Rebecca E. Scully

Anthracycline associated cardiotoxicity in survivors of childhood cancer

The development of effective antineoplastic therapies for childhood cancer is a great success in modern medicine. Five year survival rates of children diagnosed with cancer in the USA and Western Europe in excess of 70% make long term survivors of childhood cancer a steadily increasing population. Although there is much to celebrate, new challenges lie ahead in treating the systemic sequelae of chemotherapy.1 Results from the Childhood Cancer Survivor Study (CCSS) showed that 30 years after treatment, the cumulative incidence of chronic health conditions in long term survivors reaches 73%, with a cumulative incidence of 42% for severe, disabling, or life threatening conditions or death.2 Severe conditions, that are significantly more common in childhood cancer survivors than in their siblings, include: major joint replacement (relative risk (RR) 54.0), congestive heart failure (RR 15.1), second malignant neoplasm (RR 14.8), severe cognitive dysfunction (RR 10.5), coronary artery disease (RR 10.4), cerebrovascular accident (RR 9.3), and renal failure (RR 8.9).2 Previous CCSS results found that patients who had survived at least 5 years after diagnosis had 10.8-fold increased rates of all cause mortality.3 The standardised mortality ratio for cardiac causes was 8.2 times higher than expected and the cumulative probability of cardiac death increased 15–25 years after cancer diagnosis. A similar study in a large Nordic cohort documented a standardised mortality ratio of 5.8 for cardiac death and elevated rates of sudden, presumed arrhythmic, deaths.4 Chief among adverse late effects is the cardiovascular toxicity of anthracyclines.5–11 Unfortunately, despite well documented dose related toxicity, the superior disease-free survival rates of regimens including anthracyclines leave limited viable treatment alternatives and the majority of long term paediatric cancer survivors in the Pediatric Oncology Group received an anthracycline during treatment.12 ### Mechanism of cardiotoxicity Several cytotoxic biochemical changes follow anthracycline exposure in …

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial

BACKGROUND Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. METHODS Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. FINDINGS 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99). INTERPRETATION Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. FUNDING US National Institutes of Health, Childrens Cardiomyopathy Foundation, University of Miami Womens Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.

Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management

Although effective anti-neoplastic agents, anthracyclines are limited by their well recognized and pervasive cardiotoxic effects. The incidence of late progressive cardiovascular disease in long-term survivors of cancer is established and may contribute to heart failure and death. To maximize the benefits of these drugs, a high-risk population has been identified and new strategies have been investigated to minimize toxic effects, including limiting the cumulative dose, controlling the rate of administration and using liposomal preparations and novel anthracycline analogues. Dexrazoxane also shows promise as a cardioprotectant during treatment. This paper reviews these strategies, as well as medications used to manage anthracycline-induced cardiotoxicity, and functional and biochemical means of monitoring cardiotoxicity, including echocardiography, radionuclide scans and biomarker analysis. The treatment of adult cancer survivors who have had anthracycline-related cardiotoxicity has not been systematically studied. Empirically, anthracycline-associated cardiac dysfunction is treated very similarly to other forms of heart failure. These treatments include avoiding additional cardiotoxic regimens, controlling hypertension, lifestyle changes, medications and heart transplantation.

Changes in Cardiac Biomarkers During Doxorubicin Treatment of Pediatric Patients With High-Risk Acute Lymphoblastic Leukemia: Associations With Long-Term Echocardiographic Outcomes

PURPOSE Doxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately identifying cardiac injury and cardiomyopathy. PATIENTS AND METHODS Children with high-risk ALL were randomly assigned to receive doxorubicin alone (n = 100; 75 analyzed) or doxorubicin with dexrazoxane (n = 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment. RESULTS cTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P = .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P = .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P < .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P = .01). Increases in hsCRP were not associated with any echocardiographic variables. CONCLUSION cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.

