Clinical Focus

  • Cancer > Cutaneous (Dermatologic) Oncology
  • Cancer > Lymphoma
  • Cancer > Radiation Oncology
  • Sarcomas - Radiation Oncology
  • Bone Cancer
  • Basal / Squamous Cell Carcinomas - Radiation Oncology
  • Brain / Central Nervous System Tumors
  • Brain / Central Nervous System Tumors - Radiation Oncology
  • Breast Cancer
  • Breast Cancer - Radiation Oncology
  • Burkitt's Lymphoma
  • Burkitt's Lymphoma - Radiation Oncology
  • Childhood Cancers
  • Eye / Orbital Cancer
  • Eye / Orbital Cancer - Benign
  • Eye / Orbital Cancer - Malignancies
  • Germ Cell Tumors
  • Germ Cell Tumors - Radiation Oncology
  • Hodgkin's Disease
  • Hodgkin's Disease - Radiation Oncology
  • Leukemia
  • Leukemia - Radiation Oncology
  • Lymphoma
  • Melanoma
  • Melanoma - Radiation Oncology
  • Multiple Myeloma
  • Multiple Myeloma - Radiation Oncology
  • Non-Hodgkin's Lymphoma
  • Non-Hodgkin's Lymphoma - Radiation Oncology
  • Osteosarcoma
  • Pediatric Cancers
  • Pigmented Skin Lesions
  • Pigmented Skin Lesions - Radiation Oncology
  • Pituitary Adenomas
  • Pituitary Adenomas - Radiation Oncology
  • Radiation Oncology
  • Sarcomas - Bone
  • Sarcomas - Bone - Radiation Oncology
  • Sarcomas - Soft Tissue
  • Sarcomas - Soft Tissue - Radiation Oncology
  • Skin Cancer
  • Skin Cancer - Radiation Oncology
  • Therapeutic Radiology
  • Thyroid Cancers
  • Thyroid Cancers - Radiation Oncology
  • sarcoma

Administrative Appointments

  • Associate Chair, Stanford University School of Medicine - Radiation Oncology (1997 - 2011)
  • Chief, Radiation Oncology Service, Lucile Packard Children's Hospital, Stanford Hospital and Clinics (1991 - Present)
  • Associate Residency Program Director, Department of Radiation Oncology (2009 - Present)

Honors & Awards

  • Radiation Oncology Orator, Radiological Society of North America (1995)
  • Marie Curie Award, American Association for Women Radiologists (1998)
  • Member, Institute of Medicine (1999)
  • Janeway lecturer and Gold medal recipient, American Radium Society (1999)
  • Gold medal, American Society of Therapeutic Radiology and Oncology (2000)
  • Elizabeth Blackwell Award, American Medical Women's Association (2005)
  • Gold Medal, American College of Radiology (2007)
  • Pediatric Oncology Award, American Society of Clinical Oncology (2007)
  • Inaugural Lecture, Pediatric Radiation Oncology Society (2009)

Professional Education

  • Fellowship:MD Anderson Cancer Center (1971) TX
  • Internship:University of Washington School of Medicine (1969) WA
  • Board Certification: Therapeutic Radiology, American Board of Radiology (1974)
  • Fellowship:Institut Gustave-Roussy (1973) France
  • Residency:Stanford University Medical Center (1972) CA
  • Medical Education:Harvard Medical School (1968) MA
  • M.D., Harvard Medical School (1968)

Research & Scholarship

Current Research and Scholarly Interests

Combined Modality Treatment of Cancer
Late Effects of Treatment
Genetic Effects of Cancer
Hodgkins Disease
Pediatric Radiation Oncolgy
Pediatric Oncolgy
Breast Cancer
Conformal Radiotherapy/IMRT
Radiotherapy for Benign Diseases


2015-16 Courses


All Publications

  • Relapse after treatment of pediatric hodgkin lymphoma: Outcome and role of surveillance after end of therapy PEDIATRIC BLOOD & CANCER Friedmann, A. M., Wolfson, J. A., Hudson, M. M., Weinstein, H. J., Link, M. P., Billett, A., Larsen, E. C., Yock, T., Donaldson, S. S., Marcus, K., Krasin, M. J., Howard, S. C., Metzger, M. L. 2013; 60 (9): 1458-1463


    The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well defined.We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse.Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival.In pediatric HL, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted.

    View details for DOI 10.1002/pbc.24568

    View details for Web of Science ID 000321703900078

  • Low-dose radiation therapy (2 Gy × 2) in the treatment of orbital lymphoma. International journal of radiation oncology, biology, physics Fasola, C. E., Jones, J. C., Huang, D. D., Le, Q., Hoppe, R. T., Donaldson, S. S. 2013; 86 (5): 930-935


    PURPOSE: Low-dose radiation has become increasingly used in the management of indolent non-Hodgkin lymphoma (NHL), but has not been studied specifically for cases of ocular adnexal involvement. The objective of this study is to investigate the effectiveness of low-dose radiation in the treatment of NHL of the ocular adnexa. METHODS AND MATERIALS: We reviewed the records of 20 NHL patients with 27 sites of ocular adnexal involvement treated with low-dose radiation consisting of 2 successive fractions of 2 Gy at our institution between 2005 and 2011. The primary endpoint of this study is freedom from local relapse (FFLR). RESULTS: At a median follow-up time of 26 months (range 7-92), the overall response rate for the 27 treated sites was 96%, with a complete response (CR) rate of 85% (n=23) and a partial response rate of 11% (n=3). Among all treated sites with CR, the 2-year FFLR was 100%, with no in-treatment field relapses. The 2-year freedom from regional relapse rate was 96% with 1 case of relapse within the ipsilateral orbit (outside of the treatment field). This patient underwent additional treatment with low-dose radiation of 4 Gy to the area of relapse achieving a CR and no evidence of disease at an additional 42 months of follow-up. Orbital radiation was well tolerated with only mild acute side effects (dry eye, conjunctivitis, transient periorbital edema) in 30% of treated sites without any reports of long-term toxicity. CONCLUSIONS: Low-dose radiation with 2 Gy × 2 is effective and well tolerated in the treatment of indolent NHL of the ocular adnexa with high response rates and durable local control with the option of reirradiation in the case of locoregional relapse.

    View details for DOI 10.1016/j.ijrobp.2013.04.035

    View details for PubMedID 23726002

  • Low-Dose Radiation Therapy (2 Gy x 2) in the Treatment of Orbital Lymphoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Fasola, C. E., Jones, J. C., Huang, D. D., Quynh-Thu Le, Q. T., Hoppe, R. T., Donaldson, S. S. 2013; 86 (5): 930-935
  • Changes in Health Status Among Aging Survivors of Pediatric Upper and Lower Extremity Sarcoma: A Report From the Childhood Cancer Survivor Study ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION Marina, N., Hudson, M. M., Jones, K. E., Mulrooney, D. A., Avedian, R., Donaldson, S. S., Popat, R., West, D. W., Fisher, P., Leisenring, W., Stovall, M., Robison, L. L., Ness, K. K. 2013; 94 (6): 1062-1073


    To evaluate health status and participation restrictions in survivors of childhood extremity sarcomas.Members of the Childhood Cancer Survivor Study cohort with extremity sarcomas who completed questionnaires in 1995, 2003, or 2007 were included.Cohort study of survivors of extremity sarcomas.Childhood extremity sarcoma survivors (N=1094; median age at diagnosis, 13y (range, 0-20y); current age, 33y (range, 10-53y); 49% male; 87.5% white; 75% had lower extremity tumors) who received their diagnosis and treatment between 1970 and 1986.Not applicable.Prevalence rates for poor health status in 6 domains and 5 suboptimal social participation categories were compared by tumor location and treatment exposure with generalized estimating equations adjusted for demographic/personal factors and time/age.In adjusted models, when compared with upper extremity survivors, lower extremity survivors had an increased risk of activity limitations but a lower risk of not completing college. Compared with those who did not have surgery, those with limb-sparing (LS) and upper extremity amputations (UEAs) were 1.6 times more likely to report functional impairment, while those with an above-the-knee amputation (AKA) were 1.9 times more likely to report functional impairment. Survivors treated with LS were 1.5 times more likely to report activity limitations. Survivors undergoing LS were more likely to report inactivity, incomes <$20,000, unemployment, and no college degree. Those with UEAs more likely reported inactivity, unmarried status, and no college degree. Those with AKA more likely reported no college degree. Treatment with abdominal irradiation was associated with an increased risk of poor mental health, functional impairment, and activity limitation.Treatment of lower extremity sarcomas is associated with a 50% increased risk for activity limitations; upper extremity survivors are at a 10% higher risk for not completing college. The type of local control influences health status and participation restrictions. Both of these outcomes decline with age.

    View details for DOI 10.1016/j.apmr.2013.01.013

    View details for Web of Science ID 000319954400008

  • Risk of Salivary Gland Cancer After Childhood Cancer: A Report From the Childhood Cancer Survivor Study INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Boukheris, H., Stovall, M., Gilbert, E. S., Stratton, K. L., Smith, S. A., Weathers, R., Hammond, S., Mertens, A. C., Donaldson, S. S., Armstrong, G. T., Robison, L. L., Neglia, J. P., Inskip, P. D. 2013; 85 (3): 776-783


    To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS).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.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 = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) 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.Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after 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.

    View details for DOI 10.1016/j.ijrobp.2012.06.006

    View details for Web of Science ID 000314687000044

    View details for PubMedID 22836059

  • Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer JOURNAL OF CLINICAL ONCOLOGY Kovalchik, S. A., Ronckers, C. M., Veiga, L. H., Sigurdson, A. J., Inskip, P. D., de Vathaire, F., Sklar, C. A., Donaldson, S. S., Anderson, H., Bhatti, P., Hammond, S., Leisenring, W. M., Mertens, A. C., Smith, S. A., Stovall, M., Tucker, M. A., Weathers, R. E., Robison, L. L., Pfeiffer, R. M. 2013; 31 (1): 119-127


    We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.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.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).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.

    View details for DOI 10.1200/JCO.2012.41.8996

    View details for Web of Science ID 000312911900025

    View details for PubMedID 23169509

  • Finding the Balance in Pediatric Hodgkin's Lymphoma JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S. 2012; 30 (26): 3158-3159

    View details for DOI 10.1200/JCO.2012.42.6890

    View details for Web of Science ID 000308707100009

    View details for PubMedID 22649142

  • Association Between Radiotherapy vs No Radiotherapy Based on Early Response to VAMP Chemotherapy and Survival Among Children With Favorable-Risk Hodgkin Lymphoma JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Metzger, M. L., Weinstein, H. J., Hudson, M. M., Billett, A. L., Larsen, E. C., Friedmann, A., Howard, S. C., Donaldson, S. S., Krasin, M. J., Kun, L. E., Marcus, K. J., Yock, T. I., Tarbell, N., Billups, C. A., Wu, J., Link, M. P. 2012; 307 (24): 2609-2616


    More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects.To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.Multi-institutional, unblinded, nonrandomized single group phase 2 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, and December 9, 2008. Follow-up data are current to March 12, 2012.The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy.Two-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.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%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or 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 nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free Identifier: NCT00145600.

    View details for Web of Science ID 000305692600029

    View details for PubMedID 22735430

  • Local Control With Reduced-Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group D9602 Study INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Breneman, J., Meza, J., Donaldson, S. S., Raney, R. B., Wolden, S., Michalski, J., Laurie, F., Rodeberg, D. A., Meyer, W., Walterhouse, D., Hawkins, D. S. 2012; 83 (2): 720-726


    To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study.Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the 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 primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies.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 three failures for this group.In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does 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 nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.

    View details for DOI 10.1016/j.ijrobp.2011.06.2011

    View details for Web of Science ID 000303920800058

    View details for PubMedID 22104356

  • A Tribute to Malcolm A. Bagshaw-An Innovative Physician Who Soared to Success INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Hoppe, R. T., Donaldson, S. S. 2012; 83 (1): 6-7

    View details for DOI 10.1016/j.ijrobp.2012.02.010

    View details for Web of Science ID 000302993900023

    View details for PubMedID 22516381



    To compare the dosimetric parameters of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in patients with intermediate-risk rhabdomyosarcoma and to analyze their effect on locoregional control and failure-free survival (FFS).The study population consisted of 375 patients enrolled in the Children's Oncology Group protocol D9803 study, receiving IMRT or 3D-CRT. Dosimetric data were collected from 179 patients with an available composite plan. The chi-square test or Fisher's exact test was used to compare the patient characteristics and radiotherapy parameters between the two groups. The interval-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards regression analysis was used to examine the effect of the treatment technique on FFS after adjusting for primary site and risk group.The median follow-up time was 5.7 and 4.2 years for patients receiving 3D-CRT and IMRT, respectively. No differences in the 5-year failure of locoregional control (18% vs. 15%) or FFS (72% vs. 76%) rates were noted between the two groups. Multivariate analysis revealed no association between the two techniques and FFS. Patients with primary tumors in parameningeal sites were more likely to receive IMRT than 3D-CRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50 Gy, photon energy of ?6 MV, and >5 radiation fields than those who received 3D-CRT. The coverage of the IMRT planning target volume by the prescription dose was improved compared with the coverage using 3D-CRT with similar target dose heterogeneity.IMRT improved the target dose coverage compared with 3D-CRT, although an improvement in locoregional control or FFS could not be demonstrated in this population. Future studies comparing the integral dose to nontarget tissue and late radiation toxicity between the two groups are warranted.

    View details for DOI 10.1016/j.ijrobp.2011.01.036

    View details for Web of Science ID 000301891300045

    View details for PubMedID 21470795

  • Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Green, D. M., Cox, C. L., Zhu, L., Krull, K. R., Srivastava, D. K., Stovall, M., Nolan, V. G., Ness, K. K., Donaldson, S. S., Oeffinger, K. C., Meacham, L. R., Sklar, C. A., Armstrong, G. T., Robison, L. L. 2012; 30 (3): 246-255


    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.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).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.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.

    View details for DOI 10.1200/JCO.2010.34.4267

    View details for Web of Science ID 000302620200011

    View details for PubMedID 22184380

  • Resectable pediatric nonrhabdomyosarcoma soft tissue sarcoma: which patients benefit from adjuvant radiation therapy and how much? ISRN oncology Million, L., Donaldson, S. S. 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.

    View details for DOI 10.5402/2012/341408

    View details for PubMedID 22523704

  • Chemotherapy and Thyroid Cancer Risk: a Report from the Childhood Cancer Survivor Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Veiga, L. H., Bhatti, P., Ronckers, C. M., Sigurdson, A. J., Stovall, M., Smith, S. A., Weathers, R., Leisenring, W., Mertens, A. C., Hammond, S., Neglia, J. P., Meadows, A. T., Donaldson, S. S., Sklar, C. A., Friedman, D. L., Robison, L. L., Inskip, P. D. 2012; 21 (1): 92-101


    Although 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.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 with life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.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 of 20 Gy or less, 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 more than 20 Gy.Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing.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.

    View details for DOI 10.1158/1055-9965.EPI-11-0576

    View details for Web of Science ID 000299051500010

    View details for PubMedID 22028399

  • Controversies in radiotherapy for pediatric Hodgkin's lymphoma EXPERT REVIEW OF ANTICANCER THERAPY Wiegner, E. A., Donaldson, S. S. 2011; 11 (9): 1357-1366


    Cure rates for pediatric Hodgkin's lymphoma remain among the highest in pediatric oncology. Research efforts are currently focused on minimizing treatment-related toxicity without compromising outcomes. For children with early stage/favorable Hodgkin's lymphoma, the standard treatment includes 2-4 cycles of combination chemotherapy, generally followed by low-dose involved-field radiotherapy. Children with advanced stage/unfavorable disease require more intense treatment than those with favorable disease. The standard treatment for advanced stage/unfavorable disease is 4–6 cycles of intense multiagent non-cross-resistant chemotherapy and involved-field radiotherapy. Response-adapted therapy is emerging as a promising strategy to attenuate therapy and thereby reduce toxicity in children with an excellent prognosis and intensify therapy in those children at higher risk of progression or relapse.

    View details for DOI 10.1586/ERA.10.91

    View details for Web of Science ID 000296034500013

    View details for PubMedID 22029056

  • Rhabdomyosarcoma in Infants Younger Than 1 Year A Report From the Children's Oncology Group CANCER Malempati, S., Rodeberg, D. A., Donaldson, S. S., Lyden, E. R., Anderson, J. R., Hawkins, D. S., Arndt, C. A. 2011; 117 (15): 3493-3501


    Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been reported for infants diagnosed with RMS than for older children.The authors analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants aged < 1 year with nonmetastatic RMS who received multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803.Seventy-six infants with nonmetastatic RMS were treated on the 3 protocols from 1991 to 2005. Their median age was 7.4 months (range, 0.1-12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). A parameningeal primary tumor site was less common in this infant cohort (3%) than in all patients who were treated on IRS-IV (25%). The estimated 5-year failure-free survival and overall survival rates (95% confidence interval [CI]) were 57% (95% CI, 44%-67%) and 76% (95% CI, 65%-85%), respectively, for infants compared with 81% (95% CI, 79%-83%) and 87% (95% CI, 85%-89%), respectively, for children ages 1 to 9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with distant failure (n = 3) or without distant failure (n = 20). The overall local failure rate was 30%. The median time to treatment failure was 13 months. The failure-free survival rate was worse for infants who had IRS Group III tumors and for those who received less than protocol-recommended radiation therapy.Infants with RMS appeared to have worse outcomes than older patients, in part because of high rates of local failure. The authors concluded that concerns regarding morbidity in infants and reluctance to use aggressive local control measures may lead to higher rates of local failure.

