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1.  Risk of Salivary Gland Cancer Following Childhood Cancer: A Report From The Childhood Cancer Survivor Study 
Purpose
To evaluate effects of radiotherapy, chemotherapy, cigarette smoking and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS).
Methods
Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking and alcohol consumption.
Results
During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR=39.4; 95% CI: 25.4–7.8). The EAR was 9.8 per 100,000 person years. Risk increased linearly with radiation dose (excess relative risk=0.36 per gray; 95% CI: 0.06 to 2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking or alcohol intake.
Conclusion
While the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least two decades following exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.
doi:10.1016/j.ijrobp.2012.06.006
PMCID: PMC3500417  PMID: 22836059
2.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
Purpose
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
Results
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
Conclusion
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
doi:10.1200/JCO.2012.41.8996
PMCID: PMC3530689  PMID: 23169509
3.  Local Control with Reduced Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report from the Children’s Oncology Group D9602 Study 
Purpose
To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated on the COG D9602 study.
Methods and Materials
Patients with low-risk RMS were non-randomly assigned to receive radiotherapy doses dependent upon the completeness of surgical resection of the primary tumor (Clinical Group) and presence of involved regional lymph nodes. After resection most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primaries received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets that had a higher risk of relapse in IRSG III and IV studies.
Results
Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n=5) resulted in 3 failures for this group.
Conclusions
Compared to IRS III and IV results, reduced-dose radiotherapydoes not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected non-bladder GU tumors require radiotherapy for post-surgical residual tumor in order to achieve optimal local control.
doi:10.1016/j.ijrobp.2011.06.2011
PMCID: PMC3305826  PMID: 22104356
Rhabdomyosarcoma; Radiotherapy; Low-risk; Local Control
4.  The effect of radiation therapy techniques (IMRT vs. 3DCRT) on outcome in patients with intermediate risk rhabdomyosarcoma enrolled in COG D9803—A report from Children’s Oncology Group 
Purpose
To compare dosimetric parameters of intensity modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) in patients with intermediate risk rhabdomyosarcoma (RMS), and to analyze their effect on local-regional control (LRC) and failure-free survival (FFS).
Methods and Materials
The study population consisted of 375 patients enrolled on Children’s Oncology Group protocol D9803, receiving IMRT or 3DCRT. Dosimetric data was collected from 179 patients with an available composite plan. Chi-square or Fisher’s exact tests were used to compare patient characteristics and radiotherapy (RT) parameters between the two groups. Time-to- event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox analysis was used to examine the effect of RT technique on FFS after adjusting for primary site and risk group.
Results
The median follow-up time was 5.7 and 4.2 years for patients receiving 3DCRT and IMRT respectively. No differences in 5 year failure of LRC (18% vs. 15%) and FFS (72% vs. 76%) were noted between the two groups. Multivariate analysis revealed no association between RT technique and FFS. Patients with primary tumors in parameningeal (PM) sites were more likely to receive IMRT than 3DCRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50Gy, photon energy of ≤6MV, and >5 RT fields than those who received 3DCRT. There was improved coverage of the IMRT planning target volume (PTV) by the prescription dose compared to the 3DCRT with similar target dose heterogeneity.
Conclusions
IMRT improved target dose coverage when compared to 3DCRT, though an improvement in LRC or FFS could not be demonstrated in this population. Future studies comparing integral dose to non-target tissue and late RT toxicity between the two groups is warranted.
doi:10.1016/j.ijrobp.2011.01.036
PMCID: PMC3154985  PMID: 21470795
Rhabdomyosarcoma; Intermediate risk; IMRT/3DCRT
5.  Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):246-255.
Purpose
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Results
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Conclusion
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
doi:10.1200/JCO.2010.34.4267
PMCID: PMC3269951  PMID: 22184380
6.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
Background
While ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors, and the possible joint effects of chemotherapy and radiotherapy.
Methods
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated using life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Results
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses ≤ 20 Gy, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P-trend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses >20 Gy.
Conclusions
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range under 20 Gy, where cell sparing likely predominates over cell killing.
Impact
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
doi:10.1158/1055-9965.EPI-11-0576
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
7.  ASSOCIATION BETWEEN RADIOTHERAPY VS NO RADIOTHERAPY BASED ON EARLY RESPONSE TO VAMP CHEMOTHERAPY AND SURVIVAL AMONG CHILDREN WITH FAVORABLE RISK HODGKIN LYMPHOMA 
Context
Maintaining excellent cure rates in pediatric Hodgkin lymphoma while minimizing toxicity.
