ASCO, Author Interviews, Biomarkers, Cancer Research, Cost of Health Care, Immunotherapy / 07.06.2016
Chemotherapy and Toxicities of Immune Checkpoint Inhibitors May Be Prohibitively Expensive
MedicalResearch.com Interview with:
Neil T. Mason, MBA
Personalized Medicine Strategist
Personalized Cancer Medicine
Division of Population Science
Moffitt Cancer Center
MedicalResearch: What is the background for this study? What are the main findings?
Response: Immune checkpoint inhibitors targeting PD-1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) have revolutionized the treatment of metastatic disease in melanoma and non-small cell lung cancer with additional indications showing positive results. These drugs have elicited profound and durable responses in a significant number of patients, but have been criticized for their high cost. Though the price of the drugs themselves can reach over $100,000 per year, they can also cause severe, life threatening toxicities that are difficult and expensive manage.
This model utilizes patient data from a large, NCI-designated cancer center to estimate the average cost of treatment with immune checkpoint inhibitors based on average duration of treatment and reported incidence of major toxicities. Based on the model, PD-1 inhibitor therapies are less costly than ipilimumab due to the significantly higher cost per dose of ipilimumab and average treatment duration of less than a year for PD-1 inhibitors. Managing drug-related toxicities were estimated to contribute between $8,200 and $9,600 to the cost of therapy with nivolumab adding the most cost.
Dr. Maria Schwaederle[/caption]
Maria Schwaederle PharmD
Clinical Research Scientist
Center for Personalized Cancer Therapy
UCSD Moores Cancer Center
La Jolla, CA 92093
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Schwaederle: We performed this analysis with experts in the field, including but not limited to Drs Schilsky, Lee, Mendelsohn and Kurzrock, all known for their experience in the area of precision/personalized medicine.
Historically, phase I trials (which are often first in human or highly experimental in other ways) were believed to be examining only toxicity. Our meta-analysis of 13,203 patients shows that in the era of precision medicine, this historical belief needs to be discarded. Second, it is the use of precision medicine that makes this belief outdated.
Indeed, Phase I trials that utilized a biomarker-driven approach that is the essence of precision medicine had a median response rate of about 31%, which is higher than many FDA approved drugs, and this is in spite of the fact that phase I patients are a highly refractory group having failed multiple lines of conventional therapy.
Importantly, however, it was not the use of targeted agents alone that was important. It was the biomarker-based approach where patients are matched to drugs. Without matching, response rates were dismal—about 5%.
Dr. Vincent Chung[/caption]
Dr Vincent Chung
Assistant Professor, Jockey Club School of Public Health and Primary Care
Associate Director (Education), Hong Kong Institute of Integrative Medicine
Registered Chinese Medicine Practitioner
The Chinese University of Hong Kong
MedicalResearch.com: What is the background for this study?
Response: Primary carpal tunnel syndrome (CTS) is one of the most common forms of peripheral entrapment neuropathy. It is a major cause of disability on the upper extremity incurring considerable limitation on daily activities among patients. Currently, there is no consensus on appropriate treatment for patients with chronic (≥6 months) mild to moderate symptoms [Archives of physical medicine and rehabilitation. 2014;95(12):2253-63].
Electroacupuncture is a common technique for managing pain and neuropathy in Chinese medicine. Current CTS treatment guidelines from the UK National Institute for Health and Care Excellence (NICE), American Academy of Orthopaedic Surgeons (AAOS) and the American College of Occupational and Environmental Medicine (ACOEM) made no specific recommendations for or against electroacupuncture.
Dr. Sara Brownell[/caption]
Sara E. Brownell PhD
School of Life Sciences
Arizona State University
Tempe, AZ
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Brownell: Our group has been broadly interested in gender biases in introductory biology
since we published a study that showed that women underperform on course
exams and under participate in whole class discussions compared to men
(http://www.lifescied.org/content/13/3/478.full). We were curious why women
might be under performing on these course exams so in this new study, we
examined characteristics of the exams to see if that had an impact. What we
found was that women and men perform equally on questions that test basic
memorization. However, when questions tested more higher-level critical
thinking skills, women were not scoring as high as men. This happened even
when we took into account the academic ability of the students - women and men
who had the same ability coming into the class. We also found that students
from lower socioeconomic statuses also underperformed on these higher-level
critical thinking questions compared to students from higher socioeconomic
statuses, again even when we took into account academic ability.
