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Background: Cancers in adolescents and young adults (AYAs) form a distribution distinct from those in children and older adults. As the increasing interest in AYA oncology has developed, the current classification system of neoplasms in AYAs has become outdated. Based on emerging knowledge in cancer biology and clinical advances, a new classification is proposed. Methods: The new system is based on morphologies and primary sites in the population aged 15 to 39 years. It accommodates information in WHO Blue Books on numerous groups of neoplasms and the recent update of the International Classification of Diseases for Oncology. Data from the Surveillance, Epidemiology and End Results (SEER) program of the US National Cancer Institute illustrate the proposed classification. Findings: The distinct distribution of cancers in AYAs reflects the inclusion of benign/borderline tumors of the CNS, in situ lesions for various carcinomas and neuroendocrine tumors in several locations. Diseases with striking increases in incidence, peculiar to AYAs in the SEER dataset, notably neuroendocrine tumors of the appendix and a re-named variant of carcinoma of the thyroid, are highlighted. New categories have been created to address Blood and Lymphatic Vessel Tumors and Nerve Sheath Tumors. Less than 0·5% of all cancers were designated as Unspecified Malignant Neoplasms Except CNS and fewer than 0·001% were not classifiable in the SEER data. Interpretation: The proposed classification system addresses the choice of the age range 15 to 39 years for AYAs and affords contrast with the previous classification as well as cancers in children and older adults. Characteristics which distinguish neoplasia in AYAs are emphasized. The ultimate goal of the new system is to improve cancer registration, diagnosis, treatment and health-related outcomes in this age group through standardized groupings of primary site and histology among different populations and over time. Funding Statement: The authors state: "No external funding." Declaration of Interests: The authors have no conflicts of interests to declare. Ethics Approval Statement: Not required.

Each year, 70,000 adolescents and young adults (AYAs) between ages 15 and 39 years in the United States are diagnosed with cancer. In 2006, a National Cancer Institute (NCI) Progress Review Group (PRG) examined the state of science associated with cancer among AYAs. To assess the impact of the PRG and examine the current state of AYA oncology research, the NCI, with support from the LIVESTRONG Foundation, sponsored a workshop entitled "Next Steps in Adolescent and Young Adult Oncology" on September 16 and 17, 2013, in Bethesda, Maryland. This report summarizes the findings from the workshop, opportunities to leverage existing data, and suggestions for future research priorities. Multidisciplinary teams that include basic scientists, epidemiologists, trialists, biostatisticians, clinicians, behavioral scientists, and health services researchers will be essential for future advances for AYAs with cancer.

Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled “Next Steps in Adolescent and Young Adult Oncology” summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics. Cancer 2016;122:1017–1028. © 2016 American Cancer Society

Author(s): Keegan, Theresa HM; Ries, Lynn AG; Barr, Ronald D; Geiger, Ann M; Dahlke, Deborah Vollmer; Pollock, Bradley H; Bleyer, W Archie; National Cancer Institute Next Steps for Adolescent and Young Adult Oncology Epidemiology Working Group | Abstract: BackgroundWith prior reports indicating a lack of progress in survival improvement in older adolescents and young adults (AYAs) aged 15 to 39 years with cancer compared with both younger and older patients with cancer, the current analysis provides an update of survival trends of cancers among AYAs, children, and older adults.MethodsData from the National Cancer Institute Surveillance, Epidemiology, and End Results database for 13 regions were used to ascertain survival trends of the 34 most frequent cancers diagnosed in AYAs compared with children and older adults.ResultsAs of 2002 through 2006, the 5-year relative survival rate for all invasive cancers in AYAs was 82.5% (standard error, 0.2%). In AYAs, 14 cancers demonstrated evidence of a statistically significant improvement in their 5-year relative survival since 1992. Survival improved less in AYAs than in children for acute myeloid leukemia and medulloblastoma. Fourteen cancers had survival improvements that were found to be less in AYAs compared with older adults, including hepatic carcinoma, acute myeloid leukemia, high-grade astrocytoma, acute lymphocytic leukemia, pancreatic carcinoma, low-grade astrocytoma, gastric carcinoma, renal carcinoma, cancer of the oral cavity and pharynx, Hodgkin lymphoma, ovarian cancer, fibromatous sarcoma, other soft tissue sarcoma, and thyroid carcinoma.ConclusionsImprovements in the survival of several cancer types that occur frequently in AYAs are encouraging. However, survival does not appear to be improving to the same extent in AYAs as in children or older adults for several cancers. Further investment in exploring the distinct biology of tumors in this age group, and of their hosts, must be a priority in AYA oncology.

Incidence rates and trends of cancers in adolescents and young adults (AYAs) ages 15 to 39 years were reexamined a decade after the US National Cancer Institute AYA Oncology Progress Review Group was established.Data from the Surveillance, Epidemiology, and End Results program through 2011 were used to ascertain incidence trends since the year 2000 of the 40 most frequent cancers in AYAs, including tumors with nonmalignant/noninvasive behavior.Seven cancers in AYAs exhibited an overall increase in incidence; in 4, the annual percent change (APC) exceeded 3 (kidney, thyroid, uterus [corpus], and prostate cancer); whereas, in 3, the APC was between 0.7 and 1.4 (acute lymphoblastic leukemia and cancers of the colorectum and testis). Eight cancers exhibited statistically significant decreases in incidence among AYAs: Kaposi sarcoma (KS), fibromatous neoplasms, melanoma, and cancers of the anorectum, bladder, uterine cervix, esophagus, and lung, each with an APC less than -1. AYAs had a higher proportion of noninvasive tumors than either older or younger patients.An examination of cancer incidence patterns in AYAs observed over the recent decade reveal a complex pattern. Thyroid cancer by itself accounts for most of the overall increase and is likely caused by overdiagnosis. Reductions in cervix and lung cancer, melanoma, and KS can be attributed to successful national prevention programs. A higher proportion of noninvasive tumors in AYAs than in children and older adults indicates a need to revise the current system of classifying tumors in this population.

