Wendy Landier

Monitoring for Cardiovascular Disease in Survivors of Childhood Cancer: Report From the Cardiovascular Disease Task Force of the Children's Oncology Group

Curative therapy for childhood cancer has improved significantly in the last 2 decades such that, at present, ∼80% of all children with cancer are likely to survive ≥5 years after diagnosis. Prevention, early diagnosis, and treatment of long-term sequelae of therapy have become increasingly more significant as survival rates continue to improve. Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer. The Childrens Oncology Group Late Effects Committee and Nursing Discipline and Patient Advocacy Committee have recently developed guidelines for follow-up of long-term survivors of pediatric cancer. A multidisciplinary task force critically reviewed the existing literature to evaluate the evidence for the cardiovascular screening recommended by the Childrens Oncology Group guidelines. In this review we outline the clinical manifestations of late cardiovascular toxicities, suggest modalities and frequency of monitoring, and address some of the controversial and unresolved issues regarding cardiovascular disease in childhood cancer survivors.

Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group

PURPOSE Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. PATIENTS AND METHODS One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. RESULTS A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. CONCLUSION This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m(2). Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.

Nonadherence to Oral Mercaptopurine and Risk of Relapse in Hispanic and Non-Hispanic White Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

PURPOSE Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity. PATIENTS AND METHODS A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed. RESULTS After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites. CONCLUSION Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence-an observation currently under investigation.

Systematic Review: Surveillance for Breast Cancer in Women Treated With Chest Radiation for Childhood, Adolescent, or Young Adult Cancer

BACKGROUND Women treated with therapeutic chest radiation may develop breast cancer. PURPOSE To summarize breast cancer risk and breast cancer surveillance in women after chest radiation for pediatric or young adult cancer. DATA SOURCES Studies from MEDLINE, EMBASE, the Cochrane Library, and CINAHL (1966 to December 2008). STUDY SELECTION Articles were selected to answer any of 3 questions: What is the incidence and excess risk for breast cancer in women after chest radiation for pediatric or young adult cancer? For these women, are the clinical characteristics of breast cancer and the outcomes after therapy different from those of women with sporadic breast cancer in the general population? What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation? DATA EXTRACTION Three investigators independently extracted data and assessed study quality. DATA SYNTHESIS Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by age 40 to 45 years ranged from 13% to 20%. Risk for breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population; mammography can detect breast cancer, although sensitivity is limited. LIMITATION The quality of evidence for key questions 2 and 3 is limited by substantial study heterogeneity, variation in study design, and small sample size. CONCLUSION Women treated with chest radiation have a substantially elevated risk for breast cancer at a young age, which does not seem to plateau. In this high-risk population, there seems to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance.

A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence‐based methods, we provide a framework for the harmonization of guidelines for the long‐term follow‐up of childhood and young adult cancer survivors. Pediatr Blood Cancer 2013; 60: 543–549.

Long-term follow-up of pediatric cancer survivors: Education, surveillance, and screening

Cancer and its treatment predispose childhood cancer survivors to chronic or late occurring health problems that may not become clinically significant until many years after therapy. Frequently, long‐term survivors of childhood cancer report late cancer‐related effects that diminish quality of life and increase the risk of early mortality. Risk‐based health care that involves a personalized plan for surveillance, screening, and prevention is recommended to reduce cancer‐related morbidity in childhood cancer survivors. To implement optimal risk‐based care, the survivor and health care provider must have accurate information about cancer diagnosis, treatment modalities, and potential cancer‐related health risks to guide screening and risk‐reducing interventions. However, previous studies evaluating health knowledge of childhood cancer survivors demonstrate noteworthy deficits and misperceptions about their cancer diagnosis, treatment, and cancer‐related health risks. In addition, because of the relative rarity of childhood cancer, many health care providers lack familiarity with cancer‐related health risks and risk‐reduction methods relevant for this population. To correct these deficits, the Scottish Intercollegiate Guidelines Network (SIGN) and the Childrens Oncology Group (COG) developed clinical practice guidelines to foster appropriate risk‐based survivor care. Herein, we discuss the development, benefits, and limitations of the SIGN and COG guidelines and the foundation they provide for standardizing long‐term follow‐up care of the ever‐growing vulnerable population of childhood cancer survivors. Pediatr Blood Cancer 2006;46:149–158.