    View details for DOI 10.1002/cncr.25887

    View details for Web of Science ID 000293103800023

    View details for PubMedID 21264837



    To evaluate the incidence and prognostic factors for regional failure, with attention to the in-transit pathways of spread, in children with nonmetastatic rhabdomyosarcoma of the extremity.The Intergroup rhabdomyosarcoma studies III, IV-Pilot, and IV enrolled 226 children with rhabdomyosarcoma of the extremity. Failure at the in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) lymph nodes was evaluated. The median follow-up for the surviving patients was 10.4 years.Of the 226 children, 55 (24%) had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement at diagnosis. The actuarial 5-year risk of regional failure was 12%. The prognostic factors for poor regional control were female gender and lymph node involvement at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit lymph node involvement at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure was 12% and 8%, respectively. The in-transit failure rate was 0% for patients who underwent radiotherapy and/or underwent lymph node sampling of the in-transit nodal site but was 15% for those who did not (p = .07). However, the 5-year event-free survival rate did not differ between these two groups (64% vs. 55%, respectively, p = .47).The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in patients with rhabdomyosarcoma of the extremity. In patients with distal extremity tumors, in-transit failures were as common as failures in more proximal regional sites. Patients who underwent complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, were at a slightly lower risk of in-transit failure.

    View details for DOI 10.1016/j.ijrobp.2010.03.050

    View details for Web of Science ID 000292486200027

    View details for PubMedID 20542386

  • 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 Walterhouse, D. O., Meza, J. L., Breneman, J. C., Donaldson, S. S., Hayes-Jordan, A., Pappo, A. S., Arndt, C., Raney, R. B., Meyer, W. H., Hawkins, D. S. 2011; 57 (1): 76-83


    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.We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies.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.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.

    View details for DOI 10.1002/pbc.22928

    View details for Web of Science ID 000290452400014

    View details for PubMedID 21298768



    Postoperative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if noncompliance with RT protocol guidelines influenced local-regional control.All operative bed recurrences among 695 Group II rhabdomyosarcoma patients in Intergroup Rhabdomyosarcoma Study Group (IRS) I through IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as >10% or 6-10% of the prescribed dose (40-60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (preoperative tumor volume and 2- to 5-cm margin), respectively. No RT was a major deviation.Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46, 41%), followed by dose (17/46, 37%), volume (9/46, 20%), and dose and volume deviation (1/46, 2%). Only 7 operative bed recurrences occurred in IRS IV (5% local-regional failure) with only 3 RT protocol deviations. Sixty-three (76%) patients with recurrence died of disease despite retrieval therapy, including 13 of 19 nonirradiated children.Over half of the operative bed recurrences were associated with noncompliance; omission of RT was the most common protocol deviation. Three fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II rhabdomyosarcoma.

    View details for DOI 10.1016/j.ijrobp.2010.01.058

    View details for Web of Science ID 000290837100003

    View details for PubMedID 20646841



    To evaluate the outcome of children with rhabdomyosarcoma (RMS) of the hand or foot treated with surgery and/or local radiotherapy (RT).Forty-eight patients with nonmetastatic RMS of the hand or foot were enrolled on Intergroup Rhabdomyosarcoma Study III, IV-Pilot, and IV. Patients received multiagent 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 after prior amputation. Median follow-up for surviving patients was 9.7 years.Actuarial 10-year local control was 100%; 10-year event-free survival and overall survival rates were 62% and 63%, respectively. Poor prognostic factors for recurrence included 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 with the surgery group. There was no difference in 10-year event-free survival (57% vs. 66%) or overall survival (63% vs. 63%) between patients who underwent surgery or local RT. Among relapsing patients, there were no long-term survivors. No secondary malignancies have been observed.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 that maintains form and function as primary local therapy rather than amputation in patients with hand or foot RMS.

    View details for DOI 10.1016/j.ijrobp.2010.01.053

    View details for Web of Science ID 000290006300030

    View details for PubMedID 20646853

  • Decreased fertility among female childhood cancer survivors who received 22-27 Gy hypothalamic/pituitary irradiation: a report from the Childhood Cancer Survivor Study FERTILITY AND STERILITY Green, D. M., Nolan, V. G., Kawashima, T., Stovall, M., Donaldson, S. S., Srivastava, D., Leisenring, W., Robison, L. L., Sklar, C. A. 2011; 95 (6): 1922-U76


    To evaluate the effect of hypothalamic/pituitary radiation (HPT RT) dose on the occurrence of first pregnancy.Retrospective cohort study of childhood cancer 5-year survivors (CCS) diagnosed between 1970 and 1986 before 21 years of age at one of 26 North American pediatric cancer treatment centers.Self-administered questionnaire.A total of 3,619 female CCS who participated in the Childhood Cancer Survivor Study and received no or scatter (?0.1 Gy) radiation to the ovaries and 2,081 female siblings (Sibs) of the participants.None.Self-reported pregnancy events.As a group, CCS were as likely to report being pregnant as Sibs (hazard ratio 1.07, 95% confidence interval 0.97-1.19). 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.These results support the hypothesis that exposures of 22-27 Gy HPT RT may be a contributing factor to infertility among female CCS.

    View details for DOI 10.1016/j.fertnstert.2011.02.002

    View details for Web of Science ID 000289620900016

    View details for PubMedID 21376314

  • 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 Rodeberg, D. A., Garcia-Henriquez, N., Lyden, E. R., Davicioni, E., Parham, D. M., Skapek, S. X., Hayes-Jordan, A. A., Donaldson, S. S., Brown, K. L., Triche, T. J., Meyer, W. H., Hawkins, D. S. 2011; 29 (10): 1304-1311


    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.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).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.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.

    View details for DOI 10.1200/JCO.2010.29.4611

    View details for Web of Science ID 000288990100027

    View details for PubMedID 21357792

  • 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 Bhatti, P., Veiga, L. H., Ronckers, C. M., Sigurdson, A. J., Stovall, M., Smith, S. A., Weathers, R., Leisenring, W., Mertens, A. C., Hammond, S., Friedman, D. L., Neglia, J. P., Meadows, A. T., Donaldson, S. S., Sklar, C. A., Robison, L. L., Inskip, P. D. 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.

    View details for DOI 10.1667/RR2240.1

    View details for Web of Science ID 000285031500009

    View details for PubMedID 21128798

  • 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 Mascarenhas, L., Lyden, E. R., Breitfeld, P. P., Walterhouse, D. O., Donaldson, S. S., Paidas, C. N., Parham, D. M., Anderson, J. R., Meyer, W. H., Hawkins, D. S. AMER SOC CLINICAL ONCOLOGY. 2010: 4658-4663


    To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression.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/m(2)/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m(2) administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m(2)/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.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%).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.

    View details for DOI 10.1200/JCO.2010.29.7390

    View details for Web of Science ID 000283056400036

    View details for PubMedID 20837952

  • 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 Raney, R. B., Anderson, J. R., Brown, K. L., Huh, W. W., Maurer, H. M., Meyer, W. H., Parham, D. M., Rodeberg, D. A., Wolden, S. L., Donaldson, S. S. 2010; 55 (4): 612-616


    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.Chart review and standard statistical procedures. PATIENTS AND TUMORS: Patients were 1-18 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.Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 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.Patients with Stage 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 Stage 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.

    View details for DOI 10.1002/pbc.22520

    View details for Web of Science ID 000281542900007

    View details for PubMedID 20806360

  • 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 Minn, A. Y., Lyden, E. R., Anderson, J. R., Million, L., Arndt, C. A., Brown, K., Hawkins, D. S., Donaldson, S. S. 2010; 28 (27): 4228-4232


    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 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.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.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.

    View details for DOI 10.1200/JCO.2010.29.0247

    View details for Web of Science ID 000281909700020

    View details for PubMedID 20713850

  • Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study JOURNAL OF THE NATIONAL CANCER INSTITUTE Friedman, D. L., Whitton, J., Leisenring, W., Mertens, A. C., Hammond, S., Stovall, M., Donaldson, S. S., Meadows, A. T., Robison, L. L., Neglia, J. P. 2010; 102 (14): 1083-1095


    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.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.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.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.

    View details for DOI 10.1093/jnci/djq238

    View details for Web of Science ID 000280269400013

    View details for PubMedID 20634481

  • Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy JOURNAL OF CLINICAL ONCOLOGY O'Brien, M. M., Donaldson, S. S., Balise, R. R., Whittemore, A. S., Link, M. P. 2010; 28 (7): 1232-1239


    Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

    View details for DOI 10.1200/JCO.2009.24.8062

    View details for Web of Science ID 000274892500025

    View details for PubMedID 20124178

  • Fertility of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Green, D. M., Kawashima, T., Stovall, M., Leisenring, W., Sklar, C. A., Mertens, A. C., Donaldson, S. S., Byrne, J., Robison, L. L. 2010; 28 (2): 332-339


    This study was undertaken to determine the effect of treatment for childhood cancer on male fertility.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.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).This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.

    View details for DOI 10.1200/JCO.2009.24.9037

    View details for Web of Science ID 000273418000025

    View details for PubMedID 19949008

  • Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort BRITISH MEDICAL JOURNAL Mulrooney, D. A., Yeazel, M. W., Kawashima, T., Mertens, A. C., Mitby, P., Stovall, M., Donaldson, S. S., Green, D. M., Sklar, C. A., Robison, L. L., Leisenring, W. M. 2009; 339


    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.Retrospective cohort study.26 institutions that participated in the Childhood Cancer Survivor Study.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.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.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/m(2) 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.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.

    View details for DOI 10.1136/bmj.b4606

    View details for Web of Science ID 000272697300001

    View details for PubMedID 19996459

  • 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 Arndt, C. A., Stoner, J. A., Hawkins, D. S., Rodeberg, D. A., Hayes-Jordan, A. A., Paidas, C. N., Parham, D. M., Teot, L. A., Wharam, M. D., Breneman, J. C., Donaldson, S. S., Anderson, J. R., Meyer, W. H. 2009; 27 (31): 5182-5188


    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 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 alpha level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC.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.For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

    View details for DOI 10.1200/JCO.2009.22.3768

    View details for Web of Science ID 000271274300013

    View details for PubMedID 19770373

  • Neurocognitive Status in Long-Term Survivors of Childhood CNS Malignancies: A Report From the Childhood Cancer Survivor Study NEUROPSYCHOLOGY Ellenberg, L., Liu, Q., Gioia, G., Yasui, Y., Packer, R. J., Mertens, A., Donaldson, S. S., Stovall, M., Kadan-Lottick, N., Armstrong, G., Robison, L. L., Zeltzer, L. K. 2009; 23 (6): 705-717


    To assess neurocognitive functioning in adult survivors of childhood Central Nervous System (CNS) malignancy, a large group of CNS malignancy survivors were compared to survivors of non-CNS malignancy and siblings without cancer on a self-report instrument (CCSS-NCQ) assessing four factors, Task Efficiency, Emotional Regulation, Organization and Memory. Additional multiple linear regressions were used to assess the contribution of demographic, illness, and treatment variables to reported neurocognitive functioning in CNS malignancy survivors and the relationship of reported neurocognitive functioning to socioeconomic indicators. Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all CCSS-NCQ factors than non-CNS cancer survivors or siblings (p < .01). Within the CNS malignancy group, medical complications (hearing deficits, paralysis and cerebrovascular incidents) resulted in a greater likelihood of reported deficits on all CCSS-NCQ factors. Total or partial brain irradiation and ventriculoperitoneal (VP) shunt placement was associated with greater impairment on Task Efficiency and Memory. Female gender was associated with a greater likelihood of impaired scores on Task Efficiency and Emotional Regulation, while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor. CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p < .01), less household income (p < .001), less full time employment (p < .001), and fewer marriages (p < .001). Survivors of childhood CNS malignancy were found to be at significant risk for neurocognitive impairment that continues to adulthood and is correlated with lower socioeconomic achievement.

    View details for DOI 10.1037/a0016674

    View details for Web of Science ID 000271689300003

    View details for PubMedID 19899829



    Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder of the synovium with locally aggressive behavior. We reviewed our experience using radiation therapy in the treatment of PVNS.Seventeen patients with 18 sites of PVNS were treated with radiation between 1993 and 2007. Cases were retrospectively reviewed for patient information, treatment parameters, complications, and outcome. Seven sites were primary presentations and 11 were recurrent with an average of 2.5 prior surgical interventions. The most common location was the knee joint (67%). Cytoreductive surgery was performed before radiation therapy in 16/18 sites with all having proven or suspected residual disease. Radiation was delivered using 4-15 MV photons with an average total dose 34 Gy (range, 20-36 Gy). Seventeen of 18 sites (94%) had postradiotherapy imaging.With average follow-up of 46 months (range, 8-181 months), initial local control was achieved in 75% (12/16) of the sites with prior cytoreductive surgery (mean time to recurrence, 38 months). Ultimate local control was 100% after repeat resection (mean follow-up, 61 months). Two additional sites without prior cytoreductive surgery showed growth after radiotherapy (mean time to documented growth, 10.5 months). Seventeen of the 18 involved joints (94%) were scored as excellent or good PVNS-related function, one site (5%) as fair function, and no site with poor function. No patient required amputation; and there were no Grade 3/4 treatment-related complications.Postoperative external beam radiation is effective in preventing disease recurrence and should be offered following maximal cytoreduction to enhance local control in PVNS.

    View details for DOI 10.1016/j.ijrobp.2008.10.058

    View details for Web of Science ID 000269328700031

    View details for PubMedID 19211195

  • Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Inskip, P. D., Robison, L. L., Stovall, M., Smith, S. A., Hammond, S., Mertens, A. C., Whitton, J. A., Diller, L., Kenney, L., Donaldson, S. S., Meadows, A. T., Neglia, J. P. 2009; 27 (24): 3901-3907


    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.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.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.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.

    View details for DOI 10.1200/JCO.2008.20.7738

    View details for Web of Science ID 000269064300007

    View details for PubMedID 19620485

  • Long-Term Outcomes Among Adult Survivors of Childhood Central Nervous System Malignancies in the Childhood Cancer Survivor Study JOURNAL OF THE NATIONAL CANCER INSTITUTE Armstrong, G. T., Liu, Q., Yasui, Y., Huang, S., Ness, K. K., Leisenring, W., Hudson, M. M., Donaldson, S. S., King, A. A., Stovall, M., Krull, K. R., Robison, L. L., Packer, R. J. 2009; 101 (13): 946-958


    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.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.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.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.

    View details for DOI 10.1093/jnci/djp148

    View details for Web of Science ID 000267666900012

    View details for PubMedID 19535780

  • Fertility of Female Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Green, D. M., Kawashima, T., Stovall, M., Leisenring, W., Sklar, C. A., Mertens, A. C., Donaldson, S. S., Byrne, J., Robison, L. L. 2009; 27 (16): 2677-2685


    This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility.We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy.There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose > or = 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant.This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.

    View details for DOI 10.1200/JCO.2008.20.1541

    View details for Web of Science ID 000266454600018

    View details for PubMedID 19364965

  • The Childhood Cancer Survivor Study: A National Cancer Institute-Supported Resource for Outcome and Intervention Research JOURNAL OF CLINICAL ONCOLOGY Robison, L. L., Armstrong, G. T., Boice, J. D., Chow, E. J., Davies, S. M., Donaldson, S. S., Green, D. M., Hammond, S., Meadows, A. T., Mertens, A. C., Mulvihill, J. J., Nathan, P. C., Neglia, J. P., Packer, R. J., Rajaraman, P., Sklar, C. A., Stovall, M., Strong, L. C., Yasui, Y., Zeltzer, L. K. 2009; 27 (14): 2308-2318


    Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.

    View details for DOI 10.1200/JCO.2009.22.3339

    View details for Web of Science ID 000266195200002

    View details for PubMedID 19364948

  • Second Neoplasms in Survivors of Childhood Cancer: Findings From the Childhood Cancer Survivor Study Cohort JOURNAL OF CLINICAL ONCOLOGY Meadows, A. T., Friedman, D. L., Neglia, J. P., Mertens, A. C., Donaldson, S. S., Stovall, M., Hammond, S., Yasui, Y., Inskip, P. D. 2009; 27 (14): 2356-2362


    To review the reports of subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort that were made through January 1, 2006, and published before July 31, 2008, and to discuss the host-, disease-, and therapy-related risk factors associated with SNs.SNs were ascertained by survivor self-reports and subsequently confirmed by pathology findings or medical record review. Cumulative incidence of SNs and standardized incidence ratios for second malignant neoplasms (SMNs) were calculated. The impact of host-, disease-, and therapy-related risk factors was evaluated by Poisson regression.Among 14,358 cohort members, 730 reported 802 SMNs (excluding nonmelanoma skin cancers). This represents a 2.3-fold increase in the number of SMNs over that reported in the first comprehensive analysis of SMNs in the CCSS cohort, which was done 7 years ago. In addition, 66 cases of meningioma and 1,007 cases of nonmelanoma skin cancer were diagnosed. The 30-year cumulative incidence of SMNs was 9.3% and that of nonmelanoma skin cancer was 6.9%. Risk of SNs remains elevated for more than 20 years of follow-up for all primary childhood cancer diagnoses. In multivariate analyses, risks differ by SN subtype, but include radiotherapy, age at diagnosis, sex, family history of cancer, and primary childhood cancer diagnosis. Female survivors whose primary childhood cancer diagnosis was Hodgkin's lymphoma or sarcoma and who received radiotherapy are at particularly increased risk. Analyses of risk associated with radiotherapy demonstrated different dose-response curves for specific SNs.Childhood cancer survivors are at a substantial and increasing risk for SNs, including nonmelanoma skin cancer and meningiomas. Health care professionals should understand the magnitude of these risks to provide individuals with appropriate counseling and follow-up.

