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Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event-free survival (EFS), and overall survival rates from multidisciplinary therapy in Ewing's sarcoma. Methods and Materials: Between 1983 and 1988, 184 children with Ewing's sarcoma were enrolled onto Pediatric Oncology Group 8346 (POG 8346). A total of 178 (97%) met eligibility criteria; 6 had pathology other than Ewing's sarcoma. Induction chemotherapy of cyclophosphamide/doxorubicin (adriamycin )(C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy and C/A, dactinomycin, and vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. Forty patients were randomized to receive SF, whole bone radiation to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy, and the remainder were assigned to IF radiation. Results: Of 178 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases at presentation. Their 5-year EFS was 51% (SE 5%) and 23% (SE 7%) respectively. The response rate to induction chemotherapy was 88% (28% complete, 60% partial), but after radiotherapy the response rate increased to 98%. Thirty-seven of the localized patients underwent resection, of whom 16 (43%) required postoperative radiotherapy; the 5-year EFS of these surgical patients was 80% (SE 7%). The remaining 104 localized patients were eligible for randomization or assignment to receive radiotherapy; the 5-year EFS of these patients was 41% (SE 5%), with no significant difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5-year EFS: distal extremity 65% (SE 8%), central 63% (SE 10%), proximal extremity 46% (SE 8%), and pelvic–sacral 24% (SE 10%) ( p = 0.004). Initial tumor size did not correlate significantly with EFS. Patterns of failure among the 141 localized patients revealed 23% of patients experienced a local failure, while 40% had a systemic failure. The 5-year local control rate for the surgical patients +/- postoperative radiotherapy was 88% (SE 6%), while for the patients undergoing radiotherapy alone it was 65% (SE 7%). There was no difference in local control between those randomized to SF vs. IF. The 5-year local control rate for the patients with pelvic–sacral tumors was 44% (SE 15%), significantly worse than the local control rates for those with central tumors 82% (SE 8%), distal extremity 80% (SE 8%), or proximal extremity 69% (SE 9%) ( p = 0.023). However, quality of radiotherapy correlated with outcome. Patients who had appropriate radiotherapy had a 5-year local control of 80% (SE 7%), while those with minor deviations had 5-year local control of 48% (SE 14%), and those with major deviations had a local control of only 16% (SE 15%) ( p = 0.005). The local failure was within an irradiated volume in 62% of patients, outside the irradiated volume in 24% of cases, while the precise location could not be determined in the remaining 14%. Conclusions: As most failures in Ewing's sarcoma are systemic, improved EFS requires more effective systemic chemotherapy. Adequate IF radiotherapy requires treatment to appropriate volumes as defined by MRI imaging and full radiation doses. Pretreatment review of radiologic images with a musculoskeletal radiologist to determine appropriate tumor volumes, as well as use of conformal radiotherapy techniques are important for improved outcome.

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. Med. Pediatr. Oncol. 29:181–189, 1997. © 1997 Wiley-Liss, Inc.

Despite incomplete understanding of the etiology of Hodgkin's disease and its malignant cell of origin, the majority of children and adolescents diagnosed with Hodgkin's disease will be longterm survivors. Staging and treatment for pediatric Hodgkin's disease has evolved over the past 30 years in attempts to reduce late treatment sequelae. Today, most children are clinically staged and treated with multitreatment chemotherapy, either alone or in conjunction with low-dose, involved field radiation therapy. Initial results with "risk-adapted" combined modality regimens limiting chemotherapy cycles and radiation doses and volumes demonstrate maintenance of cure rates for early stage, favorable Hodgkin's disease. Challenges for the future include identification of prognostic factors in patients at risk for treatment failure who may benefit from intensification of therapy.

