Cancer is the second leading cause of death (after accidents) in children and adolescents in the United States despite significant progress in diagnosis, treatment, and survival. Mortality rates have declined approximately 2% per year over the past 3 decades, and survival rates for many childhood cancers have greatly improved (Figure 1). The overall 5-year survival rate for childhood cancer now exceeds 79%. Most notable is the progress in treating acute lymphoblastic leukemia (ALL), which represents about a third of all cases of pediatric cancer (Figure 2). Improved critical care, infectious disease management, and nutritional support and the widespread use of central venous catheters have increased survival overall for children with malignancies. Approximately 1 in every 250 adults is expected to be a childhood cancer survivor by 2010. The potential social, economic, and medical impact of this advance is second only to that of the treatment of adult breast cancer.
Overview of Childhood Cancers
Childhood cancers comprise a spectrum of malignancies that differ in histologic type, site of origin, and incidence across age groups. Importantly, they also differ from adult cancers in significant ways. Whereas most adult cancers are epithelial and may be influenced by environmental factors (eg, smoking and diet), most pediatric cancers are dysontogenic in nature. Therefore, screening or prevention programs are less likely to be effective. Further, tolerance of therapy is quantitatively and qualitatively different in children and adults because of dissimilar host characteristics, such as physiology and organ maturation.
Because childhood cancer is rare, successful therapy depends on focused, collaborative clinical research supported by governmental agencies and public philanthropy. This model is anchored in a strong clinical research infrastructure and the effective collaboration of a multidisciplinary team composed of pediatric oncologists, surgeons, radiation therapists, and other professionals. Paramount to these efforts is the contribution of basic and translational scientists who define important biologic and genetic components of childhood cancer that can guide risk-based therapy.
The international community has made significant contributions to this success. Collaborative pediatric oncology research models have also laid the foundation for research alliances for the treatment of asthma, cystic fibrosis, AIDS, and other chronic childhood diseases. Further, fundamental principles gained through protocol-based treatment of pediatric cancer have translated to improved management of adult cancers. These key principles are summarized in Table 1 and further elaborated below.
Many challenges remain. Survival remains poor for children with tumors such as disseminated neuroblastoma or diffuse pontine glioma, and for others we have reached a survival plateau. There is poor understanding of the biology of some tumor subtypes. The physical, psychosocial, and financial consequences of effective therapy have created a need for specialized care for survivors and new venues for research. There is room for improvement in the collection of late effects and outcome data. There is little financial incentive or support for the development of new drugs and biologic therapies. There are disparities in outcomes in adolescents and young adults, and many children worldwide lack access to effective therapy. This article will review specific examples of progress, the challenges that remain across the spectrum of childhood cancer, and future areas of work.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics. CA Cancer J Clin 56:106-130, 2006.
2. Ries LAG, Percy CL, Bunin GR: in Ries LAG, Smith MA, Gurney JG, et al (eds): Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, pp 1-16. Bethesda, Md; National Cancer Institute, SEER Program; 1999.
3. Bleyer WA: The impact of childhood cancer on the United States and the world. CA Cancer J Clin 40:355-367, 1990.
4. Murphy SB: The national impact of clinical cooperative group trials for pediatric cancer. Med Pediatr Oncol 24:279-280, 1995.
5. Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166-178, 2006.
6. Silverman LB, Gelber RD, Dalton VK, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 97:1211-1218, 2001.
7. Willenbrock H, Juncker AS, Schmiegelow K, et al: Prediction of immunophenotype, treatment response, and relapse in childhood acute lymphoblastic leukemia using DNA microarrays. Leukemia 18:1270-1277, 2004.
8. Brown P, Levis M, Shurtleff S, et al: FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood 105:812-820, 2005.
9. Rieter A, Schrappe M, Ludwig WD, et al: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. Blood 84:3122-3133, 1994.
10. Pui CH, Relling MV, Evans WE: Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia. Best Pract Res Clin Haematol 15:741-756, 2002.
11. Willman KY, Cox RS, Donaldson SS: Radiation induced height impairment in pediatric Hodgkin' disease. Int J Radiat Oncol Biol Phys 28:85-92, 1994.
12. Donaldson SS, Link MP: Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin' disease. J Clin Oncol 5:742-749, 1987.
13. Donaldson SS, Hancock SL: Second cancers after Hodgkin' disease in childhood. N Engl J Med 334:792-794, 1996.
14. Friedman DL, Constine LS: Late effects of treatment for Hodgkin lymphoma. J Natl Compr Canc Netw 4:249-257, 2006.
15. Friedberg JW, Fischman A, Neuberg D, et al: FDG-PET is superior to gallium scintigraphy in staging and more sensitive in the follow-up of patients with de novo Hodgkin lymphoma: A blinded comparison. Leuk Lymphoma 45:85-92, 2004.