    View details for DOI 10.1200/JCO.2008.21.1920

    View details for Web of Science ID 000266195200006

    View details for PubMedID 19255307

  • High-Risk Populations Identified in Childhood Cancer Survivor Study Investigations: Implications for Risk-Based Surveillance JOURNAL OF CLINICAL ONCOLOGY Hudson, M. M., Mulrooney, D. A., Bowers, D. C., Sklar, C. A., Green, D. M., Donaldson, S. S., Oeffinger, K. C., Neglia, J. P., Meadows, A. T., Robison, L. L. 2009; 27 (14): 2405-2414


    Childhood cancer survivors often experience complications related to cancer and its treatment that may adversely affect quality of life and increase the risk of premature death. The purpose of this manuscript is to review how data derived from Childhood Cancer Survivor Study (CCSS) investigations have facilitated identification of childhood cancer survivor populations at high risk for specific organ toxicity and secondary carcinogenesis and how this has informed clinical screening practices. Articles previously published that used the resource of the CCSS to identify risk factors for specific organ toxicity and subsequent cancers were reviewed and results summarized. CCSS investigations have characterized specific groups to be at highest risk of morbidity related to endocrine and reproductive dysfunction, pulmonary toxicity, cerebrovascular injury, neurologic and neurosensory sequelae, and subsequent neoplasms. Factors influencing risk for specific outcomes related to the individual survivor (eg, sex, race/ethnicity, age at diagnosis, attained age), sociodemographic status (eg, education, household income, health insurance) and cancer history (eg, diagnosis, treatment, time from diagnosis) have been consistently identified. These CCSS investigations that clarify risk for treatment complications related to specific treatment modalities, cumulative dose exposures, and sociodemographic factors identify profiles of survivors at high risk for cancer-related morbidity who deserve heightened surveillance to optimize outcomes after treatment for childhood cancer.

    View details for DOI 10.1200/JCO.2008.21.1516

    View details for Web of Science ID 000266195200012

    View details for PubMedID 19289611

  • Medical care in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Nathan, P. C., Greenberg, M. L., Ness, K. K., Hudson, M. M., Mertens, A. C., Mahoney, M. C., Gurney, J. G., Donaldson, S. S., Leisenring, W. M., Robison, L. L., Oeffinger, K. C. 2008; 26 (27): 4401-4409


    To evaluate whether childhood cancer survivors receive regular medical care focused on the specific morbidities that can arise from their therapy.We conducted a cross-sectional survey of health care use in 8,522 participants in the Childhood Cancer Survivor Study, a multi-institutional cohort of childhood cancer survivors. We assessed medical visits in the preceding 2 years, whether these visits were related to the prior cancer, whether survivors received advice about how to reduce their long-term risks, and whether screening tests were discussed or ordered. Completion of echocardiograms and mammograms were assessed in patients at high risk for cardiomyopathy or breast cancer. We examined the relationship between demographics, treatment, health status, chronic medical conditions, and health care use.Median age at cancer diagnosis was 6.8 years (range, 0 to 20.9 years) and at interview was 31.4 years (range, 17.5 to 54.1 years). Although 88.8% of survivors reported receiving some form of medical care, only 31.5% reported care that focused on their prior cancer (survivor-focused care), and 17.8% reported survivor-focused care that included advice about risk reduction or discussion or ordering of screening tests. Among survivors who received medical care, those who were black, older at interview, or uninsured were less likely to have received risk-based, survivor-focused care. Among patients at increased risk for cardiomyopathy or breast cancer, 511 (28.2%) of 1,810 and 169 (40.8%) of 414 had undergone a recommended echocardiogram or mammogram, respectively.Despite a significant risk of late effects after cancer therapy, the majority of childhood cancer survivors do not receive recommended risk-based care.

    View details for DOI 10.1200/JCO.2008.16.9607

    View details for Web of Science ID 000259350700009

    View details for PubMedID 18802152

  • Understanding the risk of second malignant tumors in children with Hodgkin's disease INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Donaldson, S. S., O'Brien, M. M. 2008; 72 (1): 4-5

    View details for DOI 10.1016/j.ijrobp.2008.05.007

    View details for Web of Science ID 000258741700002

    View details for PubMedID 18722256

  • Results in patients with cranial parameningeal sarcoma and metastases (stage 4) treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II-IV, 1978-1997: Report from the children's oncology group PEDIATRIC BLOOD & CANCER Raney, B., Anderson, J., Breneman, J., Donaldson, S. S., Huh, W., Maurer, H., Michalski, J., Qualman, S., Ullrich, F., Wharam, M., Meyer, W. 2008; 51 (1): 17-22


    Determine outcome of patients with cranial parameningeal sarcoma and concurrent metastases treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II-IV.We identified 91 patients in the database, which includes newly diagnosed subjects <21 years old with rhabdomyosarcoma (RMS) and undifferentiated sarcoma, and reviewed their charts in detail.The 54 males and 37 females were <1-19 years at diagnosis. Primary sites were nasopharynx-nasal cavity, middle ear/mastoid and parapharyngeal area ("better" sites, 55%), paranasal sinus and infratemporal-pterygopalatine area ("worse" sites, 42%), and other (3%). Sixty-eight percent of informative patients had direct intracranial extension. Major metastatic sites at diagnosis were lung (63%), bone marrow (33%), and bone (27%). Treatment included vincristine, actinomycin D, and cyclophosphamide (VAC) chemotherapy and radiotherapy to the primary tumor and up to five metastatic sites/tissues.The estimated 10-year failure-free survival (FFS) rate was 32% (95% confidence interval [CI]: 22%, 42%). Sixty patients had progressive disease (N = 49) or death as a first event (N = 11); another developed myelodysplastic syndrome and died. Sites of first progression/relapse were distant (55%), local (12%), CNS extension (8%), mixed (6%), and uncertain (18%). Factors indicating likelihood of 10-year FFS included tumor arising in "better" versus "worse" sites (FFS 46% vs. 18%, P = 0.02) and embryonal versus other histology (FFS 37% vs. 19%, P = 0.06).Cure was possible for some patients with metastatic cranial parameningeal sarcoma. Patients with the best outlook had embryonal RMS located in the nasopharynx/nasal cavity, middle ear/mastoid, or parapharyngeal region. Distant metastases were the most frequent type of recurrence, indicating that more effective systemic agents are needed to eliminate residual disease.

    View details for DOI 10.1002/pbc.21492

    View details for Web of Science ID 000255816800005

    View details for PubMedID 18266224

  • Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study BLOOD Bluhm, E. C., Ronckers, C., Hayashi, R. J., Neglia, J. P., Mertens, A. C., Stovall, M., Meadows, A. T., Mitby, P. A., Whitton, J. A., Hammond, S., Barker, J. D., Donaldson, S. S., Robison, L. L., Inskip, P. D. 2008; 111 (8): 4014-4021


    Second primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. We assessed mortality and second malignant neoplasms (SMNs) among 1082 5-year survivors of non-Hodgkin lymphoma (NHL) in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of cancer survivors diagnosed from 1970 to 1986. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated using US population rates. Relative risks for death and solid tumor SMNs were calculated based on demographic, clinical, and treatment characteristics using Poisson regression models. There were 87 observed deaths (SMR = 4.2; 95% CI, 1.8-4.1) with elevated rates of death from solid tumors, leukemia, cardiac disease, and pneumonia. Risk for death remained elevated beyond 20 years after NHL. Risk factors for death from causes other than NHL included female sex (rate ratio [RR] = 3.4) and cardiac radiation therapy exposure (RR = 1.9). There were 27 solid tumor SMNs (SIR = 3.9; 95% CI, 2.6-5.7) with 3% cumulative incidence between 5 and 20 years after NHL diagnosis. Risk factors were female sex (RR = 3.1), mediastinal NHL disease (RR = 5.2), and breast irradiation (RR = 4.3). Survivors of childhood NHL, particularly those treated with chest RT, are at continued increased risk of early mortality and solid tumor SMNs.

    View details for DOI 10.1182/blood-2007-08-106021

    View details for Web of Science ID 000255134700022

    View details for PubMedID 18258798

  • Treatment of Pediatric Hodgkin Lymphoma CURRENT TREATMENT OPTIONS IN ONCOLOGY Olson, M. R., Donaldson, S. S. 2008; 9 (1): 81-94


    OPINION STATEMENT: We are increasingly successful in the treatment of Hodgkin lymphoma. Current risk adapted trials seek to maintain the excellent efficacy of older therapies, while simultaneously limiting their late toxicities. Current management of early stage/favorable disease involves the use of two to four cycles of tailored chemotherapy, often followed by low-dose, involved field radiation. Those with intermediate and advanced stage disease require more intense chemotherapy and radiation regimens. Functional imaging using [(18)F]-2 fluoro-D-2-deoxyglucose is increasingly used to determine complete vs. partial response and to detect relapse. Given the success of primary therapy, retrieval of patients remains a highly individualized challenge. The majority of children failing combined-modality treatment undergo high-dose chemotherapy followed by autologous hematopoietic stem cell rescue, oftentimes with consolidative radiotherapy.

    View details for DOI 10.1007/s11864-008-0058-0

    View details for Web of Science ID 000262835600007

    View details for PubMedID 18461462

  • Treatment of metastatuc Ewing Sarcoma/Primitive neuroectodermal tumor of bone: Evaluation of increasing the dose intensity of chemotherapy - A report from the children's oncology group PEDIATRIC BLOOD & CANCER Miser, J. S., Goldsby, R. E., Chen, Z., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S. G., Rausen, A. R., Vietti, T. J., Grier, H. E. 2007; 49 (7): 894-900


    The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis.We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days).Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%).An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S.

    View details for DOI 10.1002/pbc.21233

    View details for Web of Science ID 000250487800004

    View details for PubMedID 17584910

  • Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Link, M. P., Weinstein, H. J., Rai, S. N., Brain, S., Billett, A. L., Hurwitz, C. A., Krasin, M., Kun, L. E., Marcus, K. C., Tarbell, N. J., Young, J. A., Hudson, M. M. 2007; 25 (3): 332-337


    To evaluate outcome and assess complications in children and adolescents with low-risk Hodgkin's disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low-dose, involved-field radiation therapy (IFRT).One hundred ten children with low-risk Hodgkin's disease were treated with four cycles of VAMP and 15 Gy IFRT for those who achieved a complete response (CR) or 25.5 Gy for those with a partial response after two cycles of VAMP.With median follow-up of 9.6 years (range, 1.7 to 15.0), 5- and 10-year overall survival were 99.1% and 96.1%, respectively, and 5-and 10-year event-free survival (EFS) were 92.7% and 89.4%. Factors contributing to 10-year EFS were: early CR (P = .02), absence of B symptoms (P = .01), lymphocyte predominant histologic subtype (P = .04), and less than three initial sites of disease (P = .02). Organ toxicity has been limited to correctable hypothyroidism in 42% of irradiated patients, and one case of cardiac dysfunction. Seventeen healthy babies have been born to 106 survivors. There have been two malignant tumors: one thyroid cancer within the radiation therapy field and one Ewing's sarcoma outside the radiation therapy field.Risk-adapted, combined-modality therapy using VAMP chemotherapy with radiation is effective and well tolerated. Pediatric patients with low-risk Hodgkin's disease can be cured with therapy without an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiotherapy. Thus, these children are expected to retain normal fertility, organ function, and be at low risk of a second malignant tumor.

    View details for DOI 10.1200/JCO.2006.08.4772

    View details for Web of Science ID 000243729200016

    View details for PubMedID 17235049

  • New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the childhood cancer survivor study JOURNAL OF THE NATIONAL CANCER INSTITUTE Neglia, J. P., Robison, L. L., Stovall, M., Liu, Y., Packer, R. J., Hammond, S., Yasui, Y., Kasper, C. E., Mertens, A. C., Donaldson, S. S., Meadows, A. T., Inskip, P. D. 2006; 98 (21): 1528-1537


    Subsequent primary neoplasms of the central nervous system (CNS) have frequently been described as late events following childhood leukemia and brain tumors. However, the details of the dose-response relationships, the expression of excess risk over time, and the modifying effects of other host and treatment factors have not been well defined.Subsequent primary neoplasms of the CNS occurring within a cohort of 14,361 5-year survivors of childhood cancers were ascertained. Each patient was matched with four control subjects by age, sex, and time since original cancer diagnosis. Tumor site-specific radiation dosimetry was performed, and chemotherapy information was abstracted from medical records. Conditional logistic regression was used to estimate odds ratios (ORs), to calculate 95% confidence intervals (CIs), and to model the excess relative risk (ERR) as a function of radiation dose and host factors. For subsequent gliomas, standardized incidence ratios (SIRs) and excess absolute risks (EARs) were calculated based on Surveillance, Epidemiology, and End Results data.Subsequent CNS primary neoplasms were identified in 116 individuals. Gliomas (n = 40) occurred a median of 9 years from original diagnosis; for meningiomas (n = 66), it was 17 years. Radiation exposure was associated with increased risk of subsequent glioma (OR = 6.78, 95% CI = 1.54 to 29.7) and meningioma (OR = 9.94, 95% CI = 2.17 to 45.6). The dose response for the excess relative risk was linear (for glioma, slope = 0.33 [95% CI = 0.07 to 1.71] per Gy, and for meningioma, slope = 1.06 [95% CI = 0.21 to 8.15] per Gy). For glioma, the ERR/Gy was highest among children exposed at less than 5 years of age. After adjustment for radiation dose, neither original cancer diagnosis nor chemotherapy was associated with risk. The overall SIR for glioma was 8.7, and the EAR was 19.3 per 10,000 person-years.Exposure to radiation therapy is the most important risk factor for the development of a new CNS tumor in survivors of childhood cancers. The higher risk of subsequent glioma in children irradiated at a very young age may reflect greater susceptibility of the developing brain to radiation.

    View details for DOI 10.1093/jnci/djj411

    View details for Web of Science ID 000242379600008

    View details for PubMedID 17077355

  • Female survivors of childhood cancer: Preterm birth and low birth weight among their children JOURNAL OF THE NATIONAL CANCER INSTITUTE Signorello, L. B., Cohen, S. S., Bosetti, C., Stovall, M., Kasper, C. E., Weathers, R. E., Whitton, J. A., Green, D. M., Donaldson, S. S., Mertens, A. C., Robison, L. L., Boice, J. D. 2006; 98 (20): 1453-1461


    Improved survival after childhood cancer raises concerns over the possible long-term reproductive health effects of cancer therapies. We investigated whether children of female childhood cancer survivors are at elevated risk of being born preterm or exhibiting restricted fetal growth and evaluated the associations of different cancer treatments on these outcomes.Using data from the Childhood Cancer Survivor Study, a large multicenter cohort of childhood cancer survivors, we studied the singleton live births of female cohort members from 1968 to 2002. Included were 2201 children of 1264 survivors and 1175 children of a comparison group of 601 female siblings. Data from medical records were used to determine cumulative prepregnancy exposures to chemotherapy and radiotherapy. Logistic regression was used to estimate odds ratios (ORs) for the association between quantitative therapy exposures and preterm (<37 weeks) birth, low birth weight (<2.5 kg), and small-for-gestational-age (SGA) (lowest 10th percentile) births. All statistical tests were two-sided.Survivors' children were more likely to be born preterm than the siblings' children (21.1% versus 12.6%; OR = 1.9, 95% confidence interval [CI] = 1.4 to 2.4; P<.001). Compared with the children of survivors who did not receive any radiotherapy, the children of survivors treated with high-dose radiotherapy to the uterus (>500 cGy) had increased risks of being born preterm (50.0% versus 19.6%; OR = 3.5, 95% CI = 1.5 to 8.0; P = .003), low birth weight (36.2% versus 7.6%; OR = 6.8, 95% CI = 2.1 to 22.2; P = .001), and SGA (18.2% versus 7.8%; OR = 4.0, 95% CI = 1.6 to 9.8; P = .003). Increased risks were also apparent at lower uterine radiotherapy doses (starting at 50 cGy for preterm birth and at 250 cGy for low birth weight).Late effects of treatment for female childhood cancer patients may include restricted fetal growth and early births among their offspring, with risks concentrated among women who receive pelvic irradiation.