BACKGROUND Venoocclusive disease (VOD) of the liver is a common complication after allogenic and autologous bone marrow transplantation for malignant disease. The authors report the unusual and unexpected complication of VOD of the liver occurring in children with rhabdomyosarcoma who were receiving vincristine, actinomycin D, and cyclophosphamide (VAC) according to the chemotherapy regimens of the Intergroup Rhabdomyosarcoma Study (IRS) IV. METHODS The authors evaluated 821 patients with newly diagnosed rhabdomyosarcoma receiving treatment according to IRS IV who were considered at risk for VOD. RESULTS Ten patients developed VOD of the liver for an overall incidence of 1.2%. VOD was found only after the administration of VAC chemotherapy. The highest incidence of VOD was observed among patients who had previously received vincristine and melphalan (Regimen 48). None of the patients receiving the chemotherapy regimen of vincristine and actinomycin D (Regimen 44) developed VOD. CONCLUSIONS Patients receiving VAC-containing regimens on the IRS IV were found to be at risk for VOD. The VAC combination was used extensively in previous IRS studies (I, II, and III) and VOD was not reported during these studies, strongly suggesting that the escalation of the cyclophosphamide dose to 2.2 g/m2 (with the vincristine and actinomycin D doses and schedule remaining unchanged) triggered the development of VOD. The contributing role of previous therapy or events is unknown. At last follow-up, none of the nine surviving patients had developed recurrent VOD on continuation of chemotherapy. Cancer 1997; 79:2435-9. © 1997 American Cancer Society.

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.

Purpose: A retrospective analysis was perforned on children with nonmetastatic rhabdomyosarcomas (RMS) involving a parameningeal site treated by one of the four major cooperative groups: Intergroup Rhabdomyosarcoma Study (IRS), International Society of Pediatric Oncology (SIOP), German Cooperative Group (CWS), and Italian Cooperative Group (ICS) to analyse survival and prognostic factors. Methods and Materials: Between 1979 and 1989, 230 children (median age 6 years) were treated in the IRS III, SIOP 84, CWS 81, and ICS 79 studies. All patients received chemotherapy, and 203 were irradiated. Radiotherapy doses were similar in the four studies, although treatment volumes were not similar. The SIOP patients had smaller volumes treated. In addition, the SIOP patients with a low risk of meningeal involvement and children under 5 years of age were not irradiated if they had a complete response (CR) to chemotherapy. Time to initiation of irradiation was earlier in the IRS and Italian studies. Results: Median follow-up was 62 months (range 22–140). The 5-year survival and 5-year event-free survival were better for the IRS study (74% and 71%) than for the other study groups (55% and 36% for SIOP, 47% and 47% for CWS, and 39% and 39% for ICS). The low-risk (LR) patients in the IRS study had improved survival. However, patients with high risk of meningeal involvement had similar survival in all four studies. THe most significant prognostic factor was the size of tumor (>5 cm). Conclusion: The improved results from the IRS group, especially among the LR patients, could be related to the IRS treatment employed, particularly the systematic use of radiation, to the inclusion of patients with smaller tumors, and to the routine use of quality control of radiation.

Here, we present the case of a pediatric patient with newly diagnosed hepatocellular carcinoma causing central biliary obstruction and persistently elevated bilirubin of 3.0–4.3 mg/dl despite placement of bilateral internal–external biliary drains. The tumor was not resectable, and the patient was not a candidate for liver transplant due to nodal disease, for chemotherapy due to hyperbilirubinemia, or for local therapies aside from stereotactic body radiotherapy (SBRT). In this report, we discuss the successful use of SBRT in the management of this patient, and its role in allowing the patient to become a candidate for additional therapies.

Purpose : To disprove the common view that women who have undergone irradiation to fields excluding the pelvis are at risk for radiation-induced premature menopause, we reviewed menstrual function and fertility among women treated with subtotal lymphoid irradiation for Hodgkin's Disease. Methods and Materials : Treatment and follow-up records of all women less than age 50 at the time of diagnosis of Stage I or II supradiaphragmatic Hodgkin's Disease, treated with subtotal lymphoid irradiation alone and enrolled in radiotherapy trials from 1967 to 1985, were reviewed. In addition, patients were surveyed regarding their menstrual status and fertility history. Results : Thirty-six women, aged 10 to 40 years, with normal menstrual function at the time of Hodgkin's diagnosis, were identified. Mean follow-up was 14 years, with a range of 1.25-22.75 years. The average radiation dose to mantle and paraaortic fields was 40-44 Gy ; the calculated scatter radiation dose to the pelvis at the ovaries was 3.2 Gy. There were 38 pregnancies in 18 women ; all offspring are normal. One of 36 women (2.7%) experienced premature menopause. The reported rate of premature menopause in women who have not undergone irradiation is 1-3% ; not significantly different than the rate in our study. There is a syndrome whereby antibodies to several endocrine organs occur (including the ovary), which is associated with premature ovarian failure. This syndrome may be associated with prior radiation to the thyroid, such as that given by mantle irradiation for Hodgkin's Disease. We report such a case. Conclusion : There is little risk of premature menopause in women treated with radiation fields that exclude the pelvis. Women with presumed radiation-induced premature menopause warrant an evaluation to exclude other causes of ovarian failure, such as autoimmune disorders.