Adolescents and young adults (AYAs – ages 15 to 39) constitute approximately 40% of the world's population and contribute an estimated one million new cases of cancer annually, the great majority in low- and middle-income countries (LMICs). In high-income countries (HICs) cancer is the commonest cause of disease-related death in AYAs, though overall 5-year survival rates now exceed 80%. A very different circumstance likely holds in LMICs, but accurate assessments are not readily available. Breast cancer accounts for 40% of tumours in female AYAs and this age group includes the peak incidence of Hodgkin lymphoma. The late Professor Gianni Bonadonna contributed importantly to improved survival in patients with these two diseases. Accordingly, he would be justifiably proud of the advances in AYA oncology that are being made in Italy, especially the impact of his colleagues at the Istituto Nazionale dei Tumori (INT). The initiatives of the Associazione Italiana Ematologia Pediatrica and the Società Italiana Adolescenti con Malattie Onco-ematologiche are particularly noteworthy, with the accomplishment of productive collaboration between paediatric and adult cancer care providers serving as a model for other countries to emulate. Exporting these advances can be successful through the vehicle of “twinning”: establishing sustainable cooperation between institutions in HICs and partners in LMICs. Colleagues in Monza and at INT have been leaders in such programmes for decades. Cancer in AYAs remains a global challenge to which Gianni Bonadonna surely would have risen with enthusiasm and leadership while securing measurable achievements.

History of Adolescent Oncology.- Epidemiology and Etiology of Cancer in Adolescents and Young Adults.- Access to Care Before and During Therapy.- Older Adolescents and Young Adults with Cancer, and Clinical Trials: Lack of Participation and Progress in North America.- Acute Lymphoblastic Leukemia.- Acute Myelogenous Leukemia.- Hodgkin Lymphoma.- Non-Hodgkin Lymphoma.- Central Nervous System Tumors.- Soft-Tissue Sarcomas.- Bone Sarcomas.- Malignancies of the Ovary.- Testicular Tumors.- Non-Germ-Cell Genitourinary Tract Tumors.- Thyroid Cancer.- Malignant Melanoma.- Breast Cancer.- Liver Tumors.- Colorectal Cancer.- Models of Care and Specialized Units.- Drug Compliance by Adolescent and Young Adult Cancer Patients: Challenges for the Physician.- Psychological Support.- Psychosocial Support.- Health-Related Quality of Life.- Rehabilitation and Exercise.- Adolescent and Young Adult Cancer Survivors: Late Effects of Treatment.- Ethical Issues for the Adolescent and Young Adult Cancer Patient: Assent and End-of-Life Care.- Access to Care after Therapy.- Future Health of Survivors of Adolescent and Young Adult Cancer.- Information and Resources for Young Adults and Adolescents with Cancer.- Making Ends Meet: Financial Issues from the Perspectives of Patients and Their Healthcare Team.- Challenges and Opportunities - The Way Ahead.

Importance Although cancer remains the most common cause of disease-related death in adolescents and young adults (AYAs) in high-income countries, their overall survival rates continue to increase and now exceed 80% at 5 years in several high-income countries. This has been accomplished through progressive improvements in active treatment and supportive care, although accrual rates to therapeutic clinical trials remain disappointing. Recognition of the unique distribution of diseases in the AYA population with cancer and further understanding of the distinctive biology of cancers in AYAs will lead to continuing gains in clinical outcomes. Observations Many of the challenges faced by AYAs with a diagnosis of malignant disease are shared by others with chronic medical conditions and even their healthy peers, such as a sense of invulnerability that may contribute to delays in diagnosis. A particular need for psychological support has been identified for AYAs with cancer, even after active therapy has been completed and especially in the context of palliative care. Notable needs also include fertility preservation and navigation through the multiple transitions in the cancer journey. Additionally, there is a “cost of cure.” This is not only in the form of short-term, treatment-related morbidity and mortality but also in the burden of “late effects,” including second cancers, that compromise quality of life and limit life expectancy. Establishing clinical programs devoted to AYAs with cancer, with complementary educational initiatives, will strengthen the advances made. It is anticipated that clinical trial accrual will increase substantially, providing further gains in survival. Likewise, addressing the challenges of survivorship, including secondary prevention of long-term morbidity and mortality, will lead to additional improvements in clinical outcomes. Conclusions and Relevance Transferring this knowledge to the care of an estimated 1 million incident cases of cancer in AYAs worldwide, most of whom do not live in high-income countries, remains a considerable challenge.

