daunorubicin, mitoxantrone) is the cornerstone of the treatment of lymphoma, sarcoma, and breast cancer. Reported incidence rates of anthracycline cardiotoxicity have varied widely owing to differences in patient populations, differences in therapy and dose exposures, as well as follow-up strategies and times. For example, in those with breast cancer, one group found that cardiotoxicity occurred mainly within the first year after anthracycline-containing therapy at a rate of approximately 9% and was associated with anthracycline dose and left ventricular ejection fraction (LVEF) at the end of treatment. ^, On the contrary, a cohort study of 142 lymphoma cases, in which the patients received doxorubicin-based chemotherapy (median cumulative dose of 300 mg/m ² ) at least 5 years prior (median 8 years), noted that only one patient developed heart failure with an EF less than 30%, but decreased fractional shortening (<25%) was seen in 28% of the patients. One important issue has been the lack of a uniform definition of cardiotoxicity. In a recent consensus statement, cancer therapy-related cardiac dysfunction is defined as a decrease in LVEF by more than 10 percentage points from baseline to a value of less than 53%. Imaging and monitoring of cardiac dysfunction are discussed elsewhere in this book. However, we emphasize that that anthracycline-induced cardiac dysfunction can occur at any time and low-dose anthracycline does not eliminate the risk of cardiac dysfunction.

Cardiac late effects are increased in patients exposed to anthracycline and chest radiation. The use of therapeutic radiation also can lead to the spectrum of radiation-induced heart (RIHD) disease, including CAD, HF, valvular heart disease, pericardial disease, conduction abnormalities, autonomic dysfunction, and sudden cardiac death (see Chapter 26 ). Risk factors for RIHD in addition to concomitant adjuvant anthracycline-based chemotherapy include doses more than 30 Gy, fractionated dose more than 2 Gy/day, a large volume of irradiated heart, younger age at exposure, and longer time after exposure. Patient-specific factors include age more than 65 years and the presence of comorbid conditions (i.e., diabetes, hypertension, and preexisting cardiac disease). Notably, existing data on incidence rates date to the premodern era of radiation therapy and may overestimate the risk of cardiotoxicity compared with patients being treated today. However, there does not seem to be a “safe” dose threshold and even patients treated with chest radiation today require optimal cardiovascular care. ^,

As outlined by the Early Breast Cancer Trialists’ Collaborative Group, rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gray (95% CI, 2.9–14.5; P < .001), and event rates were higher, even in those with just one additional cardiovascular risk factor. The increase in risk was apparent within the first 5 years after RT and continued into the third decade after treatment completion. Patients with Hodgkin lymphoma experience an even higher long-term cumulative risk of RIHD, and the third patient group with high long-term survival rates and notable impact of radiation treatment are patients with testicular cancer. Mediastinal irradiation in these patients was found to be associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased myocardial infarction (MI) risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin-based chemotherapy, particularly the BEP (bleomycin, etoposide, and platinum) regimen, in these patients also needs to be taken into consideration, with a 5.7-fold higher risk (95% CI, 1.9- to 17.1-fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2- to 7.7-fold) for MI compared with age-matched control. Survivorship recommendations by age group are outlined in Table 24.1 .

Lifestyle

There are well-accepted guidelines to intervene and treat obesity, smoking, and a sedentary lifestyle in survivors. These should be the initial focus for every survivor and reinforced at every visit. Particular aspects of the importance of exercise are captured in the chapters on exercise and rehabilitation (see Chapters 13 and 34 ). Patients with cancer, including survivors, should be informed about the risks of and cautioned against a sedentary lifestyle.