Background. This study was designed to investigate the costs associated with the use of magnetic resonance imaging (MRI) in the workup of spinal cord compression caused by metastatic disease, an area in which it has proven to be diagnostically useful. Methods. The study was divided into two parts. Part 1 consisted of a retrospective review of the hospital charts of 46 patients, half of whom were diagnosed with cord compression in the pre-MRI era and the other half diagnosed after MRI availability ; costs for these two groups were compared. Part 2 consisted of a review of several major studies comparing the sensitivities and specificities of MRI with alternative imaging techniques, usually myelography. Cost effectiveness and cost/cost ratios were derived for diagnostic usefulness using prevalence, sensitivity, specificity, and cost estimates of MRI and its alternatives, including costs of false-negative and false-positive testing. Results. Our hospital-based experience yielded an average cost of $3664 per patient without MRI and $2283 per patient when MRI was available (1991 dollar amounts). The cost of diagnosis was 65% more expensive without MRI. Use of the literature-based experience demonstrated that the cost of diagnosis was at least 82% more costly without MRI than when it was available. However, when key variables were altered during sensitivity analysis, this difference of increased cost of diagnosis without MRI ranged from 25% to 98%. Conclusion. This work suggests that MRI may result in significant economic benefits in diagnosing metastatic cord compression, but further work is needed on physician behavior and referral patterns with MRI versus myelography as is long term follow-up for potential reductions in patient debility using MRI. Cancer 1995 ;75 :2579-86.

The effect of radiation on epiphyseal bone growth is one of the most important dose-limiting factors in the radiotherapeutic management of children with malignant neoplasms. Clinical and laboratory evidence suggest that many factors may influence the severity of radiation-induced growth arrest. However, the absence of a consistent scoring system for late effects has hampered efforts to analyze the influence of various therapeutic maneuvers or to compare and collate results from different reported series. In this review, laboratory and clinical studies of radiation effects on growing bone are summarized, and a late effects scoring system is proposed.

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 survival.clinicaltrials.gov Identifier: NCT00145600.

Objective: To study short-term changes in the radiopharmaceutical bone scan (BS) appearance of Ewing's sarcoma for indicators of decreased survival or future disease progression. Methods: One-hundred and four patients with non-metastatic Ewing's sarcoma were evaluated at three time points: time of diagnosis (pre-biopsy), after induction chemotherapy (13 weeks) and after radiation therapy (20 weeks). Radiographs, computed tomograms (CTs) and BSs were obtained at each interval. Primary lesion activity and size on BS were evaluated and compared to radiographic and CT findings. Results: No significant relationship was found at any time point between absolute radiopharmaceutical activity within the primary lesion and either disease progression or patient survival. Relative changes in BS activity between time points were also not significantly related to disease progression or survival despite a significant decrease in activity among the three time points. The size of the BS abnormality compared to the CT abnormality at the primary lesion site was related to both survival and disease progression at the post-induction chemotherapy time point ( P = 0.025 and P = 0.014, respectively) with larger BS abnormalities indicating worse prognosis and survival. This relationship lost its significance at the post-radiation time point. No other significant relationship between the relative size of the BS abnormality and the size of the plain radiographic or CT abnormality was detected. Conclusion: Our data suggest that BS imaging of the primary lesion of Ewing's sarcoma provides little information in terms of predicting long-term survival or disease progression in patients with non-metastatic Ewing's sarcoma.

Curious, adventuresome, resourceful, flexible, persistent, and caring! These stellar qualities are exhibited by the many women in Radiation Oncology who have pioneered through difficult times. These women are recognized as researchers, healers, and mentors. They have emerged as our leaders and models and, thus, have influenced hundreds of women. Like a human pyramid, they have helped build our discipline. There have been many inspiring women, from all over the world, who have contributed as physicists, biologists, and clinicians over the past 100 years. This article highlights only a few of the women who have contributed as research-scientists, clinician-healers, and educators. In acknowledging these women it is important to remember that in the early days it was not acceptable for a woman to be educated, let alone study science, or work with large heavy machines and dangerous equipment. These women have made numerous scientific contributions that stand out in history, but their personal stories reveal their many qualities that have contributed to their success. These personal stories are described in the following vignettes of a few of the pioneering women in Radiation Oncology.