Morphologically, the distinction between undifferentiated embryonal sarcoma of the liver (UESL) and biliary tract rhabdomyosarcoma (RMS) can be uncertain because of some shared pathologic similarities. Patients with UESL have been consistently but erroneously enrolled in Children's Oncology Group (COG) treatment protocols because UESL was equated with RMS, despite the differing primary treatment modalities of these entities. Review of COG pathology files yielded 20 cases of UESL that were compared to 25 cases of biliary tract RMS. Clinicopathologic features including immunohistochemical staining were examined. In the UESL cases, the male:female ratio was 1:1 and the median age was 10.5 years. Histologically, hyaline globules and diffuse anaplasia were consistently present. The cases of RMS had a male:female ratio of 1.8:1 with a median age of 3.4 years and routinely lacked diffuse anaplasia and hyaline globules. Polyclonal desmin and muscle-specific actin were variably immunoreactive in UESL and RMS; however, myogenin and myogenic regulatory protein D1 (MyoD1) were uniformly negative in UESL and routinely positive in the majority of biliary tract RMS. Myogenin, in particular, was highly significant ( P = 0.0003) in distinguishing RMS from UESL. With a median follow-up of 8 months, 11 of 18 patients with UESL were still alive. The estimated 5-year survival for biliary tract RMS was 66%. Establishing the correct diagnosis of these distinct clinical and pathologic entities is important, as surgery alone may be curative in UESL, whereas initial chemotherapy is often recommended for the treatment of biliary tract RMS.

Each year, 70,000 adolescents and young adults (AYAs) between ages 15 and 39 years in the United States are diagnosed with cancer. In 2006, a National Cancer Institute (NCI) Progress Review Group (PRG) examined the state of science associated with cancer among AYAs. To assess the impact of the PRG and examine the current state of AYA oncology research, the NCI, with support from the LIVESTRONG Foundation, sponsored a workshop entitled “Next Steps in Adolescent and Young Adult Oncology” on September 16 and 17, 2013, in Bethesda, Maryland. This report summarizes the findings from the workshop, opportunities to leverage existing data, and suggestions for future research priorities. Multidisciplinary teams that include basic scientists, epidemiologists, trialists, biostatisticians, clinicians, behavioral scientists, and health services researchers will be essential for future advances for AYAs with cancer.

With prior reports indicating a lack of progress in survival improvement in older adolescents and young adults (AYAs) aged 15 to 39 years with cancer compared with both younger and older patients with cancer, the current analysis provides an update of survival trends of cancers among AYAs, children, and older adults.Data from the National Cancer Institute Surveillance, Epidemiology, and End Results database for 13 regions were used to ascertain survival trends of the 34 most frequent cancers diagnosed in AYAs compared with children and older adults.As of 2002 through 2006, the 5-year relative survival rate for all invasive cancers in AYAs was 82.5% (standard error, 0.2%). In AYAs, 14 cancers demonstrated evidence of a statistically significant improvement in their 5-year relative survival since 1992. Survival improved less in AYAs than in children for acute myeloid leukemia and medulloblastoma. Fourteen cancers had survival improvements that were found to be less in AYAs compared with older adults, including hepatic carcinoma, acute myeloid leukemia, high-grade astrocytoma, acute lymphocytic leukemia, pancreatic carcinoma, low-grade astrocytoma, gastric carcinoma, renal carcinoma, cancer of the oral cavity and pharynx, Hodgkin lymphoma, ovarian cancer, fibromatous sarcoma, other soft tissue sarcoma, and thyroid carcinoma.Improvements in the survival of several cancer types that occur frequently in AYAs are encouraging. However, survival does not appear to be improving to the same extent in AYAs as in children or older adults for several cancers. Further investment in exploring the distinct biology of tumors in this age group, and of their hosts, must be a priority in AYA oncology.

Between 1977 and 1991, the Children's Cancer Group and the National Cancer Institute conducted three trials of very high-dose methotrexate (33.6 g/m2; VHD-MTX) in place of cranial radiation (CRT) as central nervous system (CNS) preventive therapy, and assessed efficacy, acute toxicity and long-term neurocognitive outcome. CCG-191P compared VHD-MTX to CRT plus intrathecal methotrexate (IT-MTX) in 181 patients and demonstrated equivalent survival. However, patients treated with CRT had poorer performance on neurocognitive testing over time. CCG-134P evaluated the addition of intensified systemic and intrathecal therapy to VHD-MTX in 128 patients with high-risk acute lymphoblastic leukemia (ALL) and demonstrated reduced CNS relapse compared to the CCG-191P trial, but equivalent survival. CCG-144P compared VHD-MTX to IT-MTX alone in 175 patients with average-risk ALL and demonstrated equivalent survival. VHD-MTX was associated with significant toxicities, particularly neutropenia, transient hepatic dysfunction and sepsis. VHD-MTX achieved similar survival to other CNS-directed therapies without the long-term impact on intelligence, but with substantial acute toxicities.

The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. For this reason, a meeting partially funded by an NIH R13 grant was convened to discuss recent advances and future directions in translational research in neuro-oncology and the BBB. Cell biology and transport across the BBB, delivery of agents to the CNS, neuroimaging, angiogenesis, immunotherapy, and gene therapy, as well as glioma, primary CNS lymphoma, and metastases to the CNS were discussed. Transport across the BBB relates to the neurovascular unit, which consists not only of endothelial cells but also of pericyte, glia, and neuronal elements.

Background With an overall objective to improve the educational programs of pediatric cancer patients, the purpose of this study was to compare the quality of educational experiences of adolescent cancer patients undergoing treatment while enrolled in hospital, homebound, or community schools. Procedure Ten students, 12–17 years of age at diagnosis, their parent and their teachers were interviewed with a structured list of open-ended questions designed to assess their perceptions of their homebound, hospital, and community school experiences. The interviews were taped, transcribed, and analyzed using qualitative methods for recurring themes. Results High achieving students engaged in extracurricular activities prior to diagnosis performed well academically in all three schooling situations. Those less engaged in school prior to diagnosis did poorly in homebound schools, better in their community schools, and best in the hospital school. Conclusions Homebound learning during cancer therapy does not appear to be as meaningful as either hospital or community learning environments. Prior academic performance, as well as social, emotional, and health factors should be considered in selecting the most appropriate formal school environment for adolescent cancer patients. Med Pediatr Oncol 2003;40:380–384. © 2003 Wiley-Liss, Inc.