Objective
To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin, methotrexate, and prednisone (VAMP) in patients with favorable risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.
Design, Setting, and Patients
Multi-institutional, unblinded, non-randomized single group phase II clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (< 3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000 through December 9, 2008. Data frozen March 12, 2012.
Interventions
Patients who achieved a complete response (n=47) after 2 cycles received no radiotherapy, and those with less than complete response (n=41) were given 25.5 Gy involved field radiotherapy.
Main Outcome Measures
2-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low.
Results
Two-year event-free survival was 90.8% (95% CI, 84.7% – 96.9%); for patients who did not require radiotherapy it was 89.4% (95% CI, 80.8% – 98%), compared with 92.5% (95% CI, 84.5% – 100%) for those who did (P=0.61). Most common acute side effects were neuropathic pain (2% of patients), nausea/vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or non-neutropenic infection. Long term side effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each, subclinical pulmonary dysfunction in 12 patients (26%) and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.
Conclusions
Among patients with favorable risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited therapy resulted in a high rate of 2-year EFS.
doi:10.1001/jama.2012.5847
PMCID: PMC3526806  PMID: 22735430
8.  Local Control and Outcome in Children with Localized Vaginal Rhabdomyosarcoma: A Report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group 
Pediatric blood & cancer  2011;57(1):76-83.
Background
The local control approach for girls with non-resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Children’s Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection.
Procedures
We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies.
Results
Forty-one patients with localized vaginal RMS were enrolled: 25 onto D9602 and 16 onto Subset 2 of ARST0331. Only four of the 39 with non-resected tumors received RT. The 5-year cumulative incidence of local recurrence was 26% on D9602, and the 2-year cumulative incidence of local recurrence was 43% on ARST0331. Increased local failure rates appeared to correlate with chemotherapy regimens that incorporated lower cumulative doses of cyclophosphamide. Estimated 5-year and 2-year failure free survival rates were 70% (95% CI: 46%, 84%) on D9602 and 42% (95% CI: 11%, 70%) on ARST0331, respectively.
Conclusions
To prevent local recurrence, we recommend a local control approach for patients with non-resected RMS of the vagina that is similar to that used for other primary sites and includes RT. We recognize that potential long-term effects of RT are sometimes unacceptable, especially for children less than 24 months of age. However, when making the decision to eliminate RT, the risk of local recurrence must be considered especially when using a chemotherapy regimen with a total cumulative cyclophosphamide dose of ≤ 4.8 g/m2.
doi:10.1002/pbc.22928
PMCID: PMC3459820  PMID: 21298768
rhabdomyosarcoma; female; genitourinary; vagina; radiotherapy
9.  Rhabdomyosarcoma in Infants Less than One Year of Age: A Report from the Children’s Oncology Group 
Cancer  2011;117(15):3493-3501.
Background
Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been seen for infants diagnosed with RMS than for older children.
Methods
We analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants < 1 year of age with non-metastatic RMS who were treated with multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803.
Results
Seventy-six infants with non-metastatic RMS were treated on the 3 protocols from 1991 to 2005. Median age was 7.4 months (range 0.1–12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). Parameningeal primary site was less common in this infant cohort (3%) than for all patients treated on IRS-IV (25%). Estimated 5-year failure-free survival and overall survival (95% confidence intervals) are 57% (44%, 67%) and 76% (65%, 85%) for infants compared to 81% (79%, 83%) and 87% (85%, 89%) for ages 1–9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with (n=3) or without (n=20) distant failure. The overall local failure rate was 30%. Median time to treatment failure was 13 months. FFS was worse for infants with Group III tumors and for those who received less than protocol recommended radiation therapy.
Conclusions
Infants with RMS appear to have worse outcomes than older patients, in part due to high rates of local failure. Concerns regarding morbidity in infants and reluctance to perform aggressive local control measures may lead to higher rates of local failure.
doi:10.1002/cncr.25887
PMCID: PMC3140625  PMID: 21264837
pediatric; sarcoma; infant; radiotherapy; rhabdomyosarcoma
10.  Regional Nodal Involvement and Patterns of Spread Along In-transit Pathways in Children with Rhabdomyosarcoma of the Extremity: A Report from the Children's Oncology Group 
Purpose
To evaluate the incidence and prognostic factors for regional failure, with attention to in-transit pathways of spread, in children with non-metastatic rhabdomyosarcoma (RMS) of the extremity.
