Efficacy of the Children's Oncology Group (COG) long-term follow-up (LTFU) guidelines in reducing risk of congestive heart failure (CHF) in childhood cancer survivors (CCS)
Reporter: J Taylor Whaley
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2012
Presenter: F. Lennie Wong, PhD Presenter's Affiliation: City of Hope, Duarte, CA
Thoracic radiation and chemotherapy increase the risk of cardiovascular disease in survivors of childhood cancer. Previous studies have suggested that cardiovascular death is responsible for more than 25% of the excess risk of death in survivors of childhood cancers.
During the 30 years after cancer treatment, survivors of childhood cancer are eight times more likely to die from cardiac causes and 15 times more likely to be diagnosed with congestive heart failure (CHF) than the general population.
The risks to the heart are related to cumulative anthracycline dose, amount of radiation delivered to the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.
The risk of cardiac toxicity from anthracyclines increases with time, prompting the need for long-term surveillance. In an effort to prevent cardiac deaths, a panel of experts created guidelines for the frequency of screening with echocardiograms, despite a lack of evidence for the suggested guidelines.
The specific mechanism for cardiovascular death is likely secondary to the increased risk of left ventricular dysfunction and subsequent CHF. Heart failure is a progressive disease with four stages, A, B, C, and D. Stages C and D are symptomatic, and the critical intervention to prevent death secondary to CHF is diagnosis during stages A and B, while the patient remains asymptomatic.
The Children's Oncology Group Long Term Follow-up Guidelines recommend screening for left ventricular dysfunction using echocardiograms (ECHOs) every 1-5 years depending on anthracycline dose, chest radiation, and age at cancer diagnosis. The frequency of screening is based on certain risk factors for individual patients. Please see the table below for details.
The relevance and cost-effectiveness of these consensus-based guidelines are unknown and may lead to wasted valuable resources. Additionally, the efficacy of these guidelines never been demonstrated.
The purpose of this study was two-fold:
First, to attempt to evaluate the efficacy and cost-effectiveness of current COG guidelines for screening.
Second, to attempt to decipher whether the screening schedule could be optimized by examining varying intervals of ECHO screening using a model.
Materials and Methods
The authors simulated a large cohort of childhood cancer survivors (CCS) and utilized a modeling approach to simulate patients' life cycles. Life expectancy and age at onset of CHF were projected using the cohort, which consisted of 1 million CCS undergoing screening ECHO per COG guidelines.
The life cycle modeled the 4 cycles of CHF with the following stages:
1- No heart abnormality
2- Asymptomatic LV dysfunction
3- Symptomatic CHF
The authors utilized the incremental cost-effectiveness ratio (ICER), which translates into the cost per quality-adjusted life-years (QALY) gained from screening. It is the cost per year of perfect health gained with screening.
QALYs and lifetime costs with and without ECHO screening were calculated. Annual non-CHF mortality was estimated from the Childhood Cancer Survivor Study and US population rates.
Costs and quality of life (QOL) adjustments were obtained from the Healthcare Cost and Utilization Project and medical literature. In the calculation of cost, the authors included the cost of screening, ECHO, consultation, confirmatory ECHO, hospitalization for CHF costs, and patient burden.
Interventions included consultation with a cardiologist, confirmatory ECHO, and ACE inhibitor initiation. The intervention for LVD with ACE-Inhibitor was modeled to reduce annual CHF risk by 30%. This was based on a randomized trial evaluating the use of ACE-I in adults in delaying progression of symptomatic CHF.
Although there is no accepted threshold value for cost effectiveness threshold, it was recently suggested that $100,000-200,000 per QALY was appropriate. Therefore, the authors used $100,000 as a benchmark for cost-effectiveness.
Following the current COG guidelines, the extra lifetime cost with screening was $520,000,000 per 100,000 survivors, or $5200 per person.
For the patient cohort, this provided 1.8 months of perfect health or and 8.5 month delay in CHF per person on average.
Using the current COG guidelines, the delay in the development of CHF ranged from 1.9 months to 1.8 years across the various risk factors.
Recommended screening strategies, as seen in the table, were cost-effective in the following:
CCS exposed to ?300mg/m² of anthracycline regardless of RT or age
CCS diagnosed at age 1-4y, exposed to RT and <300mg/m² of anthracycline.
Screening was most cost-effective for CCS diagnosed at age 1-4y exposed to RT + ?300 mg/m² of anthracycline (1.4y delay in CHF onset; $15,821/QALY gained).
The authors subsequently questioned if screening more frequently would improve efficacy. Would annual screening be more efficacious and cost-efficient?
Using this model, the results demonstrated that more frequent screening resulted in better efficacy. The improved efficacy, or delay in CHF, was best noted with annual ECHO screening.
The authors then compared the current COG guidelines (which is risk stratified) vs. annual screening. The results of the modeled comparison demonstrated that yearly screening ECHO was the most expensive possibility but could delay the development of CHF in childhood cancer survivors by 44-200% in some risk groups. The incremental cost-effectiveness ratio (ICER) for annual screening was around $58,000. For the current COG guidelines, the ICER was $41,000.
CHF onset age
Cost / QALY
The authors note the following limitations to their study:
Due to the rarity of childhood cancer, the authors created a model to study the current question; however, this is a model and its implementation is limited.
In the model, the authors assumed patients would continue to develop additional risk factors for development of cardiac disease at a rate consistent with healthy individuals. This assumption could impact the validity of the model.
The authors present the first study to quantify cost and efficacy of ECHO screening for cardiac dysfunction in CCS.
Using the currently accepted benchmark for cost-effectiveness of $100,000, annual screening is cost-effective.
Although recommended ECHO screening strategies are cost-effective for childhood cancer survivors at high risk for developed of cardiac toxicity, alternate screening strategies are needed for CCS with other exposure conditions.
Long tern follow up with childhood cancer survivors is critical as non-cancer mortality is highly correlated with quality of life and functionality.
The current proposal is certainly reasonably cost-effective and efficacious in the proposed model as annual screening demonstrated a large improvement for lower risk individuals over COG guidelines. Annual screening would produce a 7% additional QALY and 14% longer delay in CHF onset.
Additionally, annual screening would simplify a somewhat complicated current screening schedule.
The model assumes the intervention of ACE-inhibitor will delay CHF if detected on screening. This is based on adult studies and may not translate into prevention of CHF progression following childhood cancer and anthracycline use.
Finally, although annual ECHOs may be cost-effective, implementation of this could be challenging with patients frequently strained to afford current follow up recommendations.
Jul 24, 2014 - Several abstracts involving potential biomarkers of prognosis in cancer treatment were presented at a press briefing Nov. 18 at the American Association for Cancer Research -- National Cancer Institute -- European Organisation for Research and Treatment of Cancer International Conference, "Molecular Targets and Cancer Therapeutics," held from Nov. 15 to 19 in Boston.