Long-term effects of treatments for childhood cancers

Purpose of review The late effects of current treatments for childhood cancer increase the risk of morbidity and mortality and diminish the quality of life in long-term survivors. We selectively review the negative late cardiac, endocrine, and neurological effects of childhood cancer and its treatments and comment on current research and recommendations for the care of long-term survivors of childhood cancer. Recent findings Progressive cardiotoxicity has been established. Late cardiac effects can be mitigated with the concomitant use of dexrazoxane with anthracycline. When radiotherapy is used multiple organ systems must be monitored for known late effects dependent on the location. Proper diet, physical activity, and obesity are topics that must be addressed in survivors. Late neurocognitive effects impact intelligence quotient, behavior, and achievement. Systematic follow-up with appropriate clinical screening and testing is important in diagnosing and potentially preventing late effects of cancer therapy. Summary The new paradigm for defining successful cancer therapy is the balance between oncologic efficacy and toxicity/late effects. The complexity of late effects necessitates a multidisciplinary approach to long-term care of these patients. The high frequency, delayed onset, and potential severity of late effects demand increased and lifelong monitoring of these individuals.

Anthracycline cardiotoxicity in long-term survivors of childhood cancer

Anthracycline chemotherapy is a widely-used and effective treatment for a wide spectrum of childhood cancers. Its use is limited by associated progressive and clinically significant cardiotoxic effects. Onset can be acute, early, or late. While acute onset is rare, long-term survivors have significantly elevated rates of cardiac morbidity and mortality. Major complications include cardiomyopathy, coronary artery disease, and atherosclerosis. Means of prevention and treatment continue to be explored including limiting cumulative anthracycline dose, controlling the rate of administration, and using liposomal preparations and novel anthracycline analogues. Dexrazoxane prior to anthracycline chemotherapy has been shown to significantly lower rates of elevated serum cardiac troponin levels, a marker of myocyte injury, indicating a cardioprotective effect. Pilot studies indicate that exercise interventions may also be beneficial in long-term survivors with cardiac damage. Support and study of this population to decrease the morbidity and morality associated with anthracycline-induced cardiotoxicity is indicated in a time sensitive fashion.

Defining Optimal Length of Opioid Pain Medication Prescription After Common Surgical Procedures

Importance The overprescription of pain medications has been implicated as a driver of the burgeoning opioid epidemic; however, few guidelines exist regarding the appropriateness of opioid pain medication prescriptions after surgery. Objectives To describe patterns of opioid pain medication prescriptions after common surgical procedures and determine the appropriateness of the prescription as indicated by the rate of refills. Design, Setting, and Participants The Department of Defense Military Health System Data Repository was used to identify opioid-naive individuals 18 to 64 years of age who had undergone 1 of 8 common surgical procedures between January 1, 2005, and September 30, 2014. The adjusted risk of refilling an opioid prescription based on the number of days of initial prescription was modeled using a generalized additive model with spline smoothing. Exposures Length of initial prescription for opioid pain medication. Main Outcomes and Measures Need for an additional subsequent prescription for opioid pain medication, or a refill. Results Of the 215 140 individuals (107 588 women and 107 552 men; mean [SD] age, 40.1 [12.8] years) who underwent a procedure within the study time frame and received and filled at least 1 prescription for opioid pain medication within 14 days of their index procedure, 41 107 (19.1%) received at least 1 refill prescription. The median prescription lengths were 4 days (interquartile range [IQR], 3-5 days) for appendectomy and cholecystectomy, 5 days (IQR, 3-6 days) for inguinal hernia repair, 4 days (IQR, 3-5 days) for hysterectomy, 5 days (IQR, 3-6 days) for mastectomy, 5 days (IQR, 4-8 days) for anterior cruciate ligament repair and rotator cuff repair, and 7 days (IQR, 5-10 days) for discectomy. The early nadir in the probability of refill was at an initial prescription of 9 days for general surgery procedures (probability of refill, 10.7%), 13 days for women’s health procedures (probability of refill, 16.8%), and 15 days for musculoskeletal procedures (probability of refill, 32.5%). Conclusions and Relevance Ideally, opioid prescriptions after surgery should balance adequate pain management against the duration of treatment. In practice, the optimal length of opioid prescriptions lies between the observed median prescription length and the early nadir, or 4 to 9 days for general surgery procedures, 4 to 13 days for women’s health procedures, and 6 to 15 days for musculoskeletal procedures.