    View details for DOI 10.1093/jnci/djj394

    View details for Web of Science ID 000241721400009

    View details for PubMedID 17047194

  • Thyroid cancer in childhood cancer survivors: A detailed evaluation of radiation dose response and its modifiers RADIATION RESEARCH Ronckers, C. M., Sigurdson, A. J., Stovall, M., Smith, S. A., Mertens, A. C., Liu, Y., Hammond, S., Land, C. E., Neglia, J. P., Donaldson, S. S., Meadows, A. T., Sklar, C. A., Robison, L. L., Inskip, P. D. 2006; 166 (4): 618-628


    Radiation exposure at a young age is a strong risk factor for thyroid cancer. We conducted a nested case-control study of 69 thyroid cancer cases and 265 controls from a cohort of 14,054 childhood cancer survivors to evaluate the shape of the radiation dose-response relationship, in particular at high doses, and to assess modification of the radiation effects by patient and treatment characteristics. We considered several types of statistical models to estimate the excess relative risk (ERR), mainly guided by radiobiological models. A two-parameter model with a term linear in dose and a negative exponential in dose squared provided the best parsimonious description with an ERR of 1.3 per gray (95% confidence interval 0.4-4.1) at doses below 6 Gy and a relative decrease in ERR of 0.2% per unit dose squared with increasing dose, that is, decreases in the ERR/Gy of 53% at 20 Gy and 95% at 40 Gy. Further analyses using spline models suggested that the significant nonlinearity at high doses was characterized most appropriately as a true downturn rather than a flattening of the dose-response curve. We found no statistically significant modification of the dose-response relationship by patient characteristics; however, the linear parameter (i.e., the ERR/ Gy at doses less than 6 Gy) did decrease consistently and linearly with increasing age at childhood cancer diagnosis, from 4.45 for 0-1-year-olds to 0.48 for 15-20-year-olds. In summary, we applied models derived from radiobiology to describe the radiation dose-response curve for thyroid cancer in an epidemiological study and found convincing evidence for a downturn in risk at high doses.

    View details for Web of Science ID 000240883000007

    View details for PubMedID 17007558

  • Local control in pelvic Ewing sarcoma: Analysis from INT-0091 - A report from the Children's Oncology Group Yock, T. I., Krailo, M., Fryer, C. J., Donaldson, S. S., Miser, J. S., Chen, Z., Bernstein, M., Laurie, F., Gebhardt, M. C., Grier, H. E., Tarbell, N. J. AMER SOC CLINICAL ONCOLOGY. 2006: 3838-3843


    The impact of the modality used for local control of Ewing sarcoma is uncertain. We investigated the relationship between the type of local control modality, surgery, radiation (RT) or both (S + RT), and subsequent risk for local failure (LF) in patients with nonmetastatic pelvic Ewing sarcoma treated on INT-0091.Patients < or = 30 years with Ewing sarcoma, primitive neuroectodermal tumor or primitive sarcoma of bone were randomly assigned to receive chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin, (VACA) or with these four drugs alternating with ifosfamide and etoposide (VACA-IE). The local control modality, surgery, RT or both was chosen by the treating physicians. The effect of local control modality was assessed after adjusting for the size of tumor (< 8 cm, > or = 8 cm) and chemotherapy type.Seventy-five patients with pelvic tumors and a median follow-up of 4.4 years (0.6 to 11.4 years) comprised the study population. Twelve underwent surgery, 44 received RT, and 19 received both. The 5-year event-free survival (EFS) and cumulative incidence of LF was 49% and 21% (16%, LF only; 5%, LF and distant failure). There was no significant difference in EFS or LF by tumor size (< 8 cm, > or = 8 cm), local control (LC) modality, or chemotherapy. However, VACA-IE seems to confer an LC benefit (11% v 30%; P = .06).There was no significant effect of local control modality (surgery, RT or S + RT) selected by the treating physicians on rates of local failure or EFS. However, VACA-IE improves LC (11%) compared with previously published results for pelvic Ewing sarcoma.

    View details for DOI 10.1200/JCO.2006.05.9188

    View details for Web of Science ID 000240052300007

    View details for PubMedID 16921035

  • Advances toward an understanding of brainstem gliomas JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Laningham, F., Fisher, P. G. 2006; 24 (8): 1266-1272


    The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.

    View details for DOI 10.1200/JCO.2005.04.6599

    View details for Web of Science ID 000236235700006

    View details for PubMedID 16525181

  • Stroke as a late treatment effect of Hodgkin's disease: A report from the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Bowers, D. C., McNeil, D. E., Liu, Y., Yasui, Y., Stovall, M., Gurney, J. G., Hudson, M. M., Donaldson, S. S., Packer, R. J., Mitby, P. A., Kasper, C. E., Robison, L. L., Oeffinger, K. C. 2005; 23 (27): 6508-6515


    The objectives of this report are to examine the incidence of and risk factors for stroke among childhood Hodgkin's disease (HD) survivors.The Childhood Cancer Survivor Study is a multi-institutional cohort study of more than 5-year cancer survivors diagnosed between 1970 and 1986 and a sibling comparison group. Incidence rates of stroke among HD survivors (n = 1,926) and siblings (n = 3,846) were calculated and compared. Cox proportional hazards models were used to estimate the hazard ratios, reported as relative risks (RR), of developing stroke between HD survivors and siblings.Nine siblings reported a stroke, for an incidence of 8.00 per 100,000 person-years (95% CI, 3.85 to 14.43 per 100,000 person-years). Twenty-four HD survivors reported a stroke. The incidence of late-occurring stroke among HD survivors was 83.6 per 100,000 person-years (95% CI, 54.5 to 121.7 per 100,000 person-years). The RR of stroke among HD survivors was 4.32 (95% CI, 2.01 to 9.29; P = .0002). All 24 survivors received mantle radiation exposure (median dose, 40 Gy). The incidence of late-occurring stroke among HD survivors treated with mantle radiation was 109.8 per 100,000 person-years (95% CI, 70.8 to 161.1 per 100,000 person-years). The RR of late-occurring stroke among HD survivors treated with mantle radiation was 5.62 (95% CI, 2.59 to 12.25; P < .0001).Survivors of childhood HD are at increased risk of stroke. Mantle radiation exposure is strongly associated with subsequent stroke. Potential mechanisms may include carotid artery disease or cardiac valvular disease.

    View details for DOI 10.1200/JCO.2005.15.107

    View details for Web of Science ID 000232233100012

    View details for PubMedID 16170160

  • Long-term medical effects of childhood and adolescent rhabdomyosarcoma: A report from the childhood cancer survivor study PEDIATRIC BLOOD & CANCER Punyko, J. A., Mertens, A. C., Gurney, J. G., Yasui, Y., Donaldson, S. S., Rodeberg, D. A., Raney, R. B., Stovall, M., Sklar, C. A., Robison, L. L., Baker, K. S. 2005; 44 (7): 643-653


    This study was conducted to evaluate the incidence of adverse medical conditions and to assess the risk of developing these conditions in a cohort of long-term survivors of rhabdomyosarcoma (RMS) diagnosed before age 21.Using data from the Childhood Cancer Survivor Study (CCSS), we evaluated the incidence of self-reported adverse medical conditions for 606 RMS survivors and 3,701 siblings of cancer survivors. Cancer and treatment data abstracted from medical records were used to evaluate the effects of primary tumor site and combined modality therapy on the risk of developing sequelae in survivors.The relative risk (RR) for developing sequelae among survivors compared with siblings was greatest within 5 years after diagnosis. RR was elevated more than 5 years after diagnosis for several conditions (RR, 95% CI) as follows: eye impairment (cataract: 7.4, 2.9-18.9; visual disturbances: 3.2, 2.0-5.1; very dry eyes: 2.0, 1.2-3.3), endocrine impairment (growth hormone deficiency: 83.9, 33.0-213.6; hypothyroidism: 6.9, 4.1-11.3; need for medications to induce puberty: 90.4, 30.2-270.5), cardiopulmonary impairment (congestive heart failure: 43.0, 12.7-145.5; angina-like symptoms: 2.0, 1.3-2.9), neurosensory impairment (legal blindness: 9.8, 4.8-20.0; abnormal sensations: 1.5, 1.0-2.2), and neuromotor impairment (repeated seizures: 2.3, 1.2-4.4; motor problems: 3.7, 2.2-6.4; problems chewing or swallowing: 3.8, 1.9-7.5).Survivors are at risk for developing sequelae many years after their initial diagnosis and treatment. Continued medical surveillance is necessary to ensure the long-term health and well-being of RMS survivors.

    View details for DOI 10.1002/pbc.20310

    View details for Web of Science ID 000228789300012

    View details for PubMedID 15700252

  • Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRS-IV JOURNAL OF PEDIATRIC SURGERY Rodeberg, D., Arndt, C., Breneman, J., Lyden, E., Donaldson, S., Paidas, C., Andrassy, R., Meyer, W., Wiener, J. 2005; 40 (1): 256-262


    To better understand outcomes in children with rhabdomyosarcoma (RMS) and lung-only metastatic disease, the authors reviewed the experience from Intergroup Rhabdomyosarcoma Studies IV Pilot and IV.Patients with lung-only (n = 46) vs other sites of metastatic disease (n = 234) were reviewed using patient charts and the database of Children's Oncology Group (COG).Sixteen percent of patients with RMS and metastatic disease had isolated lung metastases. Thirty-one (67%) had more than 5 metastatic lung lesions. These were bilateral in 34 (74%). Only 6 patients were biopsied at diagnosis. Sixteen children (35%) did not receive any lung radiotherapy. Patients that received lung radiotherapy had fewer lung recurrences ( P = .04), although this has no significant impact on overall survival (OAS, 47% radiotherapy vs 31% no radiotherapy). Compared with patients with other sites of metastatic disease, patients with lung-only metastases have a greater proportion of favorable histology (67% vs 39%, P = .0017), negative nodal involvement (67% vs 32%, P = .0013), and parameningeal primaries (39% vs 12%) and a smaller proportion of extremity primaries (20% vs 33%, P = .0005 for site of primary tumor). Overall survival at 4 years for lung-only metastases was not significantly different from other single-site metastasis (42% vs 34%). Survival was not improved for unilateral disease or fewer than 5 metastatic lesions. Factors associated with diminished OAS include unfavorable histology (P = .0001) and age >10 years (P = .015).Children with RMS and lung-only metastases usually present with extensive bilateral disease that is frequently not biopsied nor given protocol-recommended radiotherapy (XRT). However, outcome is comparable, although slightly better, than patients with other single-site metastasis.

    View details for DOI 10.1016/j.jpedsurg.2004.09.045

    View details for Web of Science ID 000226927000073

    View details for PubMedID 15868594

  • Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease JOURNAL OF CLINICAL ONCOLOGY Hudson, M. M., Krasin, M., Link, M. P., Donaldson, S. S., BILLUPS, C., Merchant, T. E., Kun, L., Billet, A. L., Kaste, S., Tarbell, N. J., Howard, S., Friedmann, A. M., Hurwitz, C. A., Young, J. A., Marcus, K. C., Rai, S., Cowan, T., Weinstein, H. J. 2004; 22 (22): 4541-4550


    To evaluate the efficacy of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and cyclophosphamide, vincristine, and procarbazine (COP) chemotherapy and response-based, involved-field radiation, a combined-modality regimen that limits doses of alkylating agents, anthracyclines, and radiation, in children with advanced and unfavorable Hodgkin's disease.From 1993 to 2000, 159 children and adolescents with unfavorable Hodgkin's disease received three alternating cycles (total of six cycles) of VAMP/COP chemotherapy followed by response-based, involved-field radiation therapy: 15 Gy was administered to patients achieving a complete response, and 25.5 Gy was administered to those achieving a partial response after the first two cycles of chemotherapy and to all sites of bulky lymphadenopathy. Unfavorable disease was defined as clinical stage I and II with bulky peripheral nodal disease greater than 6 cm, initial bulky mediastinal mass 33% or more of the intrathoracic diameter, and/or "B" symptoms and all stage III and IV.Study enrollment was closed after an interim analysis estimated a 5-year event-free survival (EFS) rate below a predefined level. Disease presentation was localized (stage I/II) in 77 patients (48.4%) and advanced (stage III/IV) in 82 patients (51.6%). At a median follow-up of 5.8 years (range, 1.3 to 10.0 years), 38 patients had events, including relapse/progression (n = 35), second malignancy (n = 2), and accidental death (n = 1); nine relapses (25.7%) occurred greater than 4 years from diagnosis. Five-year survival and EFS estimates are 92.7% +/- 2.5% and 75.6% +/- 4.1%, respectively.Risk-adapted combined-modality therapy with VAMP/COP and response-based, involved-field radiation therapy results in an unsatisfactory outcome for pediatric patients with unfavorable presentations of Hodgkin's disease.

    View details for DOI 10.1200/JCO.2004.02.139

    View details for Web of Science ID 000225175600016

    View details for PubMedID 15542805

  • Genetic effects of radiotherapy for childhood cancer: Gonadal dose reconstruction INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Stovall, M., Donaldson, S. S., Weathers, R. E., Robison, L. L., Mertens, A. C., Winther, J. F., Olsen, J. H., Boice, J. D. 2004; 60 (2): 542-552


    To estimate the doses of radiation to organs of interest during treatment of childhood cancer for use in an epidemiologic study of possible heritable diseases, including birth defects, chromosomal abnormalities, cancer, stillbirth, and neonatal and premature death.The study population was composed of more than 25,000 patients with cancer in Denmark and the United States who were survivors of childhood cancer and subsequently had nearly 6,500 children of their own. Radiation therapy records were sought for the survivors who parented offspring who had adverse pregnancy outcomes (>300 offspring), and for a sample of all survivors in a case-cohort design. The records were imaged and centrally abstracted. Water phantom measurements were made to estimate doses for a wide range of treatments. Mathematical phantoms were used to apply measured results to estimate doses to ovaries, uterus, testes, and pituitary for patients ranging in age from newborn to 25 years. Gonadal shielding, ovarian pinning (oophoropexy), and field blocking were taken into account.Testicular radiation doses ranged from <1 to 700 cGy (median, 7 cGy) and ovarian doses from <1 to >2,500 cGy (median, 13 cGy). Ten percent of the records were incomplete, but sufficient data were available for broad characterizations of gonadal dose. More than 49% of the gonadal doses were >10 cGy and 16% were >100 cGy.Sufficient radiation therapy data exist as far back as 1943 to enable computation of gonadal doses administered for curative therapy for childhood cancer. The range of gonadal doses is broad, and for many cancer survivors, is high and just below the threshold for infertility. Accordingly, the epidemiologic study has >90% power to detect a 1.3-fold risk of an adverse pregnancy outcome associated with radiation exposure to the gonads. This study should provide important information on the genetic consequences of radiation exposure to humans.

    View details for DOI 10.1016/j.ijrobp.2004.03.017

    View details for Web of Science ID 000223966500027

    View details for PubMedID 15380591

  • Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: A report from the soft tissue sarcoma committee of the children's oncology group CLINICAL CANCER RESEARCH Spunt, S. L., Smith, L. M., Ruymann, F. B., Qualman, S. J., Donaldson, S. S., Rodeberg, D. A., Anderson, J. R., Crist, W. M., Link, M. P. 2004; 10 (18): 6072-6079


    More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome.This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m2 on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m2 on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m2/dose; (b) 1.5 g/m2/dose; and (c) 1.8 g/m2/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others).Between October 1996 and August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis +/- other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52% (95% confidence interval, 41-64%) and 67% (95% confidence interval, 56-77%), respectively, at a median follow-up of 3 years.A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m2/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.

    View details for Web of Science ID 000224080200014

    View details for PubMedID 15447992

  • Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in intergroup rhabdomyosarcoma study group trials II through IV INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Michalski, J. M., Meza, J., Breneman, J. C., Wolden, S. L., Laurie, F., Jodoin, M., Raney, B., Wharam, M. D., Donaldson, S. S. 2004; 59 (4): 1027-1038


    To evaluate the impact of radiation treatment parameters on cancer control outcomes for children with parameningeal rhabdomyosarcoma (PM-RMS) treated on Intergroup Rhabdomyosarcoma Study Group protocols II through IV (including IRS-IV pilot).Radiation therapy (RT) treatment quality was assessed by contemporary review of portal radiographs, simulation films, treatment plans, and, in most cases, cross-sectional diagnostic imaging data for patients treated on Intergroup Rhabdomyosarcoma Study Group protocols II through IV. Five hundred ninety-five patients with PM-RMS were registered on these 4 studies between 1978 and 1997. Most of these patients (95%) had Group III disease. Radiation doses varied over the span of these trials with protocol doses ranging from 40 Gy to 50.4 Gy on IRS-II and IRS-III and 50.4 Gy to 59.4 Gy (hyperfractionated) on IRS-IV pilot and IRS-IV. Patients with high-risk signs of meningeal impingement, including cranial nerve palsy (CNP) or cranial base bone erosion (CBBE) with or without intracranial extension (ICE), were required to start radiotherapy at the time of study entry (Day 0). Among 595 patients reviewed, 385 (65%) had diagnostic images submitted to the Quality Assurance Review Center for assessment of target volume coverage. Only 123 (21%) patients, 49 (40%) of whom were treated on IRS-II, received whole brain RT.The estimated overall survival and failure-free survival rates were 73% and 69% at 5 years, respectively. The estimated 5-year local failure (LF) rate was 17%. The detection of ICE increased from 24% to 41% as more cross-sectional diagnostic images became available. For patients with any sign of meningeal impingement, starting RT <2 weeks after diagnosis (n = 315) had 18% LF compared to 33% LF if started >2 weeks after diagnosis (n = 43) (p = 0.03). For patients with ICE, starting RT <2 weeks after diagnosis (n = 177) resulted in LF in 16% compared to 37% among those who started >2 weeks after (n = 19) (p = 0.07). For patients with CNP and/or CBBE, starting RT <2 weeks after diagnosis (n = 138) resulted in 21% LF compared to 30% among those that started >2 weeks (n = 23) (p = 0.23). In none of these circumstances was the 5-year failure-free survival significantly impacted by this increase in LF. The estimated 3-year survival after local failure was 17% (95% CI, 10%-25%). For patients without signs of meningeal impingement, there was no difference in local control whether they started radiation therapy earlier or later than 10 weeks. Patients with large (> or =5 cm) Group III tumors had an LF rate of 35% if they received less than 47.5 Gy compared to an LF rate of 18% in patients who received less than 47.5 Gy with smaller tumors or a rate of 15% if they received more than 47.5 Gy, irrespective of tumor size (p = 0.14). There was no evidence that whole brain radiation therapy affected LF or reduced central nervous system (CNS) relapse. Multivariate analysis of RT parameters and clinical factors demonstrated that a radiation dose of >47.5 Gy was associated with lower LF. The presence of ICE, CNP, or CBBE and age >10 years at diagnosis were significantly associated with higher rates of local failure.The availability of cross-sectional diagnostic images (CT or MRI) has improved detection of ICE. Starting radiation therapy within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure. When no signs of meningeal impingement were present, delay of radiation therapy for more than 10 weeks did not impact local failure rates. Whole brain radiation therapy is unnecessary in PM-RMS. A dose of at least 47.5 Gy seems to be associated with lower rates of local failure, especially when tumor diameter is > or =5 cm.