Materials/Methods
Intergroup Rhabdomyosarcoma Studies III, IV-Pilot, and IV enrolled 226 children with RMS of the extremity. Failure at in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) nodes were evaluated. Median follow-up for surviving patients is 10.4 years.
Results
Fifty-five (24%) of 226 children had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement (LNI) at diagnosis. The actuarial 5-year risk of regional failure is 12%. The prognostic factors for poor regional control are female gender and LNI at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit LNI at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure are 12% and 8%, respectively. The in-transit failure rate is 0% in patients who received radiation therapy and/or underwent lymph node sampling of the in-transit nodal site, but 15% in those who did not (p=0.07), although 5-year EFS did not differ between these two groups (64% vs. 55%, p=0.47).
Conclusions
The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in RMS of the extremity. In patients with distal extremity tumors, in-transit failures are as common as failures in more proximal regional sites. Patients who undergo complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, are at a slightly lower risk of in-transit failure.
doi:10.1016/j.ijrobp.2010.03.050
PMCID: PMC3116031  PMID: 20542386
rhabdomyosarcoma; regional failure; in-transit nodes; radiation therapy; extremity
11.  Local therapy for rhabdomyosarcoma of the hands and feet: Is amputation necessary? A report from the Children's Oncology Group 
Purpose
To evaluate the outcome of children with rhabdomyosarcoma (RMS) of the hand or foot treated with surgery and/or local radiotherapy (RT).
Methods
Forty-eight patients with non-metastatic RMS of the hand or foot were enrolled on Intergroup Rhabdomyosarcoma Study Group III, IV-Pilot, and IV. Patients received multi-agent chemotherapy with surgery and/or RT. Twenty-four patients (50%) underwent surgery without local RT, of whom 4 had complete resection and 20 had an amputation. The remaining 24 patients (50%) underwent local RT, of whom 2 required RT for microscopic residual disease following prior amputation. Median follow-up for surviving patients is 9.7 years.
Results
Actuarial 10-year local control is 100%; 10-year event-free (EFS) and overall survival (OS) are 62% and 63%, respectively. Poor prognostic factors for recurrence include gross residual (Group III) disease and nodal involvement (p=0.01 and 0.05, respectively). More patients in the RT group had alveolar histology, Group III disease, and nodal involvement, as compared to the surgery group. There is no difference in 10-year EFS (57% vs. 66%) or OS (63% vs. 63%) between patients who underwent surgery or local RT. Among relapsing patients, there are no long-term survivors. No secondary malignancies have been observed.
Conclusions
Despite having high-risk features, patients treated with local RT achieved excellent local control. Complete surgical resection without amputation is difficult to achieve in the hand or foot. Therefore, we recommend either definitive RT or surgical resection which maintains form and function as primary local therapy rather than amputation in patients with hand or foot rhabdomyosarcoma.
doi:10.1016/j.ijrobp.2010.01.053
PMCID: PMC3075377  PMID: 20646853
Rhabdomyosarcoma; local control; radiotherapy; amputation
12.  DECREASED FERTILITY AMONG FEMALE CHILDHOOD CANCER SURVIVORS WHO RECEIVED 22 TO 27 Gy HYPOTHALAMIC/PITUITARY IRRADIATION. A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY 
Fertility and sterility  2011;95(6):1922-1927.e1.
Objective
To evaluate the effect of hypothalamic/pituitary radiation dose on the occurrence of first pregnancy
Design
Retrospective cohort study of childhood cancer five-year survivors (CCS) diagnosed between 1970 and 1986 prior to 21 years of age at one of 26 North American pediatric cancer treatment centers
Setting
Self-administered questionnaire
Patient(s)
3619 female CCS who participated in the Childhood Cancer Survivor Study and received no/scatter (≤ 0.1 Gy) radiation to the ovaries and 2081 female siblings (Sibs) of the participants
Intervention(s)
None
Main Outcome Measure(s)
Self-reported pregnancy events
Result(s)
As a group CCS were as likely to report being pregnant as Sibs (Hazard Ratio (HR), 1.07; 95% Confidence Interval (95%CI), 0.97 to 1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses ≥ 22 Gy compared with those CCS receiving no HPT RT.