Retroperitoneal lymph node dissection (RPLND) was used in 121 Intergroup Rhabdomyosarcoma Study (IRS) III patients with nonmetastatic paratesticular (PT) rhabdomyosarcoma (RMS) to assess retroperitoneal lymph node (RPLN) involvement so as to determine the need for x-ray therapy (XRT). Clinical node evaluation (CNE) was accomplished by a computed tomography (CT) scan in 105 and a sonogram in six. Pathological node evaluation (PNE) was performed in 113: lymphadenectomy (9 bilateral, 85 unilateral) and biopsy in 19. Vincristine and actinomycin D were used for 1 year postoperatively in 89%; all patients who had positive PNE received RPLN XRT. This study compares CNE with PNE and evaluates predictors of relapse and survival. Findings: There were clinically negative nodes (cN0) in 81% of the 121 patients. Among cN0 patients, 14% had positive nodes (pN1). Of the clinically positive (cN1) patients, 94% had pN1. RPLN relapse occurred in only two of the 121 patients. Initially both had cN0 and one had PNE that was negative. For all 121 patients, the 5-year survival was 91%. For cN0 patients, the 5-year survival was 96% compared with 69% for cN1 patients ( P P Conclusions: (1) Results of RPLN imaging studies were negative in 81% of patients with PT RMS (specificity 99%, sensitivity 57%). (2) RPLN recurrence is uncommon (even when RPLN are initially involved) if regional XRT and appropriate chemotherapy are used. (3) RPLN biopsy is not necessary to confirm positivity in patients with clinically positive nodes. (4) Node positivity is associated with decreased patient survival and helps identify patients who have an increased risk for relapse and death.

Purpose : A retrospective review of patients with Hodgkin's disease treated at Stanford University Medical Center was undertaken to determine if, within the pediatric population, children ≤ 10 years of age have a unique prognosis and response to treatment. Methods and Materials : Records of all patients treated for Hodgkin's disease at SUMC between 1961 and 1991 were reviewed. Results : Of 2238 patients with Hodgkin's disease, 91 (4%) were ≤ 10 years of age. There is a predominance of male patients (80%) and a higher percentage of mixed cellularity (33%) and lymphocyte predominance (13%) histologies among the very young patients compared to adolescents and adults. The 5 and 10-year survival is 94 ± 3% and 92 ± 3%, respectively, for children s 10 vs. 93 ± 2% and 86 ± 3% for adolescents and 84 ± 1% and 73 ± 1% for adults. Five and 10-year freedom from relapse is also higher in the youngest children (88 ± 4% and 85 ± 4%, respectively) compared to adolescents (78 ± 3% and 74 ± 3%, respectively) and adults (70 ± 1% and 67 ± 1%, respectively). Actuarial survival at 25 years for children ≤ 10 years is 78%, which is slightly better than for adolescents (67%) and significantly better than for adults (41%) (p = 0.001). Actuarial 25-year freedom from relapse is also significantly better for children ≤ 10 (78%) compared to adolescents (74% [p = 0.05]1) and adults (65% [p = 0.001]1). For all stages of disease, children ≤ 10 fare similarly to or slightly better than adolescents and substantially better than adults. For those with Stage I or II disease, survival at 5, 10, and 25 years is 98 ± 2%, 93 ± 4% and 73%, respectively, for children aged ≤ 10; 98 ± 1%, 91 ± 3%, and 79%, respectively, for adolescents and 89 ± 1%, 80 ± 1%, and 45%, respectively, for adults. The greatest difference between age groups is seen for Stage III and IV patients. Those aged ≤ 10 have an 89 ± 5% 5 and 10-year survival, and 89% actuarial 25-year survival compared to 87 ± 4%, 80 ± 5%, and 28%, respectively, for adolescents and 77 ± 2%, 64 ± 2%, and 41%, respectively, for adults. Of patients ≤ 10 years of age, 28 (31%) were treated with primary external beam radiotherapy, and 59 (65%) received combined modality therapy consisting of low-dose radiation and chemotherapy. With a median follow-up of 11 years, freedom from relapse is 64% and survival 75% for the radiotherapy group, compared to 97% (p = 0.000) and 93% (p = 0.21) for those treated with combined modality therapy. Conclusion : Results indicate that young age is a favorable prognostic factor in Hodgkin's disease. Combined modality therapy has led to improved freedom from relapse and survival rates for all stages of disease and is currently the treatment of choice for the majority of very young children.