    View details for DOI 10.1016/j.ijrobp.2004.02.064

    View details for Web of Science ID 000222541300013

    View details for PubMedID 15234036

  • Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: Evaluation of combination ifosfamide and etoposide - A children's cancer group and pediatric oncology group study JOURNAL OF CLINICAL ONCOLOGY Miser, J. S., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S., Rausen, A. R., Vietti, T. J., Grier, H. E. 2004; 22 (14): 2873-2876


    One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes.Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days.Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms.Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.

    View details for DOI 10.1200/JCO.2004.01.041

    View details for Web of Science ID 000222729000017

    View details for PubMedID 15254055

  • Subspecialty training and certification for radiation oncology. Journal of the American College of Radiology Donaldson, S. S., Halperin, E. C. 2004; 1 (7): 488-492


    To address the recurring issues regarding subspecialty training and certification in radiation oncology, and using pediatric radiation oncology as an example, the authors considered the problem of inadequate case material for resident teaching. Potential solutions to the identified problems are addressed, and the roles of oversight committees and regulatory bodies are clarified. The problem of the nonuniform distribution of pediatric case material across residency programs cannot be solved by removing pediatric radiation oncology from the core radiation oncology educational curriculum or by offering fellowship training to those who may select it. As a result, the authors believe that subspecialty training and certification in radiation oncology is not a near-term possibility.

    View details for PubMedID 17411637

  • Results of treatment of fifty-six patients with localized retroperitoneal and pelvic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study-IV, 1991-1997 PEDIATRIC BLOOD & CANCER Raney, R. B., Stoner, J. A., Walterhouse, D. O., Andrassy, R. J., Donaldson, S. S., Laurie, F., Meyer, W. H., Qualman, S. J., Crist, W. A. 2004; 42 (7): 618-625


    We reviewed 56 IRS-IV patients with localized rhabdomyosarcoma [RMS] of the retroperitoneum/pelvis to assess outcome and prognostic factors, including the value of initially excising >or=50% of the tumor (debulking) before chemotherapy.Patients had embryonal RMS [N=38], alveolar RMS [N = 7], RMS not otherwise specified [NOS, N = 7], or undifferentiated sarcoma [N = 4]. Fifteen patients were debulked; 41 patients were biopsied. All received VAC; most received radiotherapy.Estimated 5-year failure-free survival [FFS] and overall survival rates were 70 and 75%, respectively. FFS rates were better for patients <10 years old and those with embryonal RMS compared to alveolar RMS/undifferentiated sarcoma. After adjusting for age and histological differences, FFS was better for patients whose tumor was debulked prior to beginning therapy [P = 0.02].These results are superior to those of previous protocols for patients with RMS of the retroperitoneum/pelvis. Initial excision of >or=50% of the tumor may be associated with increased FFS.

    View details for DOI 10.1002/pbc.20012

    View details for Web of Science ID 000221225800011

    View details for PubMedID 15127417

  • Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/prostate rhabdomyosarcoma? Results from Intergroup Rhabdomyosarcoma Study IV JOURNAL OF UROLOGY Arndt, C., Rodeberg, D., Breitfeld, P. P., Raney, R. B., Ullrich, F., Donaldson, S. 2004; 171 (6): 2396-2403


    We determine patient and tumor characteristics, event-free and overall survival, methods of local control, rate of bladder preservation and proportion with normal bladder function for patients with localized bladder/prostate (BP) rhabdomyosarcoma (RMS) treated on the Fourth Intergroup Rhabdomyosarcoma Study (IRS IV).We reviewed the records of 90 patients with nonmetastatic BP RMS enrolled on IRS IV for presenting characteristics, details of therapy and outcome.Of the 90 records 88 had sufficient information for review. Patient age distribution was less than 1 year for 7 patients, 1 to 9 years for 71 and 10 or greater years for 10. Tumors commonly arose in the bladder (70%), had favorable histology (embryonal or botryoid 80%), large (69% greater than 5 cm), unresectable (84% group III) and invasive (56% T2). Local therapy included radiation in 74 patients, and most patients underwent second-look operations after radiation. All patients received alkylating based chemotherapy. With a median followup of 6.1 years there have been 3 second malignancies, 1 toxic death and 18 relapses, for an event-free survival rate of 77%. Bladders were retained without relapse at last contact in 55 patients. Of those 55 patients 36 and of the entire group 40% had normal function determined by history.Of patients with nonmetastatic BP RMS on IRS IV 82% survived 6 years. Bladder function was preserved in 55% (36/66) of event-free survivors. Of all patients entered on study 40% (36 of 88) survive event-free with apparently normal functioning bladders. More precise long-term evaluation of bladder and sexual function will require application of better tools such as urodynamic studies and validated patient surveys.

    View details for DOI 10.1097/01.ju.0000127752.41749.a4

    View details for Web of Science ID 000221510300093

    View details for PubMedID 15126860

  • Failure pattern and factors predictive of local failure in rhabdomyosarcoma: A report of group III patients on the third intergroup rhabdomyosarcoma study JOURNAL OF CLINICAL ONCOLOGY Wharam, M. D., Meza, J., Anderson, J., Breneman, J. C., Donaldson, S. S., Fitzgerald, T. J., Michalski, J., Teot, L. A., Wiener, E. S., Meyer, W. H. 2004; 22 (10): 1902-1908


    To analyze patterns of failure and factors predictive of local treatment failure in children enrolled on the third Intergroup Rhabdomyosarcoma Study who had either biopsy only or subtotal resection of their primary tumor, had no distant metastases, and received radiation therapy for local control.Treatment failure was categorized as local, regional nodal, or distant metastatic. The 5-year cumulative risk of failure was estimated for each category and factors predictive of local failure risk were determined using the Cox model and binary recursive partitioning.The estimated 5-year cumulative incidence rates by failure category were: total local (with or without concurrent regional or distant failure), 19%; total regional nodal, 2%; total distant, 11%; and death from toxicity or unknown recurrence type, 4%. Lymph node involvement at diagnosis was the single factor most predictive of increased total local failure risk (5-year cumulative incidence 32%) compared with children with negative nodes or unknown node status (16%). No significant effect on local failure risk was observed by total radiotherapy dose over the prescribed range of 41.4 Gy to 50.4 Gy. For all patients (N = 405), the estimated 5-year failure-free survival and overall survival were, respectively, 70% and 78%.Local failure after radiotherapy for group III rhabdomyosarcoma patients is the predominant type of relapse. Involved lymph nodes at diagnosis predict a higher risk of local and distant treatment failure compared with patients whose lymph nodes are negative.

    View details for Web of Science ID 000221492600018

    View details for PubMedID 15143083

  • Part of proceedings - Ewing sarcoma: Radiation dose and target volume PEDIATRIC BLOOD & CANCER Donaldson, S. S. 2004; 42 (5): 471-476


    The outcome of children and adolescents with Ewing sarcoma is impacted by many prognostic factors and often measured by estimates of: event-free, relapse-free, disease-free, or overall survival. However, the preferred assessment following radiation therapy is local control.A review of large group experiences over the past several decades was undertaken to assess the optimal radiation dose and volume for patients with localized, osseous Ewing sarcoma. New approaches and techniques to improve local control were also investigated.With multidisciplinary therapy, 5-year overall local control rates range from 58 to 93%. Following definitive irradiation, they are 53-86%. Recommended radiation therapy doses are 55.8-60.0 Gy. In the postoperative setting, gross disease requires 55.8 Gy; microscopic disease requires 45 Gy. Altered fractionation schemes have not improved local control. The appropriate irradiated volume is an involved field to the pretreatment tumor volume plus 2.0-2.5 cm margin, followed by a boost to the post-induction chemotherapy tumor volume with margin. Good radiation quality control with central review improves local control. Use of an involved radiation field requires accuracy in defining tumor volume. Techniques to improve local control include risk-adapted multidisciplinary therapy, intraoperative boost radiation, and high radiation doses as delivered by 3-dimensional conformal radiation. Intensity modulated and proton beam radiotherapy may offer an advantage at special sites.Innovative uses of radiation in the multidisciplinary setting will continue to provide excellent local control, improved function, and quality of life for young patients with localized Ewing sarcoma of bone.

    View details for DOI 10.1002/pbc.10472

    View details for Web of Science ID 000220869100018

  • High-dose Therapy and Autologous Hemapoietic Stem-cell Transplantation for Recurrent or Refractory Pediatric Hodgkin's Disease: Results and Prognostic Indices Journal of Clinical Oncology Lieskovsky YYE, Donaldson SS, Torres MA, Wong RM, Amylon MD, Link MP, Agarwal R 2004; 22: 4532-4540
  • Failure Pattern and Factors Predictive of Local Failure in Rhabdomyosarcoma: A Report of Group III Patients on the Third Intergroup Rhabdomyosarcoma Study Journal of Clinical Oncology Wharam MD, Meza J, Anderson J, Breneman JC, Donaldson SS, Fitzgerald TJ, Michalski J, Teot LA, Wiener ES, Meyer WH 2004; 22: 1902-1908
  • Genetic Effects of Radiotherapy for Childhood Cancer: Gonadal Dose Reconstruction International Journal of Radiation Oncology, Biology, and Physics Stovall M, Donaldson S, Weathers RE, Robison LL, Mertens AC, Winther JF, Olsen JH, Boice JD 2004; 60: 542-552
  • Influence of Radiation Therapy Parameters on Outcome in Children Treated with Radiation Therapy for Localized Parameningeal Rhabdomyosarcoma in the Intergroup Rhabdomyosarcoma Study Group Trials II through IV International Journal of Radiation Oncology, Biology, and Physics Michalski JM, Meza J, Breneman JC, Wolden SL, Laurie F, Jodoin MA, Raney B, Wharam MD, Donaldson SS 2004; 59: 1027-1038
  • Risk-adapted Combined-modality Therapy with VAMP/COP and Response-based Involved-field Radiation for Unfavorable Pediatric Hodgkin's Disease Journal of Clinical Oncology Hudson MM, Krasin M, Link MP, Donaldson SS, Billups C, Merchant TE, Kun L, Billey AL, Kaste S, Tarbell NJ, Howard S, Friedman AM, Hurwitz CA, Young JA, Marcus KC, Rai S, Cowen T, Weinstein HJ 2004; 22: 4541-4550
  • Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: Childhood cancer survivor study JOURNAL OF CLINICAL ONCOLOGY Packer, R. J., Gurney, J. G., Punyko, J. A., Donaldson, S. S., Inskip, P. D., Stovall, M., Yasui, Y., Mertens, A. C., Sklar, C. A., Nicholson, H. S., Zeltzer, L. K., Neglia, J. P., Robison, L. L. 2003; 21 (17): 3255-3261


    To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits.Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume.Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder.Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.

    View details for DOI 10.1200/JCO.2003.01.202

    View details for Web of Science ID 000185091300014

    View details for PubMedID 12947060

  • Outcome and local control (LC) for bladder prostate rhabdomyosarcoma (BP RMS) on IRS IV Arndt, C. A., Rodeberg, D. A., Ullrich, F., Donaldson, S. S., Anderson, J. R., Raney, R. B., Breitfeld, P. P. NATURE PUBLISHING GROUP. 2003: 269A-269A
  • Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone NEW ENGLAND JOURNAL OF MEDICINE Grier, H. E., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S., Rausen, A. R., Vietti, T. J., Miser, J. S. 2003; 348 (8): 694-701


    Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease.Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide.A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01).The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.

    View details for Web of Science ID 000181014400004

    View details for PubMedID 12594313

  • Treatment of localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma: Lessons learned from intergroup rhabdomyosarcoma studies III and IV JOURNAL OF CLINICAL ONCOLOGY Pappo, A. S., Meza, J. L., Donaldson, S. S., Wharam, M. D., Wiener, E. S., Qualman, S. J., Maurer, H. M., Crist, W. M. 2003; 21 (4): 638-645


    The characteristics and clinical outcomes of children and adolescents with localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma (RMS) treated on national protocols from the Intergroup Rhabdomyosarcoma Group are reported.We conducted a retrospective review of 164 children and adolescents enrolled in the third and fourth Intergroup Rhabdomyosarcoma Studies. Variables analyzed included age, sex, primary tumor site, histologic subtype, clinical group, therapy, site and rate of treatment failure, and time to initial recurrence.Localized nonorbital, nonparameningeal RMS accounted for 9% of all cases of RMS. The median age at diagnosis was 5 years; the median follow-up was 6.6 years. Estimated 5-year failure-free survival (FFS) and survival (S) rates were 76% (95% CI, 69% to 83%) and 83% (95% CI, 77% to 89%), respectively. In multivariate analysis, patients with clinically involved regional nodes (N1) had worse FFS (P =.02). For patients with embryonal tumors, FFS was significantly improved, especially among patients with Group I/II without nodal disease clinical Group I, II N0. For patients with alveolar/undifferentiated histology, FFS was significantly worse in children under the age of 1 year. Actuarial estimates of recurrences at 15 years were local (19%), regional (5%), and distant (9%).More than 80% of patients with RMS of the head and neck are cured of their disease using surgery and vincristine, dactinomycin +/- cyclophosphamide with or without radiotherapy. Our results indicate that early, limited exposure to cyclophosphamide might reduce recurrence in low-risk embryonal patients and that reduced dosages might achieve comparable results with improved toxicity profiles. These hypotheses will be tested in the next generation of trials from the Soft Tissue Committee of the Children's Oncology Group.

    View details for DOI 10.1200/JCO.2003.01.032

    View details for Web of Science ID 000181002500012

    View details for PubMedID 12586800

  • A discourse: The 2002 Wataru W. Sutow Lecture - Hodgkin disease in children - Perspectives and progress MEDICAL AND PEDIATRIC ONCOLOGY Donaldson, S. S. 2003; 40 (2): 73-81


    THE PIONEER: Wataru W. Sutow, 1912-1981, was a remarkable and pivotal leader in pediatric oncology. Early in his medical career, he conducted important clinical and anthropometric studies among Japanese and Marshall Island children exposed to atomic radiation. These studies established standards for childhood growth and development still in use today. Dr. Sutow pioneered the multidisciplinary approach to childhood cancer by combining multidrug chemotherapy protocols with surgery and radiotherapy in the common childhood solid tumors. The textbook "Clinical Pediatric Oncology," of which he was the senior editor, served to define the discipline of pediatric oncology and educate a new era of oncologists in the curative treatment for childhood cancer. THE PAST AND PRESENT: The first edition of "Clinical Pediatric Oncology," published in 1973, demonstrated that only children with early-stage localized Hodgkin disease had a realistic opportunity for cure. Soon the use of combined-modality therapy consisting of low-dose, involved-field radiation plus multi-agent chemotherapy emerged, and made the goal of cure realistic for all patients. This approach is now universal. Today, the 5-year relative survival rate for American children with Hodgkin disease, who are under 14 years of age, is 94%, a dramatic and remarkable achievement. FUTURE: Management of children with Hodgkin disease now involves clinical staging and risk-adapted, combined-modality therapy. Clinical and translational research initiatives that hold promise for children with Hodgkin disease in the future include: use of the WHO Classification System combining morphologic and biologic criteria; noninvasive staging procedures with increased sensitivity and specificity; development of a useful prognostic index to define groups for risk-adapted therapy; high-dose therapy with stem cell transplantation; and novel therapies.

    View details for DOI 10.1002/mpo.10219

    View details for Web of Science ID 000179873900001

    View details for PubMedID 12461789

  • A Discourse: The 2002 Wataru W. Sutow Lecture; Hodgkin's Disease in Children: Perspectives and Progress Medical and Pediatric Oncology Donaldson SS 2003; 40: 73-81
  • Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma - A report from the intergroup rhabdomyosarcoma study IV JOURNAL OF CLINICAL ONCOLOGY Breneman, J. C., Lyden, E., Pappo, A. S., Link, M. P., Anderson, J. R., Parham, D. M., Qualman, S. J., Wharam, M. D., Donaldson, S. S., Maurer, H. M., Meyer, W. H., Baker, K. S., Paidas, C. N., Crist, W. M. 2003; 21 (1): 78-84


    To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV).Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points.One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P =.026) and increasing number of metastatic sites (P =.028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P =.007 and.006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%.Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.