Dr. Andrew Anglemyer[/caption]
Andrew Anglemyer, PhD MPH
Operations Research Department
U.S. Naval Postgraduate School
Monterey, CA 93943
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Anglemyer: Suicide prevention programs in the military are ubiquitous. We aimed to identify the trends in suicide for each service specifically and explore any nonclinical factors that may be associated with the chosen methods of suicide. The trends in suicide are similar to what others have found.
The differences in those rates between services are striking, though. Not only are most suicides in the active duty military among the Army personnel, but the suicide rate among Army personnel is the highest and has been every year since 2006. Additionally, among Army personnel and Marines who committed suicide, those with an infantry or special operations job classification were significantly more likely to use a firearm to commit suicide than those without those job classifications.
Dr. Jeffrey Schussler[/caption]
Jeffrey M. Schussler, MD, FACC, FSCAI, FSCCT, FACP
Baylor Scott & White Health Care System
Cardiology: Baylor University Medical Center, Dallas, Tx
Medical Director: CVICU Hamilton Heart and Vascular Hospital
Professor of Medicine: Texas A&M School of Medicine
MedicalResearch.com: What is the background for this study?
Dr. Schussler: For the past few years, there has been an increased interest in performing coronary catheterization through the wrist. This is a technique that has been done (with great success and low complication rate) in other countries for years, with adoption rates >90% in some places. The US has been slower to adopt performing catheterization from the wrist, but the rate of using this approach has grown tremendously in the last 5 years. While less than 5% of all interventions were done using radial access previously, it now appraches 30% nationally. This increased rate of adoption been spurred on by studies which have shown lower incidences of complications, as well as some mortality benefit, and in particular in those patients who are highest risk for complications.
Pegged Software[/caption]
Myra Norton
President and COO of 
Myra Norton[/caption]
Ms. Norton: Big data and predictive analytics alone will not solve the problem of pay inequality. What these tools can do is illuminate talent in a way that removes the biases that undermine equality across gender, ethnicity, socio-economic status and other dimensions. For example, predictive analytics allows organizations to identify candidates with the highest likelihood of improving patient experience, being retained, remaining an engaged employee, lowering thirty day readmissions, and positively impacting other organizational outcomes.
Dr. Dawn Hershman[/caption]
Dawn L. Hershman, MD MS
Professor of Medicine and Epidemiology
Leader, Breast Cancer Program
Herbert Irving Comprehensive Cancer Center
Columbia University
NY NY
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Hershman: Chemotherapy induced peripheral neuropathy is a common side effect of anti cancer therapy and there are currently no ways to prevent it. We used a large clinical trials database, SWOG, and linked it to Medicare claims for patients over the age of 65. We found that age and type of taxane were associated with the development of CIPN. We also found a significant increase when a taxane was given along with a platinum agent. We found a doubling of risk among patients with a prior history of diabetes. No other chronic condition was associated with an increased risk of CIPN. We found a suggestion of a decreased risk among patients with a prior history of auto-immune disease.
Dr. Katie Greenzang[/caption]
Katie Greenzang, MD
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Greenzang: Advances made over the last several decades mean that more than 80 percent of children diagnosed with cancer will become long-term survivors. However, many of these survivors experience physical and cognitive late effects of the treatment that cured them. We surveyed 352 parents of children recently diagnosed with cancer to assess how well they understood their children’s risk of future limitations in physical abilities, intelligence, and quality of life. We found that an overwhelming majority of parents (92 percent) are very interested in learning about possible late effects, and most (86 percent) seek detailed information. Yet, parent and physician predictions of a child’s risk of experiencing late effects of treatment often don’t match. Among children identified by their oncologists as being at high risk for such challenges, only 38 percent of parents recognized this risk in physical abilities, 21 percent in intelligence, and 5 percent in quality of life.