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.

Purpose 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). Methods and Materials 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. Results 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. Conclusions 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.

Background. Intergroup Rhabdomyosarcoma Study (IRS)-II, (1978–1984) had the general goals of improving the survival and treatment of children with rhabdomyosarcoma (RMS). Methods. Nine hundred ninety-nine previously untreated eligible patients entered the study after surgery and were randomized or assigned to therapy by IRS Clinical Group (I-IV), tumor site, and histologic type. Outcomes were compared between treatments and with results of IRS-I (1972–1978). Results. Patients in Group I, excluding extremity alveolar (EA) RMS, were randomized to standard vincristine (V), dactinomycin (A), and cyclophosphamide (C) or standard VA. At 5 years, disease-free survival (DFS) and survival (S) rates were similar between VAC and VA (DFS:80%, 70%, P = 0.47; S:85%, 84%, P = 0.73). Patients in Group II, excluding EA RMS, received radiation and were randomized to intensive VA or repetitive-pulse VAC. Outcomes were similar for rates of DFS (69%, 74%, P = 0.83) and S (88%, 79%, P = 0.17). Patients in Group III, excluding certain pelvic tumors, received radiation and were randomized to repetitive-pulse VAC or repetitivepulse VAdrC-VAC (Adr, Adriamycin [doxorubicin]). Complete remission (CR) rates were close at 74%, 78%, respectively (P = 0.32), as were percentages in CR (73%) and S (66%) rates; the latter outcomes were significantly better than IRS-I (CR: 56%, P < 0.001; S:50%, P < 0.001). Central nervous system prophylaxis for Group III patients with cranial parameningeal sarcoma increased S rate to 67% from 45% in IRS-I (P < 0.001). Patients in Group IV received the same regimens as Group III; the CR rate was 53%, 38% remained in CR and S rate was 27% with and 26% without Adr (P = 0.90). At 5 years, S rate for IRS-II, including EA and all pelvic tumors, was 63%: an 8% increase over IRS-I (P < 0.001). Outcomes by primary site were as good as, or better than, the IRS-I experience. Conclusions. Combining all Groups and treatments in IRS-II, the major improvement in S rate at 5 years between studies was in nonmetastatic patients (71% for IRS-II versus 63% for IRS-I, P = 0.01).

10 radiology.rsna.org Radiology: Volume 270: Number 1—January 2014 Radiologists’ understanding of the imaging modalities they use each day would not be the same without the career of Norbert J. Pelc, ScD. Having conducted research in all medical imaging modalities, and in particular digital x-ray, computed tomographic (CT), and magnetic resonance (MR) imaging, Dr Pelc possesses extraordinary knowledge of the technical aspects of imaging and a one-of-a-kind insight into advanced applications and basic research. He has contributed to the development of these modalities as a researcher working in industry and academia; as an educator, he also has imparted his experience to aid a new generation of scientists in making their contributions. Dr Pelc serves as the Boston Scientific applied biomedical engineering professor and professor of bioengineering and radiology and, by courtesy, of electrical engineering at Stanford UniSarah S. Donaldson, MD 2013 RSNA Outstanding Researcher1

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.

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, tumors5 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.

Purpose 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. Methods and Materials 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. Results 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). Conclusion 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.

Purpose 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. Patients and Methods 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. Results 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. Conclusion 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.

Purpose This study was undertaken to determine the effect of treatment for childhood cancer on male fertility. Patients and Methods We reviewed the fertility of male Childhood Cancer Survivor Study survivor and sibling cohorts who completed a questionnaire. We abstracted the chemotherapeutic agents administered, the cumulative dose of drug administered for selected drugs, and the doses and volumes of all radiation therapy from medical records. Risk factors for siring a pregnancy were evaluated using Cox proportional hazards models. Results The 6,224 survivors age 15 to 44 years who were not surgically sterile were less likely to sire a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI, −0.49 to 0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy of more than 7.5 Gy to the testes (HR, 0.12; 95% CI, −0.02 to 0.64), higher cumulative alkylating agent dose (AAD) score or treatment with cyclophosphamide (third tertile HR, 0.42; 95% CI, −0.31 to 0.57) or procarbazine (second tertile HR, 0.48; 95% CI, −0.26 to 0.87; third tertile HR, 0.17; 95% CI, −0.07 to 0.41). Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0, a hypothalamic/pituitary radiation dose = 0 Gy, and a testes radiation dose = 0 Gy was 0.91 (95% CI, 0.73 to 1.14; P = .41). Conclusion This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.