Readiness of US General Surgery Residents for Independent Practice

Objective: This study evaluates the current state of the General Surgery (GS) residency training model by investigating resident operative performance and autonomy. Background: The American Board of Surgery has designated 132 procedures as being “Core” to the practice of GS. GS residents are expected to be able to safely and independently perform those procedures by the time they graduate. There is growing concern that not all residents achieve that standard. Lack of operative autonomy may play a role. Methods: Attendings in 14 General Surgery programs were trained to use a) the 5-level System for Improving and Measuring Procedural Learning (SIMPL) Performance scale to assess resident readiness for independent practice and b) the 4-level Zwisch scale to assess the level of guidance (ie, autonomy) they provided to residents during specific procedures. Ratings were collected immediately after cases that involved a categorical GS resident. Data were analyzed using descriptive statistics and supplemented with Bayesian ordinal model-based estimation. Results: A total of 444 attending surgeons rated 536 categorical residents after 10,130 procedures. Performance: from the first to the last year of training, the proportion of Performance ratings for Core procedures (n = 6931) at “Practice Ready” or above increased from 12.3% to 77.1%. The predicted probability that a typical trainee would be rated as Competent after performing an average Core procedure on an average complexity patient during the last week of residency training is 90.5% (95% CI: 85.7%–94%). This falls to 84.6% for more complex patients and to less than 80% for more difficult Core procedures. Autonomy: for all procedures, the proportion of Zwisch ratings indicating meaningful autonomy (“Passive Help” or “Supervision Only”) increased from 15.1% to 65.7% from the first to the last year of training. For the Core procedures performed by residents in their final 6 months of training (cholecystectomy, inguinal/femoral hernia repair, appendectomy, ventral hernia repair, and partial colectomy), the proportion of Zwisch ratings (n = 357) indicating near-independence (“Supervision Only”) was 33.3%. Conclusions: US General Surgery residents are not universally ready to independently perform Core procedures by the time they complete residency training. Progressive resident autonomy is also limited. It is unknown if the amount of autonomy residents do achieve is sufficient to ensure readiness for the entire spectrum of independent practice.

Risk Factors for Prolonged Opioid Use Following Spine Surgery, and the Association with Surgical Intensity, Among Opioid-naive Patients

Background: There is a growing concern that the use of prescription opioids following surgical interventions, including spine surgery, may predispose patients to chronic opioid use and abuse. We sought to estimate the proportion of patients using opioids up to 1 year after discharge following common spinal surgical procedures and to identify factors associated with sustained opioid use. Methods: This study utilized 2006 to 2014 data from TRICARE insurance claims obtained from the Military Health System Data Repository. Adults who underwent 1 of 4 common spinal surgical procedures (discectomy, decompression, lumbar posterolateral arthrodesis, or lumbar interbody arthrodesis) were identified. Patients with a history of opioid use in the 6 months preceding surgery were excluded. Posterolateral arthrodesis and interbody arthrodesis were considered procedures of high intensity, and discectomy and decompression, low intensity. Covariates included demographic factors, preoperative diagnoses, comorbidities, postoperative complications, and mental health disorders. Risk-adjusted Cox proportional hazard models were used to evaluate the time to opioid discontinuation. Results: This study included 9,991 patients. Eighty-four percent filled at least 1 opioid prescription on discharge. At 30 days following discharge, 8% continued opioid use; at 3 months, 1% continued use; and at 6 months, 0.1%. In the adjusted analysis, the low-intensity surgical procedures were associated with a higher likelihood of discontinuing opioid use (discectomy: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.36 to 1.50; and decompression: HR = 1.34, 95% CI = 1.25 to 1.43). Depression (HR = 0.84, 95% CI = 0.77 to 0.90) was significantly associated with a decreased likelihood of discontinuing opioid use (p < 0.001). Conclusions: By 6 months following discharge, nearly all patients had discontinued opioid use after spine surgery. As only 0.1% of the patients continued opioid use at 6 months following surgery, these results indicate that spine surgery among opioid-naive patients is not a major driver of long-term prescription opioid use. Socioeconomic status and pre-existing mental health disorders may be factors associated with sustained opioid use following spine surgery. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Cardiac Failure 30 Years after Treatment Containing Anthracycline for Childhood Acute Lymphoblastic Leukemia

In 1977, a 5-year-old girl diagnosed with acute lymphoblastic leukemia was treated on Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia Protocol 77-01, receiving a cumulative doxorubicin dose of 465 mg/m2, cranial radiation, and other drugs. After being in continuous complete remission for 34 months, she developed heart failure and was treated with digoxin and furosemide. At 16 years of age, she was diagnosed and treated for dilated cardiomyopathy. Over the years, she continued to have bouts of heart failure, which became less responsive to treatment. At 36 years of age, she received a heart transplant. Six months later, she stopped taking her medications and suffered a sudden cardiac death.