Objective: To investigate the relationship between birth weight and risk of early age childhood cancer and whether racial differences in birth weight distribution could explain differences in the incidence of cancer in white, Hispanic, and black children. Methods: We compared birth weights of 268 children younger than five years old and diagnosed with cancer in the State of Texas in 1995 to the birth weights of 2680 randomly selected, age-matched population-based controls. Birth weight, sex, race/ethnicity, maternal age, smoking status, parity, and gestational age information was ascertained from the birth certificates. Logistic regression analyses were performed to evaluate the association between high birth weight (> 4000 g) and occurrence of childhood cancer. Results: Increased odds ratios (OR) were found for “total cancer cases” (OR 1.4, 95% CI 0.9–2.1), “leukemia cases” (OR 1.7, 95% CI 0.9–3.0) and “acute lymphoblastic leukemia (ALL) cases” (OR 2.2, 95% CI 1.2–4.1). Increased ORs in the former two groups were shown to be due to ALL cases. Including the race/ethnicity variable in the regression model did not affect the ORs. Conclusion: Compared to newborns who weighed between 2500 and 4000 g at birth, children who weighed > 4000 g had an increased risk of developing childhood ALL during the first five years of life. Birth weight differences does not explain the sequence of childhood cancer incidence by race/ethnicity.

Cancer in adolescents and young adults has unique features in addition to the special medical, physical, psychological, and social needs of patients in this age group. The spectrum of malignant diseases is different from that in any other period in life, and it is strikingly different from the pattern in older persons. More people 15-25 years of age are diagnosed to have cancer than during the first 15 years of life. During the last 25 years, the incidence of cancer in this age range has increased faster while the increase in their cancer survival rates has been significantly lower than in younger or older patients, especially in comparison to results of the national pediatric cooperative cancer groups. Thus the 5-year outcome in 15-19 year olds with leukemias and sarcomas is not only worse than in younger patients, but also lower in this population at large than in patients of the same age treated at Children's Cancer Group institutions. In the United States, only approximately 5% of 15-25 year olds with cancer are entered onto clinical trials, in contrast to 60-65% of younger patients. Thus, cancer during adolescence and early adult life is an underestimated challenge that merits specific resources, solutions, and an international focus.

Purpose: This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. Patients and Methods: One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. Results: Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P 0.043; OS: 55% vs. 27%; P 0.012). Conclusions: Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IEcontaining regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 μmol•h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 μmol•h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P = .007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P = .043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

BACKGROUND Mass screening of infants for neuroblastoma began in Japan after studies suggested that survival rates could be improved by early detection. This study was initiated in 1991 to test the methodology and feasibility of screening for neuroblastoma within the U. S. health care system. METHODS Infants ages 5-10 months (mean age, 9 months, 25 days) who were born in Texas were screened for neuroblastoma. An enzyme-linked immunoadsorbent assay (ELISA) for homovanillic acid (HVA) and vanillylmandelic acid (VMA) used to quantify the HVA and VMA was performed on urine extracted from specimens dried on filter paper. Infants were recruited to participate in the study by several methods, and the effectiveness of each method was determined by calculating compliance rates. RESULTS Between February 1991 and June 1994 a total of 14,046 infants were recruited to participate in neuroblastoma screening. Neuroblastoma was detected in 2 children for an incidence rate of 1 in 7023. A total of 291,158 screening kits were distributed to the parents of these infants, resulting in an overall compliance rate of only 4.8%. Compliance rates varied by method of distribution of the test kits: Houston Women, Infants, and Children (WIC) clinic (53%), volunteers (31%), Rio Grande Valley WIC clinics (14.5%), the patient's private physician (9.9%), and by mail (4.7%). CONCLUSIONS Early detection of neuroblastoma in infants ages 5-10 months was achieved using ELISA. Compliance rates were poor, but clinics with a preventive health focus, such as the WIC clinics, achieved higher compliance rates than did private physicians. Cancer 1998;82:1593-602. © 1998 American Cancer Society.

BACKGROUND Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies. METHODS Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen. RESULTS Complete remission was induced in 97% of patients. The overall event free survival (EFS) ± the standard deviation was 60 ± 4% 6 years after diagnosis, in contrast to 36 ± 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 ± 7%. EFS was best on the NY (67 ± 7%) and the BFM (67 ± 6%) arms. These were significantly better than the EFS on the 2 LSA2-L2 regimens, with an EFS of 53 ± 8% (Regimen B) and 42 ± 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 ± 5% vs. 6 ± 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic. CONCLUSIONS The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes. Cancer 1998;82:600-612. © 1998 American Cancer Society.