16. Krasin MJ, Hudson MM, Kaste SC: Positron emission tomography in pediatric radiation oncology: Integration in the treatment-planning process. Pediatr Radiol 34:214-221, 2004.
17. Longo DL, Duffey PL, Young RC, et al: Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin' disease after combination chemotherapy: The low probability for cure. J Clin Oncol 10:210-218, 1992.
18. Schmitz N, Pfistner B, Sextro M, et al: Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin' disease: A randomised trial. Lancet 359:2065-2071, 2002.
19. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin' lymphoma in childhood. N Engl J Med 334:1238-1248, 1996.
20. Murphy SB, Fairclough DL, Hutchison RE, et al: Non-Hodgkin' lymphomas of childhood: An analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 7:186-193, 1989.
21. Pinkerton R: Continuing challenges in childhood non-Hodgkin' lymphoma, Br J Haematol 130:480-488, 2005.
22. Leverger G, Patte C: Therapeutic progress in acute lymphoblastic leukemias and stage IV Burkitt-type lymphomas in children. Bull Acad Natl Med 187:743-755, 2003.
23. Weinstein JL, Katzenstein HM, Cohn SL: Advances in the diagnosis and treatment of neuroblastoma. Oncologist 8:278-292, 2003.
24. Schmidt ML, Lal A, Seeger RC, et al: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: A Children' Cancer Group Study. J Clin Oncol 23:6474-6480, 2005.
25. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis- retinoic acid. Children' Cancer Group. N Engl J Med 341:1165-1173, 1999.
26. Berthold F, Hero B, Kremens B, et al: Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett 197:11-17, 2003.
27. Cheung NK, Kushner BH, Cheung IY, et al: Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16:3053-3060, 1998.
28. Santana VM, Furman WL, Billups CA, et al: Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach. J Clin Oncol 23:4039-4047, 2005.
29. Clouse JW, Thomas PR, Griffith RC, et al: The changing management of Wilms' tumor over a 30-year period. 1949-1978. Cancer 56:1484-1489, 1985.
30. Green DM: The treatment of stages I-IV favorable histology Wilms' tumor. J Clin Oncol 22:1366-1372, 2004.
31. Dome JS, Cotton CA, Perlman EJ, et al: Treatment of anaplastic histology Wilms' tumor: Results from the fifth National Wilms' Tumor Study. J Clin Oncol 24:2352-2358, 2006.
32. Ritchey ML, Green DM, Thomas PR, et al: Renal failure in Wilms' tumor patients: A report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 26:75-80, 1996.
33. Thomas PR, Tefft M, Compaan PJ, et al: Results of two radiation therapy randomizations in the third National Wilms' Tumor Study. Cancer 68:1703-1707, 1991.
34. Barr RD, Chalmers D, De Pauw S, et al: Health-related quality of life in survivors of Wilms' tumor and advanced neuroblastoma: A cross-sectional study. J Clin Oncol 18:3280-3287, 2000.
35. Green DM, Breslow NE, Beckwith JB, et al: Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 19:3719-3724, 2001.
36. Grundy PE, Breslow NE, Li S, et al: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: A report from the National Wilms Tumor Study Group. J Clin Oncol 23:7312-7321, 2005.
37. Raney RB, Anderson JR, Barr FG, et al: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: A selective review of Intergroup Rhabdomyosarcoma Study Group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23:215-220, 2001.
38. Stevens MC: Treatment for childhood rhabdomyosarcoma: The cost of cure. Lancet Oncol 6:77-84, 2005.
39. Wolden SL, Anderson JR, Crist WM, et al: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 17:3468-3475, 1999.
40. Heyn R, Newton WA, Raney RB, et al: Preservation of the bladder in patients with rhabdomyosarcoma. J Clin Oncol 15:69-75, 1997.
41. Arndt CA, Donaldson SS, Anderson JR, et al: What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer 91:2454-2468, 2001.
42. Wiener ES, Anderson JR, Ojimba JI, et al: Controversies in the management of paratesticular rhabdomyosarcoma: Is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg 10:146-152, 2001.