    View details for Web of Science ID 000183281100014

    View details for PubMedID 12506174

  • Genetic Effects of Radiotherapy for Childhood Cancer Health Physics Boice JD, Tawn EJ, Winther JF, Donaldson SS, Green DM, Mertens AC, Mulvihill JJ, Olsen JH, Robison LL, Stovall M 2003; 85 (1): 65-80
  • Prognostic Factors for Children with Hodgkin's Disease Treated with a Combined Modality Therapy Journal of Clinical Oncology Smith RS, Chen Q, Hudson MM, Link MP, Kun L, Weinstein H, Billen A, Marcus KJ, Tarbell NJ, Donaldson SS 2003; 21: 2026-2033
  • Pediatric Hodgkin's disease - Up, up, and beyond INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Donaldson, S. S. 2002; 54 (1): 1-8


    Juan A. del Regato, 1909-1999, was a superb clinician-educator who recognized the radiocurability of Hodgkin's disease but questioned treatment without late effects, particularly in children. The remarkable progress in pediatric Hodgkin's disease today is a tribute to this influential pioneer, who served as a role model to many. Combined modality therapy using low-dose, involved-field radiation and multiagent chemotherapy today results in a 5-year relative survival rate of 94% among American children with Hodgkin's disease. However, several areas hold promise for future advances, including a new pathology classification and biology studies that distinguish classic Hodgkin's disease from other lymphomas; new noninvasive staging techniques, including 18F-fluorodeoxyglucose-positron emission tomography; the definition of risk groups to segregate low-, intermediate-, and high-risk groups on the basis of a prognostic index, facilitating risk-adapted therapy; and myeloablative therapy followed by hematopoietic stem cell transplantation. Currently used for children with relapse, it is associated with a 5-year survival of 65% and should be considered as the initial therapy for high-risk groups. Idiopathic diffuse pulmonary toxicity after autologous transplantation is high among children with an atopic history; thus, atopy should be considered when selecting children appropriate for transplantation. Finally, novel therapies, such as the anti-CD20 antibody, rituximab, may be useful for children with CD20+, lymphocyte-predominant Hodgkin's disease. The universal goal of cure without late effects is realistic for almost all children with Hodgkin's disease today.

    View details for Web of Science ID 000177780900001

    View details for PubMedID 12182968

  • VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Hudson, M. M., Lamborn, K. R., Link, M. P., Kun, L., Billett, A. L., Marcus, K. C., Hurwitz, C. A., Young, J. A., Tarbell, N. J., Weinstein, H. J. 2002; 20 (14): 3081-3087


    To evaluate outcome and assess toxicity of children and adolescents with early-stage, favorable Hodgkin's disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and low-dose, involved-field radiation.One hundred ten patients with clinical stages I and II, favorable (nonbulky) Hodgkin's disease were treated with four cycles of VAMP chemotherapy and 15 Gy involved-field radiation for those who achieved a complete response, or 25.5 Gy for those who achieved a partial response to two cycles of VAMP.With a median follow-up of 5.6 years (range, 1.1 to 10.4 years), the 5-year survival and event-free survival were 99% (lower confidence limit [CL], 97.4%) and 93% (lower CL, 88.6%), respectively. Factors associated with event-free survival of 100% were complete response to two cycles of VAMP and histology other than nodular sclerosing Hodgkin's disease (NSHD). No serious early or late toxicity has been observed. Patients presenting with clinical stages I and IIA, nonbulky disease involving fewer than three nodal sites have a projected survival and event-free survival of 100% and 97% (lower CL, 93%), respectively, at 5 years.Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy with 15 to 25.5 Gy of involved-field radiation for patients with early-stage/favorable Hodgkin's disease is highly effective and without demonstrable late effects. These results indicate that pediatric patients with stages I and II favorable Hodgkin's disease can be cured with limited therapy that does not include an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiation therapy.

    View details for DOI 10.1200/JCO.2002.12.101

    View details for Web of Science ID 000176920000007

    View details for PubMedID 12118021

  • Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation JOURNAL OF CLINICAL ONCOLOGY Friedmann, A. M., Hudson, M. M., Weinstein, H. J., Donaldson, S. S., Kun, L., Tarbell, N. J., Link, M. P. 2002; 20 (14): 3088-3094


    Between January 1990 and April 1993, 56 pediatric patients with Hodgkin's disease were treated on a single-arm trial at three institutions with a regimen designed to maintain high cure rates while minimizing the potential late effects of treatment, such as infertility, second malignant neoplasms, and cardiopulmonary injury.The regimen used combined-modality therapy with six cycles of vinblastine, etoposide, prednisone, and doxorubicin (VEPA) chemotherapy and low-dose, involved-field radiation. Unfavorable features comprised bulky presentations of localized (stage I or II) disease or advanced (stage III or IV) Hodgkin's disease.Of 56 patients enrolled, 26 (46%) had unfavorable presentations of stage I/II disease and 30 (54%) had advanced (stage III/IV) disease. Seventy-nine percent of the patients are alive without disease at a median follow-up time of 8.9 years from diagnosis. Nineteen patients had events at a median of 1.5 years (range, 0.4 to 7.9 years) from diagnosis; 17 patients relapsed, one died of cardiomyopathy, and one died of accidental injuries. Survival and event-free survival (EFS) estimates at 5 years for the entire cohort were 81.9% (SE, 5.2%) and 67.8% (SE, 6.3%), respectively. Five-year EFS by stage was 100% for stage I, 79.2% (SE, 8.3%) for stage II, 70% (SE, 14.5%) for stage III, and 49.5% (SE, 11.3%) for stage IV patients.Combined-modality therapy with VEPA chemotherapy and low-dose, involved-field radiation is adequate for disease control of early-stage patients with unfavorable features, but it is inferior to other standard regimens for advanced-stage patients.

    View details for DOI 10.1200/JCO.2002.03.051

    View details for Web of Science ID 000176920000008

    View details for PubMedID 12118022

  • Study design and cohort characteristics of the childhood cancer survivor study: A multi-institutional collaborative project MEDICAL AND PEDIATRIC ONCOLOGY Robison, L. L., Mertens, A. C., Boice, J. D., Breslow, N. E., Donaldson, S. S., Green, D. M., Li, F. P., Meadows, A. T., Mulvihill, J. J., Neglia, J. P., Nesbit, M. E., Packer, R. J., Potter, J. D., Sklar, C. A., Smith, M. A., Stovall, M., Strong, L. C., Yasui, Y., Zeltzer, L. K. 2002; 38 (4): 229-239


    Increased attention has been directed toward the long-term health outcomes of survivors of childhood cancer. To facilitate such research, a multi-institutional consortium established the Childhood Cancer Survivor Study (CCSS), a large, diverse, and well-characterized cohort of 5-year survivors of childhood and adolescent cancer.Eligibility for the CCSS cohort included a selected group of cancer diagnoses prior to age 21 years between 1970-1986 and survival for at least 5 years.A total of 20,276 eligible subjects were identified from the 25 contributing institutions, of whom 15% are considered lost to follow-up. Currently, 14,054 subjects (69.3% of the eligible cohort) have participated by completing a 24-page baseline questionnaire. The distribution of first diagnoses includes leukemia (33%), lymphoma (21%), neuroblastoma (7%), CNS tumor (13%), bone tumor (8%), kidney tumor (9%), and soft-tissue sarcoma (9%). Abstraction of medical records for chemotherapy, radiation therapy, and surgical procedures has been successfully completed for 98% of study participants. Overall, 78% received radiotherapy and 73% chemotherapy.The CCSS represents the largest and most extensively characterized cohort of childhood and adolescent cancer survivors in North America. It serves as a resource for addressing important issues such as risk of second malignancies, endocrine and reproductive outcome, cardiopulmonary complications, and psychosocial implications, among this unique and ever-growing population.

    View details for DOI 10.1002/mpo.1316

    View details for Web of Science ID 000174673100001

    View details for PubMedID 11920786

  • Pediatric Hodgkin's Disease: Up, Up and Beyond International Journal of Radiation Oncology, Biology, and Physics Donaldson SS 2002; 54: 1-8
  • VAMP and Low-dose, Involved-field Radiation for Children and Adolescents with Favorable, Early-stage Hodkin's Disease: Results of a Prospective Clinical Trial Journal of Clinical Oncology Donaldson SS, Hudson MM, Lamborn KR, Link MP, Kun L, Billett AL, Marcus KC, Hurwitz CA, Young JA, Tarbell NJ, Weinstein HJ 2002; 20: 3081-3087
  • Study Design and Cohort Characteristics of the Childhood Cancer Survivor Study: A Multi-institutional Collaborative Project Medical and Pediatric Oncology Robinson LL, Mertens AC, Boice JD, Breslow NE, Donaldson SS, Green DM, Li FP, Meadows AT, Mulvihill JJ, Neglia JP, Nesbit ME, Packer RJ, Potter JD, Sklar CA, Smith MA, Stovall M, Strong LC, Yasui Y, Zeltser L 2002; 38: 229-239
  • Rhabdomyosarcoma of the parotid region occurring in childhood and adolescence - A report from the Intergroup Rhabdomyosarcoma Study Group CANCER Walterhouse, D. O., Pappo, A. S., Baker, K. S., Parham, D. M., Anderson, J. R., Donaldson, S. S., Paidas, C. N., Womer, R. B., Crist, W. M. 2001; 92 (12): 3135-3146


    Rhabdomyosarcoma (RMS) of the parotid region is rare and to the authors' knowledge little information is available regarding the site of tumor origin, clinical presentation, and outcome in these patients. Therefore, the authors reviewed the files of all patients with RMS of the parotid region who were registered on the Intergroup Rhabdomyosarcoma Studies (IRS) I-IV.Patient charts and the Intergroup Rhabdomyosarcoma Study Group (IRSG) database were reviewed.Sixty-two patients presenting with a mass in the parotid region were identified. None of the tumors was localized exclusively to the parotid gland, so the primary site was referred to as the "parotid region." The tumor invaded a parameningeal site in 30 patients. These cases have been designated as parameningeal-parotid tumors to distinguish them from 32 cases that did not invade a parameningeal site and were designated as nonparameningeal-parotid tumors. The majority of patients had Group III tumors in both the nonparameningeal-parotid and parameningeal-parotid subgroups. However, although there were 16 patients with Group I or II tumors in the nonparameningeal-parotid subgroup, no patients with Group I or II tumors were found in the parameningeal-parotid subgroup (P = 0.001). Fifty-six of 62 patients (90%) received radiotherapy. The parameningeal primary site designation resulted in intensification of both chemotherapy and radiotherapy for patients with parameningeal-parotid RMS. The 5-year failure-free survival rate was 81% and the 5-year survival rate was 84%. There were no deaths reported among patients with Group I or II tumors. The 5-year failure-free survival did not appear to differ when comparing patients with parameningeal-parotid tumors with patients with nonparameningeal-parotid tumors (P = 0.21).Treatment as defined by the IRS protocols has been reported to be highly effective for patients with RMS of the parotid region. Outcome for the more aggressively treated patients with parameningeal-parotid RMS appears similar to that for patients with nonparameningeal-parotid RMS.

    View details for Web of Science ID 000172757600021

    View details for PubMedID 11753993

  • Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma - A report from the IRSG INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Donaldson, S. S., Meza, J., Breneman, J. C., Crist, W. M., Laurie, F., Qualman, S. J., Wharam, M. 2001; 51 (3): 718-728


    To evaluate the outcome and toxicity of hyperfractionated radiotherapy (HFRT) vs. conventionally fractionated radiotherapy (CFRT) in children with Group III rhabdomyosarcoma (RMS).Five hundred fifty-nine children were enrolled into the Intergroup Rhabdomyosarcoma Study IV with Group III RMS. Sixty-nine were ineligible for the analysis because of incorrect group or pathologic findings. Of the 490 remaining, 239 were randomized to HFRT (59.4 Gy in 54 1.1-Gy twice daily fractions) and 251 to CFRT (50.4 Gy in 28 1.8-Gy daily fractions). The age range was <1-21 years. All patients received chemotherapy. RT began at Week 9 after induction chemotherapy for all but those with high-risk parameningeal tumors who received RT during induction chemotherapy. The patient groups were equally balanced. The median follow-up was 3.9 years.Analysis by randomized treatment assignment (intent to treat) revealed an estimated 5-year failure-free survival (FFS) rate of 70% and overall survival (OS) of 75%. In the univariate analysis, the factors associated with the best outcome were age 1-9 years at diagnosis; noninvasive tumors; tumor size <5 cm; uninvolved lymph nodes; Stage 1 or 2 disease; primary site in the orbit or head and neck; and embryonal histologic features (p = 0.001 for all factors). No differences in the FFS or OS between the two RT treatment methods and no differences in the FFS or OS between HFRT and CFRT were found when analyzed by age, gender, tumor size, tumor invasiveness, nodal status, histologic features, stage, or primary site. Treatment compliance differed by age. Of the children <5 years, 57% assigned to HFRT received HFRT and 77% assigned to CFRT received CFRT. Of the children >or=5 years, 88% assigned to both HFRT and CFRT received their assigned treatment. The reasons for not receiving the appropriate randomized treatment were progressive disease, early death, parent or physician refusal, young age, or surgery. The toxicity assessment revealed more mucositis with HFRT (66%) than with CFRT (46%) (p = 0.03) for the parameningeal patients, and more skin reactions (16%) and nausea/vomiting (13%) with HFRT than with CFRT (7% and 5%, respectively) for patients with nonparameningeal primary tumors (p = 0.03 and p = 0.02, respectively). The analysis by treatment actually received revealed a 5-year FFS rate of 73% and OS rate of 77%, with no difference between CFRT and HFRT. As well, there was no difference in FFS or OS between CFRT and HFRT when analyzed by age, gender, tumor size, tumor invasiveness, modal status, histology, stage or site of primary. The 5-year estimated cumulative incidence of failure for the irradiated patients was local, 13%; regional, 3%; and distant, 13%; with no differences between HFRT and CFRT. The 5-year local failure rate by site was orbit, 5%; head and neck, 12%; parameningeal, 16%; bladder/prostate, 19%; extremity, 7%; and all others, 14%. The 5-year regional failure rate was parameningeal,1%; extremity, 20%; and all others, 5%. The 5-year distant failure rate was orbit, 2%; head and neck, 6%; parameningeal, 11%; bladder/prostate, 15%; extremity, 28%; and all others, 17%.HFRT, as given in this study, did not improve local/regional control, FFS, or OS compared with CFRT. The risk of local/regional failure was comparable to that of distant failure in children with Group III RMS. The standard of care for Group III RMS continues to be CFRT with chemotherapy.

    View details for Web of Science ID 000171892800020

    View details for PubMedID 11597814

  • Long-term results of irradiation for patients with progressive Graves' ophthalmopathy Marquez, S. D., Lum, B. L., McDougall, I. R., Katkuri, S., Levin, P. S., MacManus, M., Donaldson, S. S. ELSEVIER SCIENCE INC. 2001: 766-774


    To determine the long-term outcome of radiotherapy (RT) in patients with progressively symptomatic thyroid eye disease and to evaluate the potential long-term sequelae.Four hundred fifty-three patients provided written informed consent and received retrobulbar RT for Graves' ophthalmopathy at Stanford University Medical Center; 197 with 1 year of follow-up were retrospectively analyzed. Of the 197 patients, 189 received RT to the bilateral retrobulbar regions, and 4 received unilateral RT. The technical information was unavailable for 4 patients. Patients were assessed by chart review, telephone interview, questionnaire, and multidisciplinary physician examination. Eye impairment was scored using the SPECS system. The end point review included the before and after treatment SPECS score, surgical intervention, and patient satisfaction. Potential complications, including cataract development, retinopathy, and tumor formation, were investigated. Multivariate analyses were performed to assess the prognostic variables.Improvement or resolution was 89% for soft-tissue findings; 70% for proptosis; 85% for extraocular muscle dysfunction; 96% for corneal abnormalities; and 67% for sight loss. The response to RT may take >6 months to stabilize. Factors predictive of response varied in the individual SPECS categories but included the initial SPECS score, pretreatment thyroid status, female gender, a 20-Gy RT dose, and a history of hypertension. Nonpredictive factors included a history of tobacco use, diabetes mellitus, steroids, and prior cataracts. Only 16% required surgical intervention to preserve their vision or restore binocular vision. Twenty-two patients (12%) developed cataracts after irradiation (median 11 years). No patient developed a tumor within the RT field during the follow-up period (range 1-29 years). Ninety-eight percent of patients were pleased with their results, and 2% believed their symptoms progressed despite RT.Retrobulbar irradiation (20 Gy) is safe and effective treatment for progressive Graves' ophthalmopathy, with a 96% overall response rate, 98% patient satisfaction rate, and no irreparable long-term sequelae, with follow-up extending 29 years. The most common late effect observed was cataract development, which occurred more frequently in older patients and was reversible with extraction. Elective surgical intervention after RT should be withheld until patients have demonstrated a plateau in response.