The outcome of children with acute lymphoblastic leukemia (ALL) and bone marrow relapse has been unsatisfactory largely because of failure to prevent subsequent leukemia relapses. Ninety-six patients were enrolled and received vincristine, prednisone, L-asparaginase, and an anthracycline as reinduction therapy. Ninety-two patients were randomized to receive either daunomycin (DNR) or idarubicin (IDR). After achievement of second complete remission (CR2), maintenance chemotherapy included the same anthracycline, IDR or DNR, high-dose cytarabine, and escalating-dose methotrexate. Compared to DNR (45 mg/m2/week x 3), IDR (12.5 mg/m2/week x 3) was associated with prolonged myelosuppression and more frequent serious infections. Halfway through the study, the dose of IDR was reduced to 10 mg/m2. Overall, second remission was achieved in 71% of patients. Reinduction rate was similar for IDR and DNR. Reasons for induction failure differed; none of 15, 1 of 5, and 5 of 7 reinduction failures were due to infection for DNR, IDR (10 mg/m2), and IDR (12.5 mg/m2), respectively. Two-year event-free survival (EFS) was better among patients who received IDR (12.5 mg/m2) (27 +/- 18%) compared to DNR (10 +/- 8%, P = 0.05) and IDR (10 mg/m2) (6 +/- 12%, P = 0.02). However, after 3 years of follow-up, late events in the high-dose IDR group result in a similar EFS to the lower-dose IDR and DNR groups. In conclusion, IDR is an effective agent in childhood ALL. When used weekly at 12.5 mg/m2 during induction, the EFS outcome during the first 2 years of treatment appears better than lower-dose IDR or DNR (45 mg/m2), although this difference was not sustained at longer periods of follow-up. Increased hematopoietic toxicity seen at this dose might be reduced through the use of supportive measures, such as hematopoietins and intestinal decontamination.

Objective: To determine the current attitude about the use of minors as bone marrow donors in pediatric bone marrow transplantation (BMT) centers in North America. Study design: A questionnaire was mailed to 70 North American BMT centers. The questionnaire asked for opinions on a number of ethical and clinical issues pertaining to the use of minors as marrow donors. A case history was included and respondents were asked to check all appropriate answers listed in the survey. Results: Fifty-six (80%) of 70 centers responded. There was general consensus on many issues. Pediatricians endorse the validity of parental consent, even in potentially controversial situations. Most are prepared to extract marrow from young (about 6 months of age) infants and are willing to use the same donor more than once. There is general approval of performing BMT with experimental protocols, and the projected outcome of BMT does not affect the decision to use a minor as a marrow donor. There is less consensus regarding the optimal management of minors donating a large volume of bone marrow. Conclusion: This survey shows a fairly consistent attitude among pediatric BMT centers about the use of minors as marrow donors. The actual management of such donors was not evaluated in detail and requires further study.

Background. National data on childhood cancer is becoming more available, but there continues to be a paucity of information, Methods. The 1991 edition of Cancer Statistics Review was scrutinized for information on the status of pediatric cancers in the United States. Results. The evidence indicates that in the United States, cancer among children younger than 15 years of age is increasing in incidence. In this age group, cancer is increasing equally among whites and blacks and among girls and boys. In white children, the increase appears to be largely due to increases in acute lymphoblastic leukemia and tumors of the brain and nervous system, and not to changes in Wilms tumor, soft tissue and bone sarcomas, lymphomas and Hodgkin disease, or other common malignancies of childhood

On September 23, 2010, as a result of the Affordable Care Act (ACA), young adults throughout the United States younger than 26 years were required, with few exceptions, to have health insurance for the first time under a parent's insurance if the policy allows for dependent coverage. The ACA also provides for elimination of coverage denial for having had a previous diagnosis of cancer or other preexisting conditions as a result of the cancer and its therapy, provision of a minimum health benefits package including preventive services and professional counseling for obesity, alcohol and substance dependence, physical activity, and nutrition improvement. How these changes and the multiple other provisions of the ACA will affect young adults during the next decade is uncertain, but it has the potential to lead to earlier diagnosis of cancer, less invasive cancer therapy, better quality of survival, and higher cure rates. In the long run, it may also help prevent cancer, at least among the country's older population. A realistic appraisal of the obstacles to the implementation of the ACA in the age group may compromise many of the desired outcomes, however. Nonetheless, ACA has provisions that should reduce the cancer problem in young adult Americans, some of which are now in effect and most of which will become available during the current decade.

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, E-rosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/microliters, male predominance, and older age. This type of presentation of ALL is referred to as the "lymphoma syndrome" (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E-rosette-positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease-free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

The latent period to forelimb paresis following photon irradiation of the cervical spinal cord was evaluated in Sprague-Dawley rats ranging in age from 9 days to adulthood. The radiation was administered dorsally in single fractions, and in 15-day-old animals, to different lengths of the rostral cord and in doses ranging from 16 to 38 Gy. The duration of the latent period was found to be directly proportional to the age of the animal at the time of irradiation, and independent of radiation dose or the volume of the cervical cord which was irradiated. In the majority of paretic animals, the irradiated segment of the spinal cord demonstrated white matter necrosis. The results indicate that in the developing rat, the manifestations of radiation myelopathy are delayed by an interval determined in part by the age of the animal at the time of irradiation.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies accounting for a significant portion of cancers occurring in children, adolescents, and young adults. The incidence increases with age as children grow into young adults. While there are greater than 30 distinct diagnostic NHL entities classified by the World Health Organization (WHO), five diseases account for >90 % of cases in CAYA—Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, and primary mediastinal B-cell lymphoma. Other B-cell, T-cell, and NK-cell lymphomas have been described in CAYA, but the incidence is relatively low. Cure rates for CAYA with NHL range from 75 % to 90 % depending on risk stratification and are generally superior to outcomes in comparison to adult data. Inasmuch, there has been a paradigm shift to treat older adolescents and young adults on pediatric protocols, resulting in encouraging results. This chapter will review the clinical and biological characteristics of NHL occurring in CAYA, with particular focus on the nuances of disease in adolescents and young adults. The ultimate goal is to achieve the same excellent curative outcomes in adolescents and young adults that have been established in the pediatric literature.