Dr. Gregory Idos[/caption]
Gregory Idos MD
Division of Gastroenterology and Hepatology
Keck School of Medicine
University of Southern California
Los Angeles, CA 90033
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Idos: Identifying individuals at increased risk for hereditary cancer prompts enhanced cancer surveillance as early detection mitigates disease specific morbidity and mortality. This justifies germ line genetic testing for specific cancer risk alleles. In recent years, the field of cancer genetics has moved from a gene by gene sequencing approach to now having the ability to examine multiple genes concurrently. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. As a result, more pathogenic mutations and variants of uncertain significance (VUS) are discovered. MGP tests are increasingly being used by cancer genetic clinics, but questions remain about the clinical utility and complexities of these tests.
We are conducting a multi center prospective trial to measure the added yield of detecting pathogenic mutations using the MGP approach. In our interim analysis of the first 1000 participants, we found that multiplex gene panel testing increased the yield of detection of pathogenic mutations by 26%. In some cases, we found patient’s who had a mutation in the BRCA gene, but their family history did not indicate a history of breast or ovarian cancer.
Dr. Sarmad Sadeghi[/caption]
Sarmad Sadeghi MD, MS, PhD
Assistant Professor of Medicine
Norris Comprehensive Cancer Center
University of Southern California
MedicalResearch.com: What is the background for this study?
Dr. Sadeghi: Several years ago analyses of outcomes for radical prostatectomy highlighted the significant impact of surgical experience on the oncological outcome for the patients. In this case experience was measured by the number of radical prostatectomies performed by the surgeon, and oncological outcome was measured by treatment failure rates (rising PSA). Despite this data, the move for redirecting patients to “high volume centers” where more experienced surgeons perform the operation has been sluggish. There was insufficient data on what is involved in referring patients to high volume centers and whether or not such action is cost effective.
In a previous study we demonstrated that for every referral to a high volume center, there would be an average of $1,800 over a follow-up period of 20 years in societal cost savings. The main source of these savings is fewer treatment failures.
The next question was who is a good candidate for referral and whether these savings can offset the referral costs.
Dr. Philip McCarthy[/caption]
Philip McCarthy, BA, MD
Professor of Oncology
Director, Blood and Marrow Transplant Program
Roswell Park Cancer Institute
Associate Professor of Medicine
Jacobs School of Medicine and Biomedical Sciences
State University of New York at Buffalo
Buffalo, NY 14263
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. McCarthy: There have been three Phase III studies that examined the role of maintenance lenalidomide after autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma patients. IFM 2005-02 (France), CALGB 100104 (Alliance, USA), GIMEMA-RVMM-PI-209 (Italy). All three studies had progression free survival (PFS) as their primary endpoint and all demonstrated a superior PFS when compared to placebo or no therapy after ASCT. However only the CALGB 100104 study demonstrated a statistically superior overall survival (OS). Thus, a meta-analysis was necessary to assess the effect of post-ASCT lenalidomide maintenance on overall survival. This study utilized a pooled analysis of updated primary-source patient data from all three studies after the primary efficacy analyses had been conducted. The meta-analysis demonstrated that there is a statistically superior OS (P value=0.001, HR=0.74 (0.62-0.89)), Median OS for no maintenance or placebo was 86 months and the median OS for lenalidomide had not been reached. The median OS for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). Thus, there is a 26% reduction in the risk of death which is an estimated 2.5 year increase in median OS. There is an increased incidence of second primary malignancies with lenalidomide maintenance when compared to placebo but this risk is less than the risk of dying when not receiving lenalidomide.
Dr Paul T Heath MB BS, FRACP, FRCPCH
Reader / Honorary Consultant
Paediatric Infectious Diseases
St George’s, University of London and Vaccine Institute
London, United Kingdom
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Heath: Vaccinating pregnant women is an important and proven strategy for protecting young infants against tetanus, influenza and pertussis. Among the infants at highest risk for complications of these infections are infants born prematurely but it is generally believed that because antibody transfer from mother to baby is maximal in the 3rd trimester, babies born prematurely may miss out on the benefits of maternal vaccination.