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.

PurposeThe purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer.MethodsWe 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.ResultsThe 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.ConclusionResults 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.

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.

Purpose This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility. Patients and Methods 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. Results 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 ≥ 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. Conclusion 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.

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.

Age of a patient when afflicted with Hodgkin's disease is an important prognostic factor. Although there are histologic and stage differences as a function of age, the younger a patient is when diagnosed, the better the cure rate. Youngsters less than age 10 years have a freedom from relapse of 80% at 26 years follow-up examination; adolescents in the 11 to 16 age group have a freedom from relapse or 74%; and adults aged 17 years or older have a freedom from relapse of 64%. These differences translate into significant survival differences as well, with children aged 10 years or younger and those aged 11 to 16 years having a 26-year survival of 74%, as compared to adults, who have a 37% survival (P = 0.003). These differences remain significant when comparing those with stage I and II disease, as opposed to those with advanced stage III and IV disease. Children present the greatest challenges with respect to staging and treatment. The older child with localized disease can be managed appropriately as an adult. However, for the younger child the use of low-dose radiation and multiagent chemotherapy is widely accepted. Using this approach, survival rates of 85% or greater are reported from many large institutional and cooperative group experiences. The goals of treatment today are cure of disease, with maximal quality of life and minimal complications from the treatment. The late effects of greatest importance to the youngest children are skeletal and bone growth abnormalities, sterility, and malignant tumor induction. Treatment programs today should be directed towards refining therapy to minimize sequelae while maximizing quality of life. These goals are best achieved when children are managed in regional centers with demonstrated expertise in the management of children with Hodgkin's disease. Whereas cure can be achieved in a large majority of children diagnosed with Hodgkin's disease, our challenge is cure, with the least sequelae and the greatest quality of life. "Children are not simply micro-adults, but have their own specific problems."

Purpose Determine outcome of patients with cranial parameningeal sarcoma and concurrent metastases treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II–IV. Patients We identified 91 patients in the database, which includes newly diagnosed subjects

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.

From 1956 to 1988, 57 children and young adults (age 4-21 years) with a diagnosis of nasopharyngeal carcinoma were treated at The University of Texas M.D. Anderson Cancer Center (42 patients) and Stanford University Medical Center (15 patients). The male to female ratio was 2:1. Forty-three patients had lymphoepithelioma, seven had undifferentiated neoplasms, and seven had squamous cell carcinoma. Two patients had Stage III disease and the remainder had Stage IV disease at the time of presentation. All patients were treated with primary radiotherapy, and 14 patients also had chemotherapy with combinations of the following drugs: dactinomycin, doxorubicin, bleomycin, cisplatin, cyclophosphamide, fluorouracil, methotrexate, and vincristine. Twenty-six patients are alive 6 to 178 months from the first day of treatment (median 93 months). The 5- and 10-year actuarial survival rates are 51% and 36%, respectively, and the corresponding disease specific survival rates were 51% and 51%. There were no recurrences after 42 months. The patterns of failure were as follows: distant metastasis only, 21 patients; locoregional metastasis only, 1; both, 5. Distant metastases most commonly occurred in bones, lungs, liver, and mediastinal lymph nodes. Chronic treatment-related morbidity was encountered in a significant number of long term survivors. Trends in the data not reaching statistical significance suggest a more favorable prognosis for a) females, b) patients less than or equal to 15 years of age, c) lymphoepithelioma or undifferentiated histologies, d) stages T3-4 NO-1 vs T1-2 N2-3 vs T3-4 N2-3, e) primary tumor dose greater than or equal to 65 Gy and f) patients who received chemotherapy.

