Long-term complications of chemotherapy

Anthracyclines

Anthracyclines are widely used chemotherapeutic agents in pediatric and adult hematologic and solid malignancies. It is estimated that over half of childhood cancer survivors have received prior anthracycline treatment. Chronic progressive cardiomyopathy is the most common presentation of anthracycline-induced cardiotoxicity. Acute cardiotoxicity is seen in less than 1% of pediatric patients, which manifests as transient and reversible left ventricular (LV) dysfunction within the first week of treatment, although persistent changes may be seen with higher cumulative doses. Early nonspecific electrocardiogram changes, conduction abnormalities, and arrhythmias can occur in 10% to 30% of patients; they are often transient. ^,

Anthracycline cardiomyopathy is typically a dilated cardiomyopathy with thinned LV walls and abnormal systolic and diastolic indices, which in childhood survivors, can progress over the longer term to a restrictive cardiomyopathy. ^, New, more sensitive assessments using echocardiographic global longitudinal strain or cardiac magnetic resonance imaging identify a greater proportion of childhood and adult cancer survivors with cardiac dysfunction. ^, It is therefore unclear whether the traditional classification into early- and late-onset anthracycline cardiotoxicity as distinct entities is justified. Rather, there may be a continuous process of maladaptive LV remodeling that ranges from subtle and asymptomatic LV dysfunction to dilated and/or restrictive cardiomyopathy to severe systolic LV dysfunction and advanced heart failure ( Fig. 25.1 ) . ^,

Decades of follow up on childhood cancer survivors show that as many as 60% develop cardiac dysfunction on echocardiography by 6 years, and almost 10% develop clinical heart failure by 20 to 30 years, with risk persisting over 30 years after treatment. The only consistent risk factor for development of anthracycline-induced cardiomyopathy is the cumulative anthracycline dose. Among childhood cancer survivors exposed to cumulative anthracycline doses (<400 mg/m ² ), the incidence of cardiomyopathy was 11% and increased to 100% for cumulative doses (>800 mg/m ² ) at a median of 7 years, with severity increasing with time. Compared with cancer survivors without anthracycline exposure, among survivors exposed to more than 300 mg/m ² , the risk was 27 times greater at a mean follow-up period of 9 years. Interestingly, an estimated three-fold increased risk has been demonstrated even with low cumulative dose exposure just above 100 mg/m ² , suggesting that there is no safe anthracycline dose. ^, Although less common, pericardial disease is another chronic complication of high-dose anthracycline treatment. In addition, a decline in exercise capacity that can be independent of measured indices of systolic function (e.g., ejection fraction [EF]) and impaired exercise hemodynamics has been shown in long-term follow up of childhood cancer survivors. Similar trends are seen among adult cancer survivors. Cardiotoxicity, defined as a reduction in LV EF from baseline of more than 10% to less than 50%, occurs at a median time of 3.5 months after treatment, with most cases presenting within the first year. Rates of symptomatic heart failure on treatment increased with cumulative anthracycline dose, to almost 50% at 700 mg/m ² . About 20% of lymphoma survivors at cumulative doses above 250 mg/m ² had evidence of cardiac dysfunction at 9 years, 7 times higher compared with the noncancer population. Compared with lymphoma survivors who received low cumulative doses (<150 mg/m ² ), those who received 250 mg/m ² or more had almost a 10-fold risk of developing symptomatic heart failure at 5 years.

Additional risk factors for anthracycline-induced cardiomyopathy include length of follow up, age at treatment (especially <5 and >65 years of age), female gender, genetic polymorphism in anthracycline metabolism, concomitant cardiotoxic agents, chest radiation, and preexisting cardiovascular conditions -especially hypertension, which has been demonstrated in both childhood and adult cancer survivors to intensify the risk by 7-to 12-fold (see Chapter 24 , Figure 24.1 ). ^, At least in some patient groups, when detected and treated early, anthracycline-related cardiac dysfunction can be mitigated, if not completely reversed. Specific recommendations for long-term screening in adult cancer survivors are not defined. Key consensus statements are provided in Chapters 7 and 27 .

Targeted HER2 therapy

Human epidermal growth factor 2 (HER2, also known as erbB2) is a cell-surface tyrosine kinase receptor that has been implicated in the development of many human cancer types, most notably breast cancer. Amplification or overexpression of HER2 is found in approximately 15% to 20% of primary invasive breast cancers and is associated with an aggressive cancer phenotype and poor clinical outcomes. Trastuzumab, a humanized monoclonal antibody against the extracellular domain of HER2, improves outcomes for patients with early-stage ^, and metastatic HER2-positive breast cancer. Many other targeted anti-HER2 therapies have since been developed, including pertuzumab, ado-trastuzuamab emtansine (TDM-1), lapatinib, and neratinib. Growing evidence indicates that therapies targeting HER2 may be effective in treating other nonbreast malignancies, such as gastric or gastroesophageal junction cancer, ovarian cancer, and lung cancer. ^,

In a pivotal trial of concurrent anthracycline- and trastuzumab-based therapy for metastatic breast cancer, symptomatic and asymptomatic cardiac dysfunction was observed in 27% of patients and severe heart failure (New York Heart Association class III or IV) was observed in 16% of patients. With administration of trastuzumab sequentially after completion of anthracyclines and implementation of routine cardiac monitoring during trastuzumab treatment, the incidence of early cardiac dysfunction and severe heart failure has decreased to 7.1% to 18.6% and 0.4% to 4.1%, respectively. ^{, , ,} The risk of cardiotoxicity is further decreased when anti-HER2 therapy is administered without anthracyclines. In a study of adjuvant paclitaxel and trastuzumab for patients with node-negative HER2-positive breast cancer, 3.2% developed asymptomatic cardiac dysfunction and 0.5% developed symptomatic heart failure.

In contrast to anthracycline-associated cardiotoxicity, partial improvement of LV function is often observed with interruption or discontinuation of anti-HER2 therapy. Nonetheless, a reduction in LVEF compared with baseline can persist after completion of trastuzumab therapy, and patients may be at risk for late clinical cardiac events. ^, Indeed, several registry-based analyses have outlined a persistent and cumulatively increasing risk of heart failure in patients treated with trastuzumab, whereas clinical trials have indicated that the cardiac risk is confined to the active treatment period (e.g., HERA trial). At present, it is not clearly defined if trastuzumab exposure is associated with late (posttherapy) development of heart failure or other clinically relevant long-term sequelae, such as decreased cardiorespiratory fitness as women age, whether such presentations are confined to those with reversible or irreversible declines in cardiac function during trastuzumab therapy, or if such sequelae could start even years after therapy.