    View details for Web of Science ID 000171892800026

    View details for PubMedID 11697323

  • Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group JOURNAL OF CLINICAL ONCOLOGY Smith, L. M., Anderson, J. R., Qualman, S. J., Crist, W. M., Paidas, C. N., Teot, L. A., Pappo, A. S., Link, M. P., Grier, H. E., Wiener, E. S., Breneman, J. C., Raney, R. B., Maurer, H. M., Donaldson, S. S. 2001; 19 (20): 4058-4064


    To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy.Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc).Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy.Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.

    View details for Web of Science ID 000171634200009

    View details for PubMedID 11600608

  • Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Seminars in pediatric surgery Wiener, E. S., Anderson, J. R., Ojimba, J. I., Lobe, T. E., Paidas, C., Andrassy, R. J., Raney, R. B., Qualman, S. J., Donaldson, S. S., Maurer, H. M., Link, M. P., Crist, W. M., Grier, H. E. 2001; 10 (3): 146-152


    Use of retroperitoneal lymph node dissection (RPLND) in paratesticular rhabdomyosarcoma (PTRMS) is controversial and has changed over the past 2 decades. The Intergroup Rhabdomyosarcoma Study Group (IRSG) required ipsilateral RPLND (IRPLND) for all patients with PTRMS treated on IRS-III (1984-91), but changed to clinical evaluation of RPLNs using computerized tomography (CT) in IRS-IV (1991 through 1997). In IRS-IV, only those patients with identified lymph node involvement on CT required surgical evaluation of the RPLNs. Nodal radiation therapy was administered only to patients with RPLNs recognized as positive; such patients received more intensive chemotherapy as well. Thus, they compared the incidence of recognized RPLN involvement using these 2 different approaches. They then analyzed patient outcome to determine whether this change in management affected outcome.Eligible patients with group I or II PTRMS who were treated on IRS III (n = 100) or IRS IV (n = 134) were analyzed. Failure-free survival (FFS) and survival (S) rates were estimated using the Kaplan-Meier method and compared using the log-rank test.There was a significant change in the distribution of patients with group I versus II tumors from IRS-III to IRS-IV (group I, 68% in IRS-III versus 82% in IRS-IV). This was the result of decreased node recognition when CT was used to stage RPLNs in IRS-IV and was most notable for adolescents (>10 years of age). Overall, 3-year FFS was 92% for patients treated on IRS-III and 86% for those treated on IRS-IV (P =.10), whereas survival estimates were 96% and 92%, respectively (P =.30). Adolescents were at higher risk of RPLN relapse than were children (<10 years of age) and their FFS and survival were worse, regardless of IRS protocol. Furthermore, adolescents with recognized group II tumors experienced better 3-year FFS than those with group I tumors on IRS-IV (100% versus 68%, P =.06), most likely as a result of receiving radiotherapy and intensified chemotherapy.Use of only CT scan evaluation of RPLN in IRS-IV led to a decrease in identification of RPLN involvement in boys who present with localized PTRMS, and a higher rate of regional relapse as compared with IRS-III. Adolescents had much higher likelihood of RPLN disease, and they fared significantly worse than did younger children on both studies. Furthermore, adolescent boys with group I tumors experienced worse FFS than those with Group II tumors on IRS-IV, probably because some patients with group II tumors were not identified by CT imaging and thus received less effective therapy. These data suggest that adolescents should have ipsilateral RPLN dissection as part of their routine staging, and those with positive lymph nodes require intensified chemotherapy as well as nodal irradiation.

    View details for PubMedID 11481652

  • Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease JOURNAL OF CLINICAL ONCOLOGY Crist, W. M., Anderson, J. R., Meza, J. L., Fryer, C., Raney, R. B., Ruymann, F. B., Breneman, J., Qualman, S. J., Wiener, E., Wharam, M., Lobe, T., Webber, B., Maurer, H. M., Donaldson, S. S. 2001; 19 (12): 3091-3102


    The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy.Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT).Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P =.42). No significant difference in outcome was noted with HF-RT versus C-RT (P =.85 and P =.90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%.VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.

    View details for Web of Science ID 000169303900015

    View details for PubMedID 11408506

  • Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: A report from the Intergroup Rhabdomyosarcoma Study Group JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Breitfeld, P. P., Lyden, E., Raney, R. B., Teot, L. A., Wharam, M., Lobe, T., Crist, W. M., Maurer, H. M., Donaldson, S. S., Ruymann, F. B. 2001; 23 (4): 225-233


    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.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.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).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 IE-containing 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.

    View details for Web of Science ID 000168710500009

    View details for PubMedID 11846301

  • Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: A selective review of Intergroup Rhabdomyosarcoma Study Group experience and rationale for intergroup rhabdomyosarcoma study V JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Raney, R. B., Anderson, J. R., Barr, F. G., Donaldson, S. S., Pappo, A. S., Qualman, S. J., Wiener, E. S., Maurer, H. M., Crist, W. M. 2001; 23 (4): 215-220


    To review the importance of prognostic factors in developing new protocols for children with rhabdomyosarcoma (RMS).Four studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group from 1972 through 1991.Favorable prognostic factors are: (1) undetectable distant metastases at diagnosis; (2) primary sites in the orbit and nonparameningeal head/neck and genitourinary nonbladder/prostate regions; (3) grossly complete surgical removal of localized tumor at the time of diagnosis; (4) embryonal/botryoid histology; (5) tumor size < or = 5 cm; and (6) age younger than 10 years at diagnosis. The IRS-V protocols are risk-based and refine therapy by reducing exposure to cyclophosphamide and radiation therapy (XRT) in patients at low risk while adding new, active agents such as topotecan or irinotecan to the standard therapy of vincristine, actinomycin D, and cyclophosphamide (VAC) plus XRT for patients with unfavorable histology or advanced disease. Collection of biologic specimens from patients with newly diagnosed disease continues to identify other factors that may distinguish patients with favorable features from those who need more intensive therapy. A new protocol that takes into account their previous treatment is needed for patients with recurrent disease. This program (being planned) does not include bone marrow/stem cell reconstitution because this strategy has thus far failed to improve survival rates of patients with metastases at diagnosis.Better understanding of biologic differences and new, active agents are needed to improve outcome of patients with unfavorable features at presentation.

    View details for Web of Science ID 000168710500007

    View details for PubMedID 11846299

  • Second malignant neoplasms in five-year survivors of childhood cancer: Childhood cancer survivor study JOURNAL OF THE NATIONAL CANCER INSTITUTE Neglia, J. P., Friedman, D. L., Yasui, Y., Mertens, A. C., Hammond, S., Stovall, M., Donaldson, S. S., Meadows, A. T., Robison, L. L. 2001; 93 (8): 618-629


    Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, we identified the risk of SMNS:A retrospective cohort of 13 581 children diagnosed with common cancers before age 21 years and surviving at least 5 years was constructed with the use of data from patients treated at 25 U.S. and Canadian institutions. SMNs were ascertained through self-administered questionnaires and verified by pathology reports. Information on therapeutic exposures was abstracted from medical records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) and excess absolute risk. Poisson multiple regression models were used to assess the impact of host and therapy factors on the risk of developing SMNS: All statistical tests were two-sided.In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 [95% CI = 12.35 to 20.83], respectively). A statistically significant excess of SMNs followed all childhood cancers. In multivariate regression models adjusted for therapeutic radiation exposure, SMNs of any type were independently associated with female sex (P<.001), childhood cancer at a younger age (P for trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P =.01, respectively), and exposure to alkylating agents (P for trend =.02). Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 years of patient follow-up.Success in treating children with cancer should not be overshadowed by the incidence of SMNS: However, patients and health-care providers must be aware of risk factors for SMNs so that surveillance is focused and early prevention strategies are implemented.

    View details for Web of Science ID 000168084800012

    View details for PubMedID 11309438

  • The Intergroup Rhabdomyosarcoma Study Group (IRSG): Major Lessons from the IRS-I through IRS-IV Studies as Background for the Current IRS-V Treatment Protocol Sarcoma Sarcoma Raney, R., Maurer HM, Anderson JR, Andrassy RJ, Donaldson SS, Qualman SJ, Wharam MD, Wiener ES, Crist WM 2001; 5: 9-15
  • The Intergroup Rhabdomyosarcoma Study Group (IRSG): Major Lessons From the IRS-I Through IRS-IV Studies as Background for the Current IRS-V Treatment Protocols. Sarcoma Raney, R. B., Maurer, H. M., Anderson, J. R., Andrassy, R. J., Donaldson, S. S., Qualman, S. J., Wharam, M. D., Wiener, E. S., Crist, W. M. 2001; 5 (1): 9-15


    Purpose. To enumerate lessons from studying 4292 patients with rhabdomyosarcoma (RMS) in the Intergroup Rhabdomyosarcoma Study Group (IRSG, 1972-1997).Patients. Untreated patients < 21 years of age at diagnosis received systemic chemotherapy, with or without irradiation (XRT) and/or surgical removal of the tumor.Methods. Pathologic materials and treatment were reviewed to ascertain compliance and to confirm response and relapse status.Results. Survival at 5 years increased from 55 to 71% over the period. Important lessons include the fact that extent of disease at diagnosis affects prognosis. Re-excising an incompletely removed tumor is worthwhile if acceptable form and function can be preserved. The eye, vagina, and bladder can usually be saved. XRT is not necessary for children with localized, completely excised embryonal RMS. Hyperfractionated XRT has thus far not produced superior local control rates compared with conventional, once-daily XRT. Patients with non-metastatic cranial parameningeal sarcoma can usually be cured with localized XRT and systemic chemotherapy, without whole-brain XRT and intrathecal drugs. Adding doxorubicin, cisplatin, etoposide, and ifosfamide has not significantly improved survival of patients with gross residual or metastatic disease beyond that achieved with VAC (vincristine, actinomycin D, cyclophosphamide) and XRT. Most patients with alveolar RMS have a tumor-specific translocation. Mature rhabdomyoblasts after treatment of patients with bladder rhabdomyosarcoma are not necessarily malignant, provided that the tumor has shrunk and malignant cells have disappeared.Discussion. Current IRSG-V protocols, summarized herein, incorporate recommendations for risk-based management. Two new agents, topotecan and irinotecan, are under investigation for patients who have an intermediate or high risk of recurrence.

    View details for DOI 10.1080/13577140120048890

    View details for PubMedID 18521303

  • Results from the IRS IV Randomized Trial of Hyperfractionated Radiotherapy in Children with Rhabdomyosarcoma: A Report from the IRSG International Journal of Radiation Oncology, Biology, and Physics Donaldson SS, Meza J, Breneman JC, Crist WM, Laurie F, Qualman SJ, Wharam M 2001; 51: 718-728
  • Second Malignant Neoplasms in Five-Year Survivors of Childhood Cancer: Childhood Cancer Survivor Study Journal of the National Cancer Institute Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadows AT, Robison LL 2001; 93: 618-29
  • Long-term Results of Irradiation for Patients with Progressive Graves' Ophthalmopathy International Journal of Radiation Oncology, Biology, and Physics Marquez SD, Lum BL, McDougall IR, Katkuri S, Levin PS, MacManus M, Donaldson SS 2001; 51: 766-774
  • Intergroup Rhabdomyosarcoma Study IV: Results for Patients with Non-metastatic Disease Journal of Clinical Oncology Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualmann SJ, Wiener E, Wharam M, Lobe T, Webber B, Maurer HM, Donaldson SS 2001; 19: 3091-3102
  • Soft-tissue sarcomas of the diaphragm: A report from the intergroup Rhabdomyosarcoma Study Group from 1972 to 1997 JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Raney, R. B., Anderson, J. R., Andrassy, R. J., Crist, W. M., Donaldson, S. S., Maurer, H. M. 2000; 22 (6): 510-514


    To describe clinical details and outcome of children and adolescents with primary sarcomas of the diaphragm treated on Intergroup Rhabdomyosarcoma Studies (IRS) I through IV.We reviewed the records of 15 patients with sarcoma of the diaphragm who were entered on IRS Group protocols between 1972 and 1997. Patient ages at diagnosis ranged from 0.5 to 20 years (median, 13 yrs), and 10 were girls. Patients had chest pain, dyspnea, and/or coughing, decreased breath sounds, and occasionally hepatomegaly.Localized, gross residual disease after initial surgery was present in 10 patients, and five had metastases at diagnosis (pleura, 3; pericardium, 1; lungs and bones, 1). Tumor subtypes were alveolar rhabdomyosarcoma (RMS) in five cases, embryonal RMS in three, undifferentiated sarcoma in three, extraosseous Ewing sarcoma in three, and unclassified sarcoma in one. Treatment consisted of radiation therapy to the primary tumor and metastases when feasible, and combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin, ifosfamide, cisplatin, and etoposide. Ten patients achieved complete remission (67%), four obtained a partial remission, and one was improved. Five patients (33%) are continuously failure-free and alive at a median of 8.8 years from diagnosis (range, 1.1-15 yrs). However, the other 10 patients experienced relapse at 0.3 to 2 years from start of therapy (median, 1 yr). Sites of relapse were local in five, distant in three, and combined in two. Death after relapse occurred at 0.39 to 2.6 years (median, 1.6 yrs) from diagnosis.Sarcomas of the diaphragm are generally deemed unresectable at diagnosis and/or are metastatic. Most of them are not embryonal rhabdomyosarcomas. Treatment with more effective primary chemotherapy to shrink the tumor, followed-up by surgical resection and radiation therapy, should improve the prognosis for patients with sarcomas arising in the diaphragm, especially for the majority who have localized tumors.

    View details for Web of Science ID 000165933100007

    View details for PubMedID 11132218

  • Soft-tissue Sarcomas of the Diaphragm: From the Intergroup Rhabdomyosarcoma Study Group from 1972-1977 Journal of Pediatric Hematology and Oncology Raney RB, Anderson JR, Andrassy RJ, Crist WM, Donaldson SS, Maurer HM 2000; 22: 510-514
  • Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the intergroup rhabdomyosarcoma studies I to III JOURNAL OF CLINICAL ONCOLOGY Wolden, S. L., Anderson, J. R., Crist, W. M., Breneman, J. C., Wharam, M. D., Wiener, E. S., Qualman, S. J., Donaldson, S. S. 1999; 17 (11): 3468-3475


    To evaluate the outcome of patients with rhabdomyosarcoma (RMS) treated with complete surgical resection and multiagent chemotherapy, with or without local radiotherapy (RT).Four hundred thirty-nine patients with completely resected (ie, group I) RMS were further treated with chemotherapy (vincristine and actinomycin D +/- cyclophosphamide, doxorubicin, and cisplatin) on Intergroup Rhabdomyosarcoma Studies (IRS) I to III between 1972 and 1991. Eighty-three patients (19%) also received local RT as a component of initial treatment.Eighty-six patients relapsed (10-year failure-free survival [FFS] 79%, overall survival 89%). Six percent of failure sites were local, 6% were regional, and 7% were distant. Poor prognostic factors were tumor size greater than 5 cm, alveolar or undifferentiated histology, primary tumor sites other than genitourinary, and treatment on IRS-I or II. For patients with embryonal RMS who were treated with RT, there was a trend for improved FFS but no difference in overall survival. On IRS-I and II, patients with alveolar or undifferentiated sarcoma who received RT compared with those who did not receive RT had greater 10-year FFS rates (73% v 44%, respectively; P =.03) and overall survival rates (82% v 52%, respectively; (P =.02). Such patients who received RT on IRS III also benefited more than those who did not receive RT (10-year FFS, 95% v 69%; P =.01; overall survival, 95% v 86%; P =.23).Patients with group I embryonal RMS have an excellent prognosis when treated with adjuvant multiagent chemotherapy without RT. Patients with alveolar RMS or undifferentiated sarcoma fare worse; however, FFS and overall survival are substantially improved when RT is added to multiagent chemotherapy (IRS-I and II). The best outcome occurred in IRS-III, when RT was used in conjunction with intensified chemotherapy.

    View details for Web of Science ID 000083473700016

    View details for PubMedID 10550144

  • Does debulking improve survival rate in advanced-stage retroperitoneal embryonal rhabdomyosarcoma? JOURNAL OF PEDIATRIC SURGERY Blakely, M. L., Lobe, T. E., Anderson, J. R., Donaldson, S. S., Andrassy, R. J., Parham, D. M., Wharam, M. D., Qualman, S. J., Wiener, E. S., Grier, H. E., Crist, W. M. 1999; 34 (5): 736-741


    BACKGROUND, METHODS, AND PURPOSE: The authors examined demographic and clinical features, therapy, and outcome of patients with advanced (group III or IV) rhabdomyosarcoma (RMS) of the retroperitoneum and nongenitourinary pelvis treated in the Intergroup Rhabdomyosarcoma Study Group (IRSG) III (1984 to 1991, n = 41) or IV pilot (1987 to 1991, n = 53) studies to assess the role of initial debulking surgery.Ninety-four patients with retroperitoneal primary tumors and gross locoregional residual tumor (group III, n = 53) or metastatic disease (group IV tumors, n = 41) were treated with combination chemotherapy (ie, vincristine, dactinomycin, and cyclophosphamide with or without other agents plus radiation therapy, RT) after biopsy only or subtotal resection. These retroperitoneal tumors usually were invasive (T2, 76%). Most patients were younger than 10 years of age (n = 69, 73%), the male to female ratio was 1.4, and tumors usually were embryonal (n = 64, 68%). Overall 4-year failure-free survival (FFS) was 50%; survival was 60%. Survival rate was better for girls (4-year survival rate, 75% v49% for boys; P = .05) and was not significantly different for patients treated in IRS-III (66%) or IRS-IV pilot (52%). However, it was better for patients with embryonal versus alveolar or undifferentiated tumors (4-year survival rate, 70% v 42%; P = .002). In adolescents, RMS is different from that seen in children less than 10 years old; most cases are alveolar or undifferentiated (16 of 29, 55%). Surgery for most (21 of 24) patients with alveolar tumors comprised biopsy only. By contrast, of 64 patients with embryonal tumors, 39 (61%) underwent biopsy only, whereas 25 (39%) had debulking surgery. Patients whose tumors were debulked fared better than those whose tumors underwent biopsy only (4-year FFS rate, 72% v48%; P = 0.03). Patients with group IV embryonal tumors fared unexpectedly better than those with group IV alveolar or undifferentiated tumors (70% versus 42% 4-year survival rate, P < .05), and patients less than 10 years of age with group IV embryonal tumors had 4-year survival rate of 77%, indicating the importance of the biology of these tumors.Multimodal therapy, including multiagent chemotherapy plus RT, appears to improve survival rate in patients with advanced embryonal RMS arising in the retroperitoneum. These data suggest that debulking tumors of embryonal histology improves outcome further. This approach will be assessed in IRSG V.