Purpose To evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL). Patients and Methods We retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Children's Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002. Results The 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% ± 2.4% v 77% ± 0.6% (P = .02) and 26 ± 2.4 v 20 ± 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesity's hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients ≥ 10 years old at diagnosis; in this subset, obesity's adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients ≥ 10 years old, obesity's adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity. Conclusion Obesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

Incidence Cancer occurring between the ages of 15 and 30 years is 2.7 times more common than cancer occurring during the first 15 years of life, yet is much less common than cancer in older age groups, and accounts for just 2% of all invasive cancer. Cancer in adolescents and young adults is unique in the distribution of the types that occur. Hodgkin lymphoma, melanoma, testis cancer, female genital tract malignancies, thyroid cancer, soft-tissue sarcomas, non-Hodgkin lymphoma, leukemia, brain and spinal cord tumors, breast cancer, bone sarcomas, and nongonadal germ cell tumors account for 95% of the cancers in this age group. The frequency distribution of cancer types changes dramatically from age 15-30, such that the pattern at the youngest age does not resemble the one at the oldest. The incidence of cancer in this age group increased steadily during the past quarter century. This increase is declining and at the older end of the age range appears to be returning to the incidence of the 1970s. Males in the 15- to 29-year age group have been at higher risk of developing cancer, with the risk directly proportional to age. Non-Hispanic whites have had the highest risk of developing cancer during this phase of life, and Asians, American Indians and Native Alaskans the lowest. Males had a worse prognosis than females. African-Americans, American Indian/Alaska Natives had a worse prognosis than white non-Hispanics and Asians. MORTALITY & SURVIVAL: At the beginning of the last quarter century, the diagnosis of cancer in 15- to 29-year-olds carried a more favorable prognosis, on the average, relative to cancer at other ages. Since then, there has been a lack of progress in survival improvement among older adolescents and young adults relative to all other ages. Survival improvement trends portend a worse prognosis for young adults diagnosed with cancer today than 25 years ago. The survival deficit is increasing with longer follow-up of the survivors, and is worse in males. Among 15- to 29-year-olds, non-Hispanic whites had the best survival and African Americans/blacks had the worst survival, with a 20% difference apparent by 5 years. Asians/Pacific Islanders had the second best survival, with Hispanics and American Indians/Alaska Natives next in sequence. Risk factors In general, there are relatively scant data to support either an environmental causation or an inherited predisposition to cancer in this age group. The majority of cases of cancer occurring before age 30 appear to be spontaneous and unrelated to either carcinogens in the environment or family cancer syndromes. Overall, family cancer syndromes appear to account for less than 5% of the cases of cancer in the age group. Melanoma, cervical carcinoma and Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin and Burkitt lymphomas accounting for the majority of environmentally induced malignancies (ultraviolet light, human papillomavirus, human immunodeficiency virus, and Epstein-Barr virus, respectively). Ultimately, a larger proportion of cases may be attributable to specific factors or genetic predisposition, but at present, most cancer in this age group appears to be sporadic and random.

Purpose: Vinorelbine (Navelbine) is an orally absorbable Vinca with broad antitumor activity. It differs from other Vinca in that it is structurally modified on the catharanthine nucleus and has differential actions on tubulin that render it less neurotoxic than other compounds in this class. We conducted a phase I study of vinorelbine given the activity of Vinca alkaloids in many pediatric tumors. Experimental Design: We evaluated the safety and pharmacokinetics of oral and i.v. vinorelbine administered weekly × 6 in children (age, 2-17 years) with different tumors. Patients with disease involvement in the bone marrow were eligible but were stratified and dose-escalated separately. Oral vinorelbine (week 1) was administered as liquid-filled gelatin capsules at thrice the i.v. dose. Intravenous vinorelbine doses of 24 to 37.5 mg/m2 were administered on weeks 2 to 6. Results: The dose-limiting toxicity in patients without marrow involvement was reversible neutropenia. Common nonhematologic toxicities included ≤ grade 2 nausea/vomiting and increased hepatic transaminases. A higher mean i.v. ClTB was observed (1.75 ± 1.0 L/h/kg) compared with adult reports, with a mean t1/2B of 16.5 ± 9.7 hours. Mean oral bioavailability was 28.5 ± 22.5%. The apparent oral clearance (12.1 ± 13.0 L/h/kg) and volume of distribution (69.4 ± 30.6 L/kg) were substantially higher than in adults given similar oral doses. Conclusions: The maximum tolerated dose in children without bone marrow involvement was 30 mg/m2, similar to that reported in adults, with myelosuppression being the dose-limiting toxicity. Higher plasma clearance resulted in lower area under the plasma concentration-time curves at a given dose compared with that reported in adults.

To investigate the relationship between birth weight and risk of early age childhood cancer and whether racial differences in birth weight distribution could explain differences in the incidence of cancer in white, Hispanic, and black children.We compared birth weights of 268 children younger than five years old and diagnosed with cancer in the State of Texas in 1995 to the birth weights of 2680 randomly selected, age-matched population-based controls. Birth weight, sex, race/ethnicity, maternal age, smoking status, parity, and gestational age information was ascertained from the birth certificates. Logistic regression analyses were performed to evaluate the association between high birth weight (4,000 g) and occurrence of childhood cancer.Increased odds ratios (OR) were found for "total cancer cases" (OR 1.4, 95% CI 0.9-2.1), "leukemia cases" (OR 1.7, 95% CI 0.9-3.0) and "acute lymphoblastic leukemia (ALL) cases" (OR 2.2, 95% CI 1.2-4.1). Increased ORs in the former two groups were shown to be due to ALL cases. Including the race/ethnicity variable in the regression model did not affect the ORs.Compared to newborns who weighed between 2500 and 4000 g at birth, children who weighed4,000 g had an increased risk of developing childhood ALL during the first five years of life. Birth weight differences does not explain the sequence of childhood cancer incidence by race/ethnicity.