Dr. George Howard[/caption]
George Howard, Dr.P.H.
Professor of biostatistics
Birmingham School of Public Health
University of Alabama
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Howard: What has been known for many decades is that death rates from stroke are much higher in the black than white population, particularly between the ages of 45 – 65 (or maybe even a little older). These racial differences in stroke are among the greatest disparities for any disease, clearly it is a priority to reduce this disparity.
However, there are two reasons more blacks could die from a disease:
1) more blacks get the disease, or
2) once you get the disease, it is more likely to kill blacks.
The implications of knowing which of these is the major contributor is profound. If the driving force is more blacks are having more stroke, then we need to focus out attention on activities before stroke occur. For example, prevention of the greater prevalence of hypertension and diabetes in blacks, and also reducing the differences in the control of blood pressure and glucose. However, if the driving force is a higher chance of death in blacks once stroke occur, then we need to focus on the disparities in how black stroke patients are cared for compared to white stroke patients. That is, the former requires community-based efforts, while the latter requires hospital-based efforts.
What we found was that nearly all the difference was that blacks are having more strokes ... not that they are more likely to die once stroke occurs.
Dr. Jennifer Lemon[/caption]
Jennifer Lemon, PhD
Research Associate
Medical Radiation Sciences
McMaster University
MedicalResearch.com: What is the background for this study?
Dr. Lemon: Research with the supplement began in 2000, as part of my doctoral degree; we developed the supplement to try to offset the severe cognitive deterioration and accelerated aging in a mouse model we were working with in the lab. Based on aging research, five mechanisms appeared to be key contributors to the process of aging; those include oxidative stress, inflammation, mitochondrial deterioration, membrane dysfunction and impaired glucose metabolism. The criteria we used for including components in the supplement were as follows: each one of the 30 components had scientific evidence to show they acted on one or more of the above mechanisms were able to be taken orally, and were available to humans over-the-counter. Even then the hope was that if the formulation was successful, this would make it more available to the general public.
Dr. Patel Prashanth[/caption]
Dr Prashanth Patel MSc, FRCP, FRCPath
Consultant Metabolic Physician/ Chemical Pathologist and Head of Service
Department of Chemical Pathology and Metabolic Diseases
Honorary Senior Lecturer
Dept of Cardiovascular Sciences
University of Leicester
MedicalResearch.com: What is the background for this study?
Dr. Patel: Hypertension (HTN) is one of the most important and common chronic treatable condition. It affects nearly one third of the adult population. Nearly one fifth of patients treated for hypertension are thought to be resistant to treatment and these patients have a high mortality from cardiovascular diseases. Percutaneous radiofrequency catheter-based renal sympathetic denervation (renal denervation, RD) may be a potential treatment for resistant hypertension. Although RD is a safe procedure, it is irreversible and expensive. It is important that patients’ suitability for renal denervation is carefully assessed to maximise the potential benefits of the procedure. Therefore causes of pseudo-resistant hypertension namely white-coat hypertension, suboptimal pharmacological antihypertensive treatment and non-adherence to antihypertensive medications and secondary hypertension are needed to be robustly ruled out before considering a patient as suitable for renal denervation.
Dr. Kenneth Iczkowski,[/caption]
Kenneth A. Iczkowski, M.D.
Department of Pathology
Medical College of Wisconsin
Milwaukee, WI 53226
MedicalResearch.com: What is the background for this study?
Dr. Iczkowski: The International Society of Urological Pathology (ISUP) in 2014 proposed use of a new 5-tier grade grouping system to supplement traditional Gleason grading to facilitate prognosis stratification and treatment1. The 5 categories subsume: Gleason 3+3=6, Gleason 3+4=7, Gleason 4+3=7, Gleason 8, and Gleason 9-10.
We desired to determine whether men with a highest Gleason score of 3+5=8 or 5+3=8 in their set of prostate biopsy specimens, would have differing outcomes from those with Gleason 4+4=8. Because Gleason 5 cancer has been demonstrated to have a higher biologic potential than Gleason 4, it was expected that Gleason score 8 pattern with any Gleason 5 pattern would have a worse outcome.
Dr. Wayne Furman[/caption]
Wayne L. Furman, MD
Department of Oncology
Jude Children's Research Hospital
Memphis, TN 38105-3678
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Furman: Despite improvement in 2-yr EFS from 46% to 66% with the inclusion of dinutuximab, a monoclonal antibody that recognizes a glycoprotein on neuroblasts called ‘GD2’ (disialoganglioside), more than one-third of children with high-risk neuroblastoma still are not cured. Therefore novel therapeutic approaches are needed for this subset of patients. The clinical evaluation of various anti-GD 2 monoclonal antibodies in children with neuroblastoma has been exclusively focused on treatment of patients after recovery from consolidation, in a state of ‘minimal residual disease’. This is because traditionally chemotherapy has been thought to be too immunosuppressive to combine with monoclonal antibodies. However recent studies suggest, even in the setting of “bulky” solid tumors, the combination of chemotherapy with monoclonal antibodies can enhance the effectiveness of the antibodies. First, chemotherapy can increase the efficacy of antibodies by depleting cells of the immune system that suppress immune function. Also chemotherapy-induced tumor cell death can trigger tumor antigen release, uptake by antigen processing cells and an enhanced antitumor immune response. There is also data that anti-GD2 monoclonal antibodies can suppress tumor cell growth independent of immune system involvement. Furthermore anti-GD2 monoclonal antibodies and chemotherapy have non-overlapping toxicities. All of these reasons were good reasons to evaluate the addition of a novel anti-GD2 monoclonal antibody, called hu14.18K322A, to chemotherapy, outside the setting of minimal residual disease, in children with newly diagnosed children with high-risk neuroblastoma.
Dr. Mary Forhan[/caption]
Dr. Mary Forhan OT Reg (Alberta), PhD, Assistant Professor ad
[caption id="attachment_24752" align="alignleft" width="100"]
Dr-Tasuku-Terada[/caption]
Dr. Tasuku Terada, post-doctoral research fellow
Faculty of Rehabilitation Medicine
University of Alberta
MedicalResearch.com: What is the background for this study?
Response: The prevalence of obesity has increased. Notably, a proportion of severe obesity (body mass index: body weight [kg] divided by height squared [m2]: >40kg/m2) has shown the most significant increase. Greater body mass increases the risk of cardiovascular disease and referrals for coronary artery graft surgery (CABG) have increased in patients with severe obesity. Interestingly, while obesity is often considered to increase the risk of complications and associated health care costs, many studies have reported better prognosis in patients with obesity compared to patients with normal weight, a phenomenon referred to as the obesity paradox. Therefore, it was not clear if patients with severe obesity were at higher risk of complications and contributed to greater resource use. A better understanding of the relationship between obesity and post-surgical adverse outcomes was needed to provide quality and efficient care.
Jimmy Celind[/caption]
Jimmy Celind
Postgraduate student
The Sahlgrenska Academy
University of Gothenburg
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The background is that there is a widespread belief that birth weights are increasing, and that this at least partly is a product of the obesity epidemic (together with decreased smoking prevalence and higher maternal age). Several studies from countries such as Sweden, Norway, Denmark, USA, Scotland, Israel and Australia have shown a slight increase during the last decades of the 20th century. Our aim was to see when the increase started and how much it had increased.
Our main findings are that the trends of birth weight are stable during the study period of 65 years (1946-2011), regarding mean, distribution, and odds ratios for being born with a high birth weight (>4,5 kg) per birth year increment.
Dr Robb Rutledge[/caption]
MedicalResearch.com Interview with:
Dr Robb Rutledge
UCL Institute of Neurology and
Max Planck UCL Centre for Computational Psychiatry and Ageing Research
University College London
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Rutledge: As we get older, dopamine levels in the brain gradually decline.