Conclusion(s)
These results support the hypothesis that exposures of 22 to 27 Gy HPT RT may be a contributing factor to infertility among female CCS.
doi:10.1016/j.fertnstert.2011.02.002
PMCID: PMC3080448  PMID: 21376314
childhood cancer survivor; hypothalamic irradiation; pituitary irradiation; alkylating agent; pregnancy
13.  Prognostic Significance and Tumor Biology of Regional Lymph Node Disease in Patients With Rhabdomyosarcoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2011;29(10):1304-1311.
Purpose
Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS.
Patients and Methods
Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients).
Results
Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS.
Conclusion
RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.
doi:10.1200/JCO.2010.29.4611
PMCID: PMC3083998  PMID: 21357792
14.  Resectable Pediatric Nonrhabdomyosarcoma Soft Tissue Sarcoma: Which Patients Benefit from Adjuvant Radiation Therapy and How Much? 
ISRN Oncology  2012;2012:341408.
It remains unclear which children and adolescents with resected nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) benefit from radiation therapy, as well as the optimal dose, volume, and timing of radiotherapy when used with primary surgical resection. This paper reviews the sparse literature from clinical trials and retrospective studies of resected pediatric NRSTS to discern local recurrence rates in relationship to the use of radiation therapy.
doi:10.5402/2012/341408
PMCID: PMC3316976  PMID: 22523704
15.  Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort 
Objectives To assess the incidence of and risks for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities among adult survivors of childhood and adolescent cancers.
Design Retrospective cohort study.
Setting 26 institutions that participated in the Childhood Cancer Survivor Study.
Participants 14 358 five year survivors of cancer diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. Comparison group included 3899 siblings of cancer survivors.
Main outcome measures Participants or their parents (in participants aged less than 18 years) completed a questionnaire collecting information on demographic characteristics, height, weight, health habits, medical conditions, and surgical procedures occurring since diagnosis. The main outcome measures were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings.
Results Survivors of cancer were significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001), myocardial infarction (HR 5.0, 95% CI 2.3 to 10.4; P<0.001), pericardial disease (HR 6.3, 95% CI 3.3 to 11.9; P<0.001), or valvular abnormalities (HR 4.8, 95% CI 3.0 to 7.6; P<0.001). Exposure to 250 mg/m2 or more of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1500 centigray or more increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold compared to non-irradiated survivors. The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis.
Conclusion Survivors of childhood and adolescent cancer are at substantial risk for cardiovascular disease. Healthcare professionals must be aware of these risks when caring for this growing population.
doi:10.1136/bmj.b4606
PMCID: PMC3266843  PMID: 19996459
16.  Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study 
Radiation research  2010;174(6):741-752.
Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose–response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8–31.5). At thyroid radiation doses >20 Gy, a downturn in the dose–response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.
doi:10.1667/RR2240.1
PMCID: PMC3080023  PMID: 21128798
17.  Randomized Phase II Window Trial of Two Schedules of Irinotecan With Vincristine in Patients With First Relapse or Progression of Rhabdomyosarcoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2010;28(30):4658-4663.
Purpose
To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression.
Patients and Methods
Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m2/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m2 administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m2/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen.
Results
Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%).
Conclusion
There was no difference in the response rates between the two irinotecan-vincristine schedules. We recommend the shorter, more convenient regimen (1B) for further investigation.
doi:10.1200/JCO.2010.29.7390
PMCID: PMC2974343  PMID: 20837952
18.  Treatment Results for Patients with Localized, Completely Resected (Group I) Alveolar Rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols -III and -IV, 1984-1997: A Report from the Children’s Oncology Group 
Pediatric blood & cancer  2010;55(4):612-616.
Purpose
To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols -III and -IV, 1984-1997.
Methods
Chart review and standard statistical procedures.
Patients and Tumors
Patients were 1 to 18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N=54), head/neck (N=9), genitourinary tract (N=7), and perineum (N=1). Thirty patients received VA±C with RT; 41 received VA±C alone. RT was assigned, not randomized.
Results
54 patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, ≤5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P=0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients.
Conclusion
Patients with Stages 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stages 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.
doi:10.1002/pbc.22520
PMCID: PMC3128801  PMID: 20806360
Soft Tissue Sarcoma; Rhabdomyosarcoma; Pediatric Oncology
19.  Early Treatment Failure in Intermediate-Risk Rhabdomyosarcoma: Results From IRS-IV and D9803—A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2010;28(27):4228-4232.
Purpose
The goal of this study was to determine the frequency and clinical features of early treatment failure during induction chemotherapy before protocol radiation therapy for children with intermediate-risk rhabdomyosarcoma (RMS).