    View details for Web of Science ID 000080447500033

    View details for PubMedID 10359174

  • Primary and metastatic rhabdomyosarcoma in the breast: Neoplasms of adolescent females, a report from the intergroup rhabdomyosarcoma study MEDICAL AND PEDIATRIC ONCOLOGY Hays, D. M., Donaldson, S. S., Shimada, H., Crist, W. M., Newton, W. A., Andrassy, R. J., Wiener, E., Green, J., Triche, T., Maurer, H. M. 1997; 29 (3): 181-189


    The occurrence of rhabdomyosarcoma (RMS) primary in or metastatic to breast has been regarded as an uncommon event, associated with an unfavorable outcome. Records of 26 patients with diagnoses of breast RMS, either primary or secondary, entered in the Intergroup Rhabdomyosarcoma Study (IRS) (1972-1992) were reviewed and compared with data regarding 47 similar patients in published reports. Of the 26 IRS cases, the histologic subtype was alveolar in 24, embryonal in 1, and not determined in 1. All were female with ages ranging from 11.5 to 20.2 years (median, 15.2 years; mode, 14-16 years). This compact age distribution of both primary (n = 7) and metastatic (n = 19) breast RMS was seen in previously reported series. Among the 19 cases of RMS with initial dissemination to breast, primary tumor sites, were extremity (n = 8), nasopharynx/paranasal sinuses (n = 7), and trunk (n = 4). IRS treatment was risk-based according to site and extent of disease. Four of 7 patients with primary RMS remain disease free 2.9 to 7 years post diagnosis. Among 19 patients with RMS initially metastatic to breast, including 7 in IRS clinical group IV at original diagnosis, three are disease free at 7.6, 15.7 and 17.0 years. Conclusions: primary or metastatic RMS in breast is almost confined to adolescent females having tumors with alveolar histology. Approximately one-half of the patients with primary breast disease and 15% of those with metastatic breast disease as an initial recurrence are long-term survivors.

    View details for Web of Science ID A1997XH25700004

    View details for PubMedID 9212842



    The early occurrence of five cases of acute myeloid leukemia (AML) in children treated for primary rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Study III (IRS III) has prompted this report. These patients received cyclophosphamide and four received etoposide in addition to other agents. There were 1,062 eligible patients entered on IRS III between 1984 and 1991. Following surgery, treatment consisted of multiagent chemotherapy and radiotherapy in select clinical groups. Median follow-up time is 3.7 years (range 0-7.4 years). Incidence densities and odds ratios for AML were calculated for various treatment groups. Five cases of secondary AML have been reported through August 1992. A single case of osteogenic sarcoma was reported in the same period and a patient with myelodysplastic syndrome has occurred since that time. Median time to development of AML was 39 months. Incidence density of AML for patients receiving neither cyclophosphamide nor etoposide was 0, for those receiving cyclophosphamide but no etoposide it was 7.6, and when both agents were given, it was 51.6. The odds ratios of AML for the latter two groups indicated a risk of AML which was seven times higher in the patients who received both agents. A history of breast cancer was present in all five families of patients with AML and several other cancers had occurred in three families. Preliminary analysis suggests a possible causal role for low-dose etoposide in addition to that assumed for cyclophosphamide in the early development of AML among pediatric patients treated for rhabdomyosarcoma.

    View details for Web of Science ID A1994NT35700005

    View details for PubMedID 8202048

  • ACUTE HYPERSENSITIVITY REACTIONS TO ETOPOSIDE IN A VEPA REGIMEN FOR HODGKINS-DISEASE JOURNAL OF CLINICAL ONCOLOGY Hudson, M. M., Weinstein, H. J., Donaldson, S. S., Greenwald, C., Kun, L., Tarbell, N. J., HUMPHREY, W. A., Rupp, C., Marina, N. M., Wilimas, J., Link, M. P. 1993; 11 (6): 1080-1084


    We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation.Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media.Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration.Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.

    View details for Web of Science ID A1993LF31000011

    View details for PubMedID 8501494


    View details for Web of Science ID A1992KA57000020

    View details for PubMedID 1447024



    Hypercalcemia is not common in Hodgkin's disease, but in reported cases is often unassociated with bone involvement. A case is presented demonstrating a mechanism involving elevated levels of 1,25-dihydroxy vitamin D3 (calcitriol). Similar cases in the literature are reviewed. Data implicating calcitriol as a hematolymphoid regulatory hormone are discussed as they may relate to lymphomas, leukemias, and paraneoplastic lymphocyte and monocyte/macrophage activity.

    View details for Web of Science ID A1989U165800009

    View details for PubMedID 2649225



    Langerhans' cell histiocytosis has been accepted by many to replace the term Histiocytosis X, describing a poorly defined continuum of diseases involving neoplastic proliferation of histiocytes. Twenty-four cases of histologically confirmed Langerhans' cell histiocytosis with head and neck involvement were seen between the years 1970 to 1986, and charts were reviewed retrospectively. Control of local osseous disease was successful using radiation therapy in 100% of those cases with follow-up. Surgical curettage of bone lesions was successful in a small number of cases. Chemotherapy alone or in combination with radiation appeared to enhance survival in patients with recurrent disease or multisystem involvement. Sixteen of the 24 patients (67%) are disease free with a mean follow-up of 6 years. Prompt diagnosis and careful follow-up are important to improve survival and prevent complications.

    View details for Web of Science ID A1987H246800002

    View details for PubMedID 3494895

  • TOPOGRAPHY OF CHILDHOOD TUMORS - PEDIATRIC CODING SYSTEM PEDIATRIC HEMATOLOGY AND ONCOLOGY Donaldson, S. S., Draper, G. J., Flamant, F., GERARDMARCHANT, R., Mouriesse, H., Newton, W. A., Lemerle, J. 1986; 3 (3): 249-258


    The importance of a uniform coding system for cancer research, tumor registry, and exchange of information is recognized. However, tumors arising in children differ from those in adults, resulting in lack of precision when one coding system is used for both. Because the topographic code of the International Classification of Disease for Oncology for adult tumors does not lend itself well to pediatric tumors, the International Society of Paediatric Oncology (SIOP) developed a four-digit topographic coding system particularly adapted to childhood tumors. The four digits correspond to anatomic site, general and specific localization, and tissue of origin. An SIOP pilot study demonstrated the usefulness of this code.

    View details for Web of Science ID A1986F094100007

    View details for PubMedID 3153237



    We present a group of eight pediatric cancer patients with a spectrum of visual afferent pathway abnormalities. Changes include decreased visual acuity, visual field alterations, abnormal visual evoked potentials, changes in the optic disc and nerve fiber layer of the retina, radiation retinopathy, and CNS injury. These changes occur in long term survivors of pediatric malignancy (especially those with prolonged, multimodal, and multicourse therapy), but they may be minimally symptomatic. The changes appear to be analogous to the CNS changes (leukoencephalopathy) described in patients with leukemia and attributed to multimodal therapy. By taking advantage of opportunities to detect adverse effects earlier in the treatment course, the present excellent cure rate may be improved by refinements in therapy that also improve the quality of survival.

    View details for Web of Science ID A1986F211000004

    View details for PubMedID 3784980



    Two children with Ewing's sarcoma developed acute nonlymphocytic leukemia (ANLL) during the course of their illness. One patient developed ANLL after apparently successful treatment of his primary malignancy with radiation therapy and multiagent chemotherapy. In the second patient, acute leukemia developed before the administration of radiotherapy or systemic chemotherapy. The development of secondary ANLL after Ewing's sarcoma has been reported only twice previously, most likely representing a therapy-induced complication. The occurrence of ANLL in Patient 2 prior to therapy suggests that these two disorders may have a more than treatment-related association. Close follow-up of long-term survivors of Ewing's sarcoma with surveillance for secondary acute leukemia is advised.

    View details for Web of Science ID A1984SW62300009

    View details for PubMedID 6727775

  • THYROID-DYSFUNCTION AFTER RADIOTHERAPY IN CHILDREN WITH HODGKINS-DISEASE CANCER Constine, L. S., Donaldson, S. S., McDougall, I. R., Cox, R. S., Link, M. P., KAPLAN, H. S. 1984; 53 (4): 878-883


    Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkin's disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 rad or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG-XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low-dose group and 31 months in the high-dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose-related occult hypothyroidism in children following external irradiation of the neck.

    View details for Web of Science ID A1984SB64800010

    View details for PubMedID 6692289



    Patients with malignancies which are treated with therapeutic radiation are at risk for nutritional problems, both from their underlying malignancy as well as from their treatment. These effects may be acute or chronic and relate to the site of the tumor and regions irradiated. There is a large experience with nutritional intervention in irradiated patients, including oral feedings and enteral and parenteral nutritional support. The indications for the specific administration of nutritional support during radiotherapy depend on the nutritional status of the patient and the area irradiated, as well as the individual prognosis. Patients who are malnourished at the time of treatment are most likely to profit from nutritional intervention. To date, prospective randomized trials of nutritional support in patients undergoing radiotherapy fail to show a benefit of routine adjuvant nutritional intervention in terms of improved response and tolerance to treatment, improved local control or survival rates, or reduction of complications from therapy.

    View details for Web of Science ID A1984SS25400016

    View details for PubMedID 6429369



    An analysis of complications of therapy requires long-term and frequent followup. Reported here is a review of 179 consecutive children with Hodgkin's disease from Stanford University Medical Center who were seen, treated, and followed over a 20-year period. Complications of treatment are related to the extent of disease and the aggressiveness of therapy. Severe complications from radiotherapy are associated with high-dose, extended-field treatment in preadolescent children. Severe chemotherapy-associated complications include immunosuppression, sterility, and secondary oncogenesis. As cure rates are increasingly optimistic among children with Hodgkin's disease, successful treatment with minimal morbidity remains our greatest challenge. Therapy programs require continual refinement utilizing assessment of short- and long-term side effects of treatment.

    View details for Web of Science ID A1982NQ55100042

    View details for PubMedID 7074658

  • John Caffey Award: chemotherapy-induced inhibition of compensatory renal growth in the immature mouse. AJR. American journal of roentgenology MOSKOWITZ, P. S., Donaldson, S. S., CANTY, E. 1980; 134 (3): 491-496


    Minimal-lethal-doses (LD1/21) of Actinomycin-D (AMD), Vincristine (VCR), or Adriamycin (ADR) inhibited compensatory renal growth in unilaterally nephrectomized weanling mice. AMD transiently inhibited compensatory renal and body growth. VCR transiently inhibited kidney growth only, while ADR produced persistent kidney and body growth inhibition. 3H thymidine uptake was decreased at 5 days from controls with AMD and ADR, and increased at 14 days from controls with ADM, VCR, and ADR. Kidney DNA concentration was increased from controls at 3 days with AMD and at 8 and 14 days with ADR, but decreased from controls of 8 days with AMD and VCR. AMD and ADR inhibit compensatory renal growth and body growth in the immature mouse. VCR selectively inhibits renal growth. Renal growth inhibition with AMD, VCR, and ADR is related, in part, to a delay in the renal mitotic response to contralateral nephrectomy, and with AMD and ADR to generalized body growth supression. Chemotherapy injury to the growing mammalian kidney may be manifest as growth inhibition.

    View details for PubMedID 6766611


    View details for Web of Science ID A1980KA92600010

    View details for PubMedID 7204121



    Extraocular muscle enlargement was symmetrical in 70% and asymmetrical in 30% of patients with Graves' ophthalmopathy. True unilateral muscle involvement occurred in 6%. Computed tomography (CT) showed bilateral orbital involvement in 50% of patients presenting clinically with unilateral eye signs. In patients without a clinically apparent ophthalmopathy, CT demonstrated muscle enlargement in 40%. The medial and inferior rectus muscles were the most frequently and most severely involved. Orbital radiation therapy can result in a decrease in size of involved muscles.

    View details for Web of Science ID A1979HT47600018

    View details for PubMedID 583152


    View details for Web of Science ID A1979HA22300006

    View details for PubMedID 377071



    Weanling mice were given 500, 1,000, 1,500, or 2,000 rads single-fraction renal irradiation immediately following unilateral nephrectomy and sacrificed 3 days or 3, 6, 12, or 24 weeks later. Inhibition of compensatory renal growth was related to both radiation dose and time following treatment; it was transient following 500 and 1,000 rads but persisted following 1,500 and 2,000 rads. Renal growth was inhibited more than body growth. These studies indicate that the weanling mouse kidney is more sensitive to radiation-induced inhibition of compensatory renal growth than adult mice or other rodents.

    View details for Web of Science ID A1978FH28200041

    View details for PubMedID 663265



    A 9-year-old schoolgirl received 6007 rads to the suprasellar region for craniopharyngioma. Five years later, a malignant astrocytoma developed in the right temporal lobe. We cite clinical and experimental evidence to support our suspicion that the glioma may have been induced by radiation.

    View details for Web of Science ID A1978ES78300015

    View details for PubMedID 632887



    Non-caseating sarcoid-like epithelioid granulomas associated with Hodgkin's disease have been found in 55 patients initially staged and treated at the Stanford University School of Medicine. These patients are compared to 553 concurrent patients not having granulomas associated with their Hodgkin's disease. Pre-treatment parameters of the two groups are presented and found not to be different. Patterns of relapse in granuloma patients are presented and no relationship between location of granulomas and subsequent relapse is found. Survival and relapse-free survival curves are significantly different in favor of the granuloma group (p = 0.005 and p = 0.03, respectively). Correlation with skin test data has been attempted using a matched control analysis and no difference is found in reaction to intradermal antigens between the two groups.

    View details for Web of Science ID A1978EQ15900024

    View details for PubMedID 630538


    View details for Web of Science ID A1977EJ73300023

    View details for PubMedID 271145



    Curative doses of radiotherapy, when directed to any portion of the gastrointestinal tract, may result in serious nutritional consequences from the effects of radiation on the altered function of normal tissues. Symptoms from radiotherapy resulting in nutritional alterations are usually dependent upon dose, time, and fractionation of radiation administered, and the volume included in the treatment field. These effects directly related to radiation may be enhanced by other associated cancer therapy, e.g., surgery or chemotherapy. Careful observation and prompt attention to supportive therapy are mandatory to minimize the nutritional consequences of radiation injury. Well-designed clinical trials are necessary to demonstrate any possible increased tolerance to radiation therapy and the preventative benefits of nutritional support.

    View details for Web of Science ID A1977DL37000015

    View details for PubMedID 861954



    During the past decade at Stanford University Medical Center, in an attempt to protect ovarian function in young female patients irradiated for Hodgkin's disease, oophoropexy has been performed at the time of surgical staging. When pelvic irradiation is administered, a 10-cm thick lead block is used to shield the ovaries in the midline. With this technique, two-thirds of women have retained ovarian function, and nine women who underwent oophoropexy prior to high-dose pelvic irradiation have become pregnant. Six patients have given birth to eight babies. An additional two patients have had therapeutic abortions and one, a spontaneous abortion. The minimum radiation dose to the ovaries was 350 to 400 rads in 39 to 46 days. No abnormalities have been observed in the children; no ectopic pregnancies have occurred.

    View details for Web of Science ID A1976CQ60600011

    View details for PubMedID 826312



    CT scans of 9 patients with orbital pseudotumor (bilateral in 6 and unilateral in 3) showed findings distinct from those observed in Graves' ophthalmopathy. In bilateral involvement, they ranged from localized mass lesions to complete obiliteration of normal orbital CT anatomical landmarks; diffuse or multifocal lesions involving the posterior globe and muscle insertions were most typical of the diagnosis. However, findings in unilateral psedotumor may be indistinguishable from orbital mass lesions other than Graves' ophthalmopathy. Serial CT scans were used to show progression of disease and response to treatment.

    View details for Web of Science ID A1976CC61100018

    View details for PubMedID 988925

  • Letter: Orbital radiotherapy for the ophthalmopathy of Graves's disease. New England journal of medicine Donaldson, S. S., Bagshaw, M. A., KRISS, J. P. 1974; 290 (14): 805-?

    View details for PubMedID 4406001