Hearing Loss, Quality of Life, and Academic Problems in Long-term Neuroblastoma Survivors: A Report From the Children's Oncology Group

OBJECTIVES. Among a cohort of long-term neuroblastoma survivors, our aims were to (1) assess the association between treatment intensity and parent-reported hearing loss in the child, (2) evaluate the strength of the association between hearing loss and parent-reported academic and psychosocial difficulties in the child, and (3) examine the association between parent-reported academic and psychosocial difficulties in the child and the childs self-reported quality of life. PATIENTS AND METHODS. Through a mailed survey that included the Pediatric Quality of Life Inventory 4.0 and an outcomes questionnaire for parents, we evaluated 137 children (aged 8–17 years) who were previously enrolled in 1 of 2 Childrens Cancer Group neuroblastoma clinical studies. RESULTS. Childhood survivors of neuroblastoma who had prevalent hearing loss, as reported by their parents, had at least twice the risk of an identified problem with reading skills, math skills, and/or attention and a similarly higher risk of a general learning disability and/or special educational needs than did neuroblastoma survivors without hearing loss. Consistent with this finding, hearing loss was associated with a 10-point-lower mean score in the school-functioning scale of the Pediatric Quality of Life Inventory 4.0. We also observed a clear pattern of poorer self-reported quality-of-life scores among children with parent-reported academic and psychosocial problems compared with those without such problems, particularly with school functioning, even after controlling for reported hearing loss. CONCLUSIONS. We found evidence that long-term neuroblastoma survivors, especially those with hearing loss, are at elevated risk for academic learning problems and psychosocial difficulties. We also found strong concordance between parent-reported learning problems in the child and indications of distress in the childs self-reported quality of life.

Long-term follow-up care for pediatric cancer survivors

Progress in therapy has made survival into adulthood a reality for most children, adolescents, and young adults diagnosed with cancer today. Notably, this growing population remains vulnerable to a variety of long-term therapy-related sequelae. Systematic ongoing follow-up of these patients, therefore, is important for providing for early detection of and intervention for potentially serious late-onset complications. In addition, health counseling and promotion of healthy lifestyles are important aspects of long-term follow-up care to promote risk reduction for health problems that commonly present during adulthood. Both general and subspecialty pediatric health care providers are playing an increasingly important role in the ongoing care of childhood cancer survivors, beyond the routine preventive care, health supervision, and anticipatory guidance provided to all patients. This report is based on the guidelines that have been developed by the Childrens Oncology Group to facilitate comprehensive long-term follow-up of childhood cancer survivors (www.survivorshipguidelines.org).

Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia

PURPOSE Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL. PATIENTS AND METHODS The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model. RESULTS MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others. CONCLUSION We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Evaluating survivors of pediatric cancer.

The past 3 decades have seen tremendous improvements in the survival of children diagnosed with cancer, with the 5-year survival rate approaching 80%. This improvement in survival has resulted in a growing population of childhood cancer survivors. Use of cancer therapy at an early age can produce complications that may not become apparent until years later. Approximately two thirds of the survivors of childhood cancer experience at least one late effect and about one fourth experience a late effect that is severe or life-threatening, although psychosocial issues in survivors and family members are often underestimated and may be more prevalent. Long-term complications in childhood cancer survivors, such as impairment in growth and development, neurocognitive dysfunction, cardiopulmonary compromise, endocrine dysfunction, renal impairment, gastrointestinal dysfunction, musculoskeletal sequelae, and subsequent malignancies, are related not only to the specific therapy used but also may be determined by individual host characteristics. We review the known late effects in survivors of childhood in order to suggest reasonable starting points for the evaluation of specific long-term problems in this unique but growing population.