Patients and Methods
Patients with intermediate-risk RMS enrolled onto the Intergroup Rhabdomyosarcoma Study-IV and the Children's Oncology Group D9803 study were reviewed for an early treatment failure. Early failure was defined as failure caused by progressive disease, death as a result of progressive disease, or death as a result of other causes occurring fewer than 120 days from study entry. Patients with parameningeal site RMS with high-risk features who received radiation therapy at week 1 were excluded from analysis. Overall survival (OS) was estimated using the Kaplan-Meier method. Fisher's exact test was used to compare differences between groups. Cumulative incidence of progression was estimated.
Results
Of 916 patients, 20 (2.2%) were found to have an early disease progression and did not receive planned protocol radiotherapy. Three additional early failures resulted from treatment-related death without progression. Median time to failure was 48 days (range, 7 to 106 days). Nineteen (95%) of the 20 patients experienced progression at their primary site. Five-year OS was 32% (95% CI, 12% to 54%) for patients experiencing an early progression.
Conclusion
A small proportion of patients with intermediate-risk RMS suffer an early failure as a result of early progression (2.2%) or treatment-related mortality (0.3%). The majority of patients with early progression had a local failure. Earlier radiotherapy could potentially improve outcome by preventing early local progression.
doi:10.1200/JCO.2010.29.0247
PMCID: PMC2953975  PMID: 20713850
20.  Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study 
Background
The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages.
Methods
The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14 359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5–56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression.
Results
Among 14 359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm.
Conclusions
As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.
doi:10.1093/jnci/djq238
PMCID: PMC2907408  PMID: 20634481
21.  Fertility of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;28(2):332-339.
Purpose
This study was undertaken to determine the effect of treatment for childhood cancer on male fertility.
Patients and Methods
We reviewed the fertility of male Childhood Cancer Survivor Study survivor and sibling cohorts who completed a questionnaire. We abstracted the chemotherapeutic agents administered, the cumulative dose of drug administered for selected drugs, and the doses and volumes of all radiation therapy from medical records. Risk factors for siring a pregnancy were evaluated using Cox proportional hazards models.
Results
The 6,224 survivors age 15 to 44 years who were not surgically sterile were less likely to sire a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI, −0.49 to 0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy of more than 7.5 Gy to the testes (HR, 0.12; 95% CI, −0.02 to 0.64), higher cumulative alkylating agent dose (AAD) score or treatment with cyclophosphamide (third tertile HR, 0.42; 95% CI, −0.31 to 0.57) or procarbazine (second tertile HR, 0.48; 95% CI, −0.26 to 0.87; third tertile HR, 0.17; 95% CI, −0.07 to 0.41). Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0, a hypothalamic/pituitary radiation dose = 0 Gy, and a testes radiation dose = 0 Gy was 0.91 (95% CI, 0.73 to 1.14; P = .41).
Conclusion
This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.
doi:10.1200/JCO.2009.24.9037
PMCID: PMC2815721  PMID: 19949008
22.  Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803 
Journal of Clinical Oncology  2009;27(31):5182-5188.
Purpose
The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC).
Patients and Methods
Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC.
Results
A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups.
Conclusion
For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.
doi:10.1200/JCO.2009.22.3768
PMCID: PMC2773476  PMID: 19770373
23.  Neurocognitive Status in Long-Term Survivors of Childhood CNS Malignancies: A Report from the Childhood Cancer Survivor Study 
Neuropsychology  2009;23(6):705-717.
Background
Among survivors of childhood cancer, those with Central Nervous System (CNS) malignancies have been found to be at greatest risk for neuropsychological dysfunction in the first few years following diagnosis and treatment. This study follows survivors to adulthood to assess the long term impact of childhood CNS malignancy and its treatment on neurocognitive functioning.
Participants & Methods
As part of the Childhood Cancer Survivor Study (CCSS), 802 survivors of childhood CNS malignancy, 5937 survivors of non-CNS malignancy and 382 siblings without cancer completed a 25 item Neurocognitive Questionnaire (CCSS-NCQ) at least 16 years post cancer diagnosis assessing task efficiency, emotional regulation, organizational skills and memory. Neurocognitive functioning in survivors of CNS malignancy was compared to that of non-CNS malignancy survivors and a sibling cohort. Within the group of CNS malignancy survivors, multiple linear regression was used to assess the contribution of demographic, illness and treatment variables to reported neurocognitive functioning and the relationship of reported neurocognitive functioning to educational, employment and income status.