43. Crist WM, Anderson JR, Meza JL, et al: Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 19:3091-3102, 2001.
44. Breitfeld PP, Meyer WH: Rhabdomyosarcoma: New windows of opportunity. Oncologist 10:518-527, 2005.
45. Marina N, Gebhardt M, Teot L, Gorlick R: Biology and therapeutic advances for pediatric osteosarcoma. Oncologist 9:422-441, 2004.
46. Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986.
47. Harris MB, Gieser P, Goorin AM, et al: Treatment of metastatic osteosarcoma at diagnosis: A Pediatric Oncology Group Study. J Clin Oncol 16:3641-3648, 1998.
48. Rougraff BT, Simon MA, Kneisl JS, et al: Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. A long-term oncological, functional, and quality-of-life study. J Bone Joint Surg Am 76:649-656, 1994.
49. Bielack SS, Kempf-Bielack B, Delling G, et al: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,072 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776-790, 2002.
50. Gitelis S, Neel MD, Wilkins RM, et al: The use of a closed expandable prosthesis for pediatric sarcomas. Chir Organi Mov 88:327-333, 2003.
51. Turc-Carel C, Aurias A, Mugneret F, et al: Chromosomes in Ewing' sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet 32:229-238, 1988.
52. Thompson AD, Teitell MA, Arvand A, et al: Divergent Ewing' sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells. Oncogene 18:5506-5513, 1999.
53. Athale UH, Shurtleff SA, Jenkins JJ, et al: Use of reverse transcriptase polymerase chain reaction for diagnosis and staging of alveolar rhabdomyosarcoma, Ewing sarcoma family of tumors, and desmoplastic small round cell tumor. J Pediatr Hematol Oncol 23:99-104, 2001.
54. Thacker MM, Temple HT, SP: Current treatment of Ewing sarcoma. Expert Rev Anticancer Ther 5:319-331, 2005.
55. Paulussen M, Ahrens S, Craft AW, et al: Ewing' tumors with primary lung metastases: Survival analysis of 114 (European Intergroup) Cooperative Ewing' Sarcoma Studies patients. J Clin Oncol 16:3044-3052, 1998.
56. Grier HE, Krailo MD, Tarbell NJ, et al: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing' sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348:694-701, 2003.
57. Vezina LG: Neuroradiology of childhood brain tumors: New challenges. J Neurooncol 75:243-252, 2005.
58. Packer RJ: Progress and challenges in childhood brain tumors. J Neurooncol 75:239-242, 2005.
59. Packer RJ, Ater J, Allen J, et al: Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86:747-754, 1997.
60. Horn B, Heideman R, Geyer R, et al: A multi-institutional retrospective study of intracranial ependymoma in children: Identification of risk factors. J Pediatr Hematol Oncol 21:203-211, 1999.
61. Merchant TE, Mulhern RK, Krasin MJ, et al: Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 22:3156-3162, 2004.
62. Gilbertson RJ, Bentley L, Hernan R, et al: ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. Clin Cancer Res 8:3054-3064, 2002.
63. Packer RJ, Goldwein J, Nicholson HS, et al: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children' Cancer Group Study. J Clin Oncol 17:2127-2136, 1999.
64. Thomas PR, Deutsch M, Kepner JL, et al: Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 16:3004-3011, 2000.
65. Packer RJ, Gajjar A, Vezina G, et al: Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202-4208, 2006.
66. Gajjar A, Chintagumpala M, Ashley D, et al: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): Long-term results from a prospective, multicentre trial. Lancet Oncol 7:813-820, 2006.
67. Lamont JM, McManamy CS, Pearson AD, et al: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10:5482-5493, 2004.
68. Ellison DW, Onilude OE, Lindsey JC, et al: Beta-catenin status predicts a favorable outcome in childhood medulloblastoma: The United Kingdom Children' Cancer Study Group Brain Tumour Committee. J Clin Oncol 23:7951-7957, 2005.
69. Gajjar A, Hernan R, Kocak M, et al: Clinical, histopathologic, and molecular markers of prognosis: Toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22:984-993, 2004.
70. Duffner PK: Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors. Neurologist 10:293-310, 2004.
71. Duffner PK, Horowitz ME, Krischer JP, et al: The treatment of malignant brain tumors in infants and very young children: An update of the Pediatric Oncology Group experience. Neuro-oncol 1:152-161, 1999.
72. Finlay JL, Zacharoulis S: The treatment of high grade gliomas and diffuse intrinsic pontine tumors of childhood and adolescence: A historical—and futuristic—perspective. J Neurooncol 75:253-266, 2005.
73. Tekautz TM, Fuller CE, Blaney S, et al: Atypical teratoid/rhabdoid tumors (ATRT): Improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 23:1491-1499, 2005.