To determine whether adolescents with cancer, who in comparison to younger patients have a higher cancer incidence and lower mortality reduction, have equal access to national cancer clinical trials.The ethnic/racial distribution of 29,859 subjects20 years of age entered onto National Cancer Institute-sponsored clinical trials between January 1, 1991, and June 30, 1994, was compared with the expected distribution of patients of the same age in the United States.The Children's Cancer Group and Pediatric Oncology Group had 29,134 (97.6%) of the total study entries among20-year-old subjects during the 3.5 years of surveillance. The adult cooperative groups accounted for3% of the clinical trials entries in the 15-19-year age range. When analyzed nationally by region, the under-representation of the older adolescent subjects was universal. From other analyses, the two pediatric cooperative groups were estimated to have registered94% of the children15 years of age who were expected to have been diagnosed to have cancer, but only 21% of the cancer patients in the 15-19-year age group.The national pediatric cancer cooperative groups allow the majority of American children15 years of age and their families equal opportunity to access clinical cancer trials, regardless of race or ethnicity. Among patients 15-19 years of age, however,75% are not being enrolled by any cooperative group sponsored by the National Cancer Institute. Thus, older adolescents are disadvantaged with respect to access to the national clinical trials, regardless of their race or ethnicity.

Purpose : This study attempted to determine if central nervous system (CNS) disease at diagnosis is a poor prognostic factor in children with acute lymphoblastic leukemia (ALL) and whether 6 Gy of spinal irradiation is an adequate dose for these patients. Methods and Materials : Previously the Children's Cancer Group (CCG) treated patients with ALL and CNS disease at diagnosis with cranio (24 Gy)-spinal (12 Gy) irradiation, as well as systemic and intrathecal chemotherapy. In a series of CCG trials completed in 1989 the spinal dose was empirically reduced to 6 Gy for patients receiving systemic chemotherapy with an intensive consolidation phase to limit hematopoietic toxicity. The spinal dose was left at 12 Gy for patients treated with a less intensive consolidation phase. Results : With a median follow-up for surviving patients of 74 months, the 5-year event-free survival for 53 patients with CNS disease at diagnosis was 69 ± 13% (±2 standard deviations), similar to the value obtained for 3364 patients without CNS disease, 67 ± 2%. Corresponding values for 5-year survival were 77 ± 12% and 80 ± 1%, and for freedom from isolated first CNS relapse, 90 ± 9% and 94 ± 1%. Event-free survival, survival, and freedom from isolated first CNS relapse in the 6-Gy group were as good as in the 12-Gy group. Conclusion : CNS disease at diagnosis is not a poor prognostic factor for children with ALL who are treated with intensive systemic chemotherapy, craniospinal irradiation, and intrathecal chemotherapy. Six Gy is an adequate dose of spinal irradiation for these patients.

Importance Evidence from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database suggests that the incidence of advanced breast cancer in young women is increasing. Objective To quantify this trend and analyze it as a function of stage at diagnosis, race/ethnicity, residence, and hormone receptor status. Design, Setting, and Patients Breast cancer incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis were obtained from 3 SEER registries that provide data spanning 1973-2009, 1992-2009, and 2000-2009. SEER defines localized as disease confined to the breast, regional to contiguous and adjacent organ spread (eg, lymph nodes, chest wall), and distant disease to remote metastases (bone, brain, lung, etc). Main Outcome Measure Breast cancer incidence trends in the United States. Results In the United States, the incidence of breast cancer with distant involvement at diagnosis increased in 25- to 39-year-old women from 1.53 (95% CI, 1.01 to 2.21) per 100 000 in 1976 to 2.90 (95% CI, 2.31 to 3.59) per 100 000 in 2009. This is an absolute difference of 1.37 per 100 000, representing an average compounded increase of 2.07% per year (95% CI, 1.57% to 2.58%; P Conclusion and Relevance Based on SEER data, there was a small but statistically significant increase in the incidence of breast cancer with distant involvement in the United States between 1976 and 2009 for women aged 25 to 39 years, without a corresponding increase in older women.

An escalating-dose trial of idarubicin, used weekly for 3 doses in combination with vincristine, prednisone, and L-asparaginase (VPLI), to reinduce remission of childhood ALL at first bone marrow relapse was conducted by the Childrens Cancer Study Group (CCSG). The maximum tolerated dose (MTD) of idarubicin, used in the manner, was determined to be 12.5 mg/m2/dose. Twelve of 16 (75%) evaluable patients in first marrow relapse of ALL treated at a dose of 10 or 12.5 mg/m2 entered a second complete remission, compared to 41 of 69 evaluable patients (59%) treated in a comparable way with daunorubicin (30 mg/m2) (VPLD). Prolonged myelosuppression was observed in both groups, but the frequency of documented bacterial sepsis and the duration of required hospitalization were greater among patients treated with idarubicin. No additional toxicity, specifically attributable to idarubicin, was observed at these doses.