Results
Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all factors assessed by the CCSS-NCQ than non-CNS cancer survivors or siblings (p<.01), with mean T scores of CNS malignancy survivors substantially more impaired that those of the sibling cohort (p<.001), with a large effect size for Task Efficiency (1.16) and a medium effect size for Memory (.68). Within the CNS malignancy group, medical complications, including hearing deficits, paralysis and cerebrovascular incidents resulted in a greater likelihood of reported deficits on all of the CCSS-NCQ factors, with generally small effect sizes (.22-.50). Total brain irradiation predicted greater impairment on Task Efficiency and Memory (Effect sizes: .65 and .63, respectively), as did partial brain irradiation, with smaller effect sizes (.49 and .43, respectively). Ventriculoperitoneal (VP) shunt placement was associated with small deficits on the same scales (Effect sizes: Task Efficiency .26, Memory .32). Female gender predicted a greater likelihood of impaired scores on 2 scales, with small effect sizes (Task Efficiency .38, Emotional Regulation .45), while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor with a moderate effect size (.64). CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p<.01), less household income (p<.001) and less full time employment (p<.001).
Conclusions
Survivors of childhood CNS malignancy are at significant risk for impairment in neurocognitive functioning in adulthood, particularly if they have received cranial radiation, had a VP shunt placed, suffered a cerebrovascular incident or are left with hearing or motor impairments. Reported neurocognitive impairment adversely affected important adult outcomes, including education, employment, income and marital status.
doi:10.1037/a0016674
PMCID: PMC2796110  PMID: 19899829
Neurocognitive functioning; brain tumors; CNS malignancies; Childhood Cancer Survivor Study
24.  Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;27(24):3901-3907.
Purpose
The purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer.
Methods
We conducted a case-control study of breast cancer in a cohort of 6,647 women who were 5-year survivors of childhood cancer and who were treated during 1970 through 1986. One hundred twenty patients with histologically confirmed breast cancer were identified and were individually matched to four selected controls on age at initial cancer and time since initial cancer. Medical physicists estimated radiation dose to the breast tumor site and ovaries on the basis of medical records.
Results
The odds ratio for breast cancer increased linearly with radiation dose, and it reached 11-fold for local breast doses of approximately 40 Gy relative to no radiation (P for trend < .0001). Risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries (P = .002). The excess odds ratio per Gy was 0.36 for those who received ovarian doses less than 5 Gy and was 0.06 for those who received higher doses. Radiation-related risk did not vary significantly by age at exposure. Borderline significantly elevated risks were seen for doxorubicin, dactinomycin, dacarbazine, and carmustine.
Conclusion
Results confirm the radiation sensitivity of the breast in girls age 10 to 20 years but do not demonstrate a strong effect of age at exposure within this range. Irradiation of the ovaries at doses greater than 5 Gy seems to lessen the carcinogenic effects of breast irradiation, most likely by reducing exposure of radiation-damaged breast cells to stimulating effects of ovarian hormones.
doi:10.1200/JCO.2008.20.7738
PMCID: PMC2734395  PMID: 19620485
25.  Long-Term Outcomes Among Adult Survivors of Childhood Central Nervous System Malignancies in the Childhood Cancer Survivor Study 
Background
Adult survivors of childhood central nervous system (CNS) malignancies are at high risk for long-term morbidity and late mortality. However, patterns of late mortality, the long-term risks of subsequent neoplasms and debilitating medical conditions, and sociodemographic outcomes have not been comprehensively characterized for individual diagnostic and treatment groups.
Methods
We collected information on treatment, mortality, chronic medical conditions, and neurocognitive functioning of adult 5-year survivors of CNS malignancies diagnosed between 1970 and 1986 within the Childhood Cancer Survivor Study. Using competing risk framework, we calculated cumulative mortality according to cause of death and cumulative incidence of subsequent neoplasms according to exposure and dose of cranial radiation therapy (RT). Neurocognitive impairment and socioeconomic outcomes were assessed with respect to dose of CNS radiotherapy to specific brain regions. Cumulative incidence of chronic medical conditions was compared between survivors and siblings using Cox regression models. All tests of statistical significance were two-sided.
Results
Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI] = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease. Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis. Neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage.
Conclusions
Survivors of childhood CNS malignancies are at high risk for late mortality and for developing subsequent neoplasms and chronic medical conditions. Care providers should be informed of these risks so they can provide risk-directed care and develop screening guidelines.
doi:10.1093/jnci/djp148
PMCID: PMC2704230  PMID: 19535780

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