Between April 1968 and February 1988, 311 patients with symptomatic and progressive Graves' ophthalmopathy were treated with megavoltage orbital radiotherapy. The patients were divided into three groups: I (156 patients) treated with 20 Gy/2 weeks; II (69 patients) treated with 30 Gy/3 weeks, and III (a most recent set of 86 patients) received 20 Gy/2 weeks. The degree of eye involvement was evaluated numerically before and after therapy for each of five parameters: soft tissue signs, proptosis, eye muscle impairment, corneal involvement, and sight loss. Pre-treatment and current thyroid diagnosis and status were also noted. To evaluate the effects of radiotherapy alone, follow-up was terminated at the time any eye surgery was done; for those not treated surgically the minimum follow-up was 12 months. Because there were significant demographic differences between the patient groups, the results of each group were analyzed separately. A stepwise linear regression analysis was performed to determine if there were any significant variables affecting outcome. Based on these data formulae were derived which enable outcome to be predicted in any patient. Before therapy more than 90% of patients in all groups had soft tissue and eye muscle involvement, whereas 65–75% had proptosis and about half 50% had some degree of sight loss. Radiotherapy arrested progression of ophthalmic parameters in all but 1–6% of the patients. Objective and symptomatic improvement was noted for all parameters assessed, but there was marked individual variability. The best responses were noted for soft tissue, corneal involvement, and sight loss; however over half the patients had some improvement in eye muscle function and proptosis. Factors which resulted in less favorable outcome included male gender, advanced age, need for concurrent therapy for hyperthyroidism, and no history of hyperthyroidism. No complications have been observed. No significant differences in outcome were observed between the two dosage schedules. Following radiotherapy 29% of patients subsequently underwent some form of eye surgery, mostly eye muscle surgery to correct diplopia. After radiotherapy corticosteroid therapy was stopped without relapse in 76%. Orbital radiotherapy can result in improvement in signs and symptoms of Graves' ophthalmopathy in the majority of patients. For the remainder of patients the disease manifestations can be stabilized to allow functional surgical correction.

Proper therapy for Hodgkin disease requires accurate staging of the disease. We compared the value of CT and lymphography with that of laparotomy for staging newly diagnosed Hodgkin disease in 46 children. The laparotomy revealed disease in one or more subdiaphragmatic sites in 46%. Correlation of the imaging studies with the laparotomy findings showed that lymphography has a greater sensitivity (80%) than does CT (40%) in detecting retroperitoneal lymph nodes. The sensitivity of CT in detecting splenic involvement was only 19%, presumably because of the small size of tumor deposits in involved spleens. Staging laparotomy altered the clinical stage in 37% of children, which resulted in a significant change of therapy in those patients. Although lymphography and, to a lesser degree, CT are useful for staging of Hodgkin disease, laparotomy continues to be the most important tool in choosing appropriate therapy for children with Hodgkin disease.

Nutrition support for the patient with cancer is an important part of the overall treatment regimen. Nutrition support for the child with cancer poses a special challenge. For the purpose of reviewing the special nutritional needs of children with cancer, a Task Force was formed by the American Academy of Pediatrics to review the current state of knowledge. The work of the Task Force was supported by the Food and Drug Administration through its Liaison Representative, Joginder Chopra, M.D., Staff support from the Academy was provided by Jean D. Lockhart, M.D., This review is prepared from the Task Force Report to the FDA. It is designed to review factors enhancing nutritional risks for the child with cancer and to discuss nutritional intervention strategies and their efficacies.

Combined radiotherapy and intensive chemotherapy have led to improved prognosis in children with non-Hodgkin's lymphoma, but the toxic effects of these forms of treatment are additive and seriously limit the benefits of their use. In an effort to limit the adverse acute and late effects of treatment, we conducted a randomized, controlled trial to determine whether irradiation of primary sites of involvement could safely be omitted from the treatment of children with localized non-Hodgkin's lymphoma (Stages I and II) who have a favorable prognosis. In addition, the chemotherapy regimen was less intense and shorter (eight months) than usual. A total of 129 patients were randomly assigned to receive either chemotherapy (vincristine, cyclophosphamide, doxorubicin, prednisone, mercaptopurine, and methotrexate) with irradiation (27 Gy) of the involved field (combined chemotherapy and radiotherapy) or chemotherapy alone. Half the patients have been followed for more than 38 months (range, 13 to 68), and the projected disease-free survival (+/- SE) at four years among patients assigned to chemotherapy alone is 87.9 +/- 8.8 percent, as compared with 87.3 +/- 9.4 percent among patients assigned to combined therapy (P = 0.44). The majority of patients tolerated therapy very well, although the toxic effects of treatment (myelosuppression, mucositis, