Bone Marrow Transplantation (2007) 40, 721–722 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00
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PERSPECTIVE
Neuroblastoma, childhood cancer survivorship, and reducing the consequences of cure
Bone Marrow Transplantation (2007) 40, 721–722; doi:10.1038/sj.bmt.1705815 Few would dispute the strategy that every reasonable, if not conceivable, effort must be made to save the life of a child with cancer. In fact, the industrialized world has made truly remarkable progress in pediatric multimodal, risk-adapted cancer treatment, resulting in long-term survival rates for most childhood malignant diseases that were unimaginable a few decades ago.1 Unfortunately, skirting this trend, highrisk neuroblastoma tumors have proven to be quite obstinate in the face of modern therapy and, even today, children with this form of cancer do not generally fare well.2,3 As evidenced by the case series presented by Trahair et al.,4 in this issue of Bone Marrow Transplantation, those who are fortunate enough to survive their disease confront many serious long-term adverse effects from neuroblastoma and its treatment. Concerted study of the ‘consequences of cure’ from cancer treatment has only recently emerged as a scientific discipline within clinical and epidemiological research arenas.5–7 Such survivorship research in the pediatric setting has focused primarily on the more common malignancies, such as acute lymphoblastic leukemia and Hodgkin’s lymphoma, with very little systematic study on late effects of neuroblastoma, perhaps with the exception of documenting the permanent ototoxic effects of cisplatin and carboplatin.8–12 From the present study4 and similar clinical followup work by Laverdie`re et al.13 and others,14 we can reach a brief understanding of the risks for multi-organ sequelae among survivors of advanced stage neuroblastoma. The most prominent are endocrine impairments, including short stature, hypothyroidism and ovarian and testicular dysfunction; musculoskeletal complications, including kyphosis and scoliosis, significant dental abnormalities, slipped capital femoral epiphysis, fractures, fibrosis and hypoplasia; major organ system impairment, most notably serious renal dysfunction, but also cardiac toxicity and lung fibrosis or other pulmonary problems; neurological disorders, including opsoclonus myoclonus (opsoclonus ataxia), neurogenic bladder, and paresis and paraplegia; and sensory impairments, including chronic pain, parasthesia, cataracts and neurosensory hearing loss. And of course, the effect that many parents fear the most (perhaps after that of recurrence) is a subsequent primary malignancy. How these conditions affect health-related quality of life of the patient,9,15,16 and the well-being of the family, is very difficult to measure
and act upon, but of enormous importance to parents and their children. As is clear from this study and others, radiation, particularly total body irradiation (TBI), is a bad actor from a late effects standpoint. Hopefully, several of the more onerous long-term adverse effects of neuroblastoma will in the future be circumvented now that the current standard of care in the United States and Europe for autologous stem cell transplantation avoids inclusion of TBI as a preparatory agent. However, local irradiation, myeloablative therapies including cytotoxic alkylating agents and platinum drugs, and surgical intervention are not going away in the foreseeable future, so the importance of understanding, monitoring and treating long-term effects of high-risk neuroblastoma (and other pediatric cancers treated with stem cell transplantation) are also here to stay. This begs the question: who provides this specialized yet heterogeneous ‘survivorship’ care? One answer, of course, is multi-disciplinary long-term cancer follow-up clinics.17 Such clinics, however, are still not equipped with proven standardized care guidelines or available in most settings, although they are slowly becoming more accepted as an important clinical means for helping patients and families identify, treat and navigate the constellation of symptoms and conditions that not only linger after the completion of treatment, but newly surface many years after the disease is defeated. The need for specialized treatment for physical impairments, hearing loss, gonadal dysfunction, subtle neurocognitive deficiencies, and psychological distress, among many other sequelae, will differ depending on the developmental milestone that the child or adolescent or young adult is negotiating at that point in time. Very few cancer centers have programs to transition primary care from childhood to adulthood; yet adult primary care physicians are not often exposed to these cases and are not familiar enough with the toxic therapies to understand the complexity of the adverse consequences that may arise. Additionally, parents and childhood cancer survivors, who need to take the lead in self-care management, often are not reliable historians of their disease or treatment.18,19 What are the oncologists and transplant team to do? Aside from the need for evidence-based clinical guidelines, which has recently been taken on by the United Kingdom Children’s Cancer Study Group, the Scottish Intercollegiate Guidelines Network and the Children’s Oncology Group,19,20 careful and repeated education and support of the parents to better understand, monitor, document and act upon late effects is the most obvious and practical approach. The current paradigm is that survivorship training starts when the disease is diagnosed and ‘treatment
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with intent to cure’ begins, not five years after treatment is completed.5 A patient care plan, focused on survivorship, needs to be implemented from day 1. Next, encouraging development of childhood cancer follow-up clinics that readily serve the complex needs of the child as he or she progresses through their developmental stages, physically and emotionally, would be of enormous help. Additionally, training and supporting Med/Peds physicians in long-term care of childhood cancer patients who could serve adolescents into their adulthood would be very valuable. And finally, encouraging and supporting integrated training in long-term cancer care and clinical outcomes research in medical teaching settings, for oncologists and nurse practitioners, but also for the many subspecialties, such as endocrinology, neurology, OB/GYN and psychology, is essential if quality of care is to improve and progress. We owe it to the kids and their families to advocate for these essential comprehensive services. JG Gurney Child Health Evaluation and Research Unit, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA E-mail:
[email protected]
References 1 Reaman GH. Pediatric cancer research from past successes through collaboration to future transdisciplinary research. J Pediatr Oncol Nurs 2004; 21: 123–127. 2 Matthay KK, Cheung NK. High risk neuroblastoma. In: Cheung NK, Cohn SL (eds). Neuroblastoma. Springer: Berlin, 2005, pp 138–149. 3 Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 1999; 341: 1165–1173. 4 Trahair TN, Vowels MR, Johnston K, Cohn RJ, Russell SJ, Neville KA et al. Long-term outcomes in children with highrisk neuroblastoma treated with autologous stem cell transplantation. Bone Marrow Transplant 2007; 40: 741–746. 5 Hewitt M, Greenfield S, Stovall E, and the Institute of Medicine’s Committee on Cancer Survivorship (eds). From Cancer Patient to Cancer Survivor: Lost in Transition. The National Academies Press: Washington, DC, 2005. 6 Ness KK, Gurney JG. Adverse late effects of childhood cancer and its treatment on health and performance. Annu Rev Public Health 2007; 28: 279–302. 7 Meadows AT. Pediatric cancer survivorship: research and clinical care. J Clin Oncol 2006; 24: 5160–5165.
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8 Gilmer-Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005; 23: 8588–8596. 9 Gurney JG, Tersak JM, Ness KK, Landier W, Matthay KK, Schmidt ML. Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors—a report from the Children’s Oncology Group. Pediatrics (in press). 10 Kushner BH, Budnick AS, Kramer K, Modak S, Cheung NKV. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 2006; 107: 417–422. 11 Parsons SK, Neault MW, Lehmann LE, Brennan LL, Eickhoff CE, Kretschmar CS et al. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant 1998; 22: 669–674. 12 Punnett A, Bliss B, Dupuis LL, Abdolell M, Doyle J, Sung L. Ototoxicity following pediatric hematopoietic stem cell transplantation: a prospective cohort study. Pediatr Blood Cancer 2004; 42: 598–603. 13 Laverdiere C, Cheung NK, Kushner BH, Kramer K, Modak S, LaQuaglia MP et al. Long-term complications in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer 2005; 45: 324–332. 14 Laverdiere C, Gurney JG, Sklar CA. Late effects of treatment. In: Cheung NK, Cohn SL (eds). Neuroblastoma. Springer: Berlin, 2005, pp 277–288. 15 Barr RD, Chalmers D, De Pauw S, Furlong W, Weitzman S, Feeny D. Health-related quality of life in survivors of Wilms’ tumor and advanced neuroblastoma: a cross-sectional study. J Clin Oncol 2000; 18: 3280–3287. 16 Nathan PC, Ness KK, Greenberg ML, Hudson M, Wolden S, Davidoff A et al. Health-related quality of life in adult survivors of childhood Wilms tumor or neuroblastoma: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2006 (July 7, E-pub ahead of print). 17 Friedman DL, Freyer DR, Levitt GA. Models of care for survivors of childhood cancer. Pediatr Blood Cancer 2006; 46: 159–168. 18 Kadan-Lottick NS, Robison LL, Gurney JG, Neglia JP, Yasui Y, Hayashi R et al. Childhood cancer survivors’ knowledge about their past diagnosis and treatment: Childhood Cancer Survivor study. JAMA 2002; 287: 1832–1839. 19 Landier W, Wallace WH, Hudson MM. Long-term follow-up of pediatric cancer survivors: education, surveillance, and screening. Pediatr Blood Cancer 2006; 46: 149–158. 20 Landier W, Bhatia S, Eshelman DA, Forte KJ, Sweeney T, Hester AL et al. Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 2004; 22: 4979–4990.