Dopamine has long been associated with risk taking and we have
recently found that it is related specifically to how willing people
are to take risks for potential rewards. It is widely believed that
older people are risk averse, but this is controversial, and it is
unknown whether age-related changes in dopamine are responsible for
changes in risk taking. In this study, we tested over 25,000 people
using a smartphone app called The Great Brain Experiment where players
tried to win as many points as they could by choosing between safe and
risky options. We found that older people were less willing to takes
risks for potential rewards than young people, the same situations
dopamine is known to be involved in.
Dr. Hsien-Yen Chang[/caption]
Hsien-Yen Chang PhD
Assistant Scientist
Johns Hopkins Bloomberg School of Public Health
Department of Health Policy & Management
Center for Drug Safety & Effectiveness
MedicalResearch.com: What is the background for this study?
Dr. Chang: Prescription opioid addiction and non-medical use are significant public health problems, responsible for about 44 daily overdose deaths in the United States. Although there are no magic bullets to address these issues, policy makers play an important role in shaping regulatory, payment and public health policies to reduce opioid-related injuries and deaths. For example, state policy-makers in the United States have used prescription drug monitoring programs (PDMPs) and “pill mill” laws to address the prescription opioid epidemic. While there is growing evidence regarding the effect of these approaches on opioid sales, little is known about how they affect specific groups of prescribers. This is important, as approximately 20% of U.S. physicians are responsible for prescribing 80% of all opioid analgesics. Therefore, in this study we evaluated the impact of PDMPs and pill mill laws on the clinical practices of high-risk prescribers in Florida, such as their total number of prescription-filling patients with an opioid prescription. Furthermore, we also characterized the concentration of opioid volume and prescriptions among this group of prescribers as well as how the policies of interest impacted these measures.
Dr. Halima Amjad[/caption]
Halima Amjad, MD, MPH
Post-doctoral Fellow
Johns Hopkins University School of Medicine
Division of Geriatric Medicine and Gerontology
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Amjad: Safety is an important aspect of dementia care. Dementia is underdiagnosed, however, and there is limited understanding of safety issues in people with undiagnosed dementia. We wanted to better understand potentially unsafe activities and living conditions in all older adults with dementia and specifically examine these activities in undiagnosed dementia. We found that in all study participants with probable dementia, the prevalence of driving, cooking, managing finances, managing medications, or going to physician visits alone was over 20%. The prevalence was higher in older adults with probable dementia without a diagnosis, and even after accounting for sociodemographic, medical, and physical impairment factors, the odds of engaging in these activities was over 2.0 in undiagnosed versus diagnosed probable dementia. Potentially unsafe living conditions including unmet needs and performance on cognitive tests were similar between these groups.
Dr. Zhenmei Zhang[/caption]
Zhenmei Zhang, Ph.D.
Associate Professor
Department of Sociology
Michigan State University
East Lansing, MI48824
MedicalResearch.com: What is the background for this study?
Dr. Zhang: Blacks are especially hard hit by cognitive impairment and dementia. Recent estimates of dementia prevalence and incidence were substantially higher for blacks than whites. Reducing racial/ethnic disparities in dementia has been identified as a national priority by the National Alzheimer’s Project Act, which was signed into law by President Obama in 2011. So I really want to contribute to the ongoing discussion of the origins and pathways through which racial disparities in cognitive impairment is produced. If we have a better understanding of the factors contributing to racial disparities in cognitive impairment in later life, more effective interventions can be conducted to reduce the racial disparities.
Dr. Andrea Wickremasinghe[/caption]
Andrea C. Wickremasinghe, MD
Neonatologist
Kaiser Santa Clara California
MedicalResearch.com: What is the background for this study?
Response: Neonatal jaundice is common and is often treated with phototherapy. Phototherapy is typically considered to be benign. In the past decade, phototherapy use has increased and it is sometimes started at bilirubin levels below recommended treatment thresholds. Beginning in the 1970’s, in-vitro and in-vivo studies have shown phototherapy to be associated with cellular changes implicated in the pathogenesis of cancer. Epidemiologic studies have yielded mixed results, with some studies showing associations between phototherapy and leukemia and other studies failing to show this association. In this study, we used a large statewide administrative dataset to investigate the relationship between neonatal phototherapy and cancer in the first year after birth.