To treat children with acute lymphoblastic leukemia, the pediatric oncologist must have a basic understanding and appreciation of the clinical pharmacology of vincristine, methotrexate, 6-mercaptopurine, cytarabine (cytosine arabinoside), and corticosteroids. The treating physician should be cognizant of the inter- and intrapatient variabilities in the pharmacokinetics and clinical effects of each of the drugs. The pharmacokinetics of other cancer chemotherapy agents used in the treatment of childhood leukemia should also be known (doxorubicin, asparaginase, teniposide, and cyclophosphamide), but these agents are less commonly used or administered for a short period of the total treatment. Recent laboratory studies and clinical observations have suggested ways in which the agents could be administered more optimally. For the antimetabolites, these include limited bioavailability and the absence of a diurnal variation in oral methotrexate and 6-mercaptopurine, new antifolates with better pharmacological characteristics for oral administration, intravenous therapy with 6-mercaptopurine, and subcutaneous therapy with methotrexate. For corticosteroid therapy, dexamethasone appears to have an advantage over prednisone and prednisolone in treating leukemic cells in the central nervous system. Intrathecal chemotherapy for the prevention of meningeal leukemia is more effective if the dosage is based on the volume of the central nervous system instead of the body surface area. Exposure of systemic tissue to cytotoxic drug concentrations after intrathecal chemotherapy is substantial with methotrexate and negligible with cytarabine.

Vincristine was inadvertently injected into a thigh of three children. In each case the accident occurred as a result of the mixing of a syringe containing vincristine with a syringe of L-asparaginase which the patient was scheduled to receive on the same day. Within minutes, each patient was treated topically with cold compresses and the area was infiltrated with a solution of 8.4% sodium bicarbonate. Only one patient had discomfort of the thigh after the injection, none of the patients have had any sequelae, either acute or delayed. Measures to avoid mistaken injection of vincristine for asparaginase are readily achievable and have prevented recurrences of intramuscular vincristine administration at the institutions where they have been implemented. Nonetheless, other instances of intramuscular vincristine injection are anticipated and should be rapidly recognized and quickly managed with local applications of cold and sodium bicarbonate.

Relapses in children treated for acute lymphoblastic leukemia (ALL) have become significantly less common over the past 25 years as primary therapy has improved. In spite of our improved ability to identify children at higher risk of relapse and the use of therapy based on the relative risk of treatment failure, however, relapses do continue to occur. In the past, efforts to produce long-term disease-free survival in patients who have experienced a relapse have yielded a rather discouraging salvage rate ranging from about 10% for patients with bone marrow relapses to as high as 70% for patients with an initial testicular relapse (7). Patients with central nervous system (CNS) relapses have had an outcome somewhere between these values as summarized in a recent review (6). The report by Kumar et al. suggests that about half of the patients with an initial CNS relapse may be responsive to salvage therapy without major sequelae in terms of neurotoxicity (4). ity to detect and quantitate residual disease will be to clarify the progression of disease that leads up to and then follows an “isolated” CNS relapse (2). Whichever mechanism is operative, the successful management of CNS relapse requires therapy that addresses the CNS and the high probability of subsequent bone marrow relapse. Current therapy for newly diagnosed patients with ALL generally includes chemotherapy systemically and intrathec~ly to prevent CNS relapse. If i~adiation is used, it is generally reserved for patients with a high risk of relapse, perhaps 30% of the total population, and for those few patients presenting with CNS disease. In the series reported here, irradiation was deferred to enable moderate dose methotrexate to be given intravenously without a high risk of leukoencephalopathy. Patients who now develop a CNS relapse are quite likely to have not received prior irradiation, as in this series in which 17 of the 18 relapses occurred in unirradiated patients. By common convention we use the term isolated CNS The results of the study by Kumar and associates are relapse to refer to the presence of lymphoblasts present similar to prior trials of cr~iospinal radiotherapy for isoin the cerebra-spinal fluid with an increased cerebro-spilated meningeal retapse in children with acute lymphonal fluid cell count (or much less commonly a mass lesion blastic leukemia. Nearly 10 years ago, the Childrens Canproducing a focal neurologic deficit) in the absence of cer Group reported 60% 3-year survival among 95 childemonstrable leukemic cells elsewhere. The key word is dren with isolated meningeal relapse (l), which may be “demonstrable.” The observation that CNS relapse is compared with the 47-97% 95% confidence interval (our frequently followed by relapse in the bone marrow within estimate) for the corresponding rate in the study of 18 a relatively short period of time forces us to consider that patients by Kumar et al. This was achieved with intratheat the time of CNS relapse, many patients already have cal methotrexate alone during induction, rather than with lymphoblasts proliferating in the bone marrow, although the triple drug therapy used by Kumar and his colleagues, at a level too low to be detected by commonly available with a lower dose of spinal radiotherapy, 12 Gy, rather techniques. An alternative explanation for the pathogenethan with the 15 Gy used in the study reported herein, sis of the subsequent bone marrow relapse is that the and with maintenance intrathecal methotrexate at 3-month marrow is repopulated from lymphoblasts that have prointervals for 2 years. The use of craniospinal irradiation liferated in the meninges or in the cortical perivascular for treatment of CNS relapse dates back almost 20 years spaces and that because of their residence in these pharto a small but convincing study conducted by the British macologically protected sites, they may emerge from the Medical Research Council (8). In that trial, craniospinal CNS with a significant degree of drug resistance. A goal irradiation offered significant protection against subsefor future studies that use techniques that extend our abilquent CNS relapse as compared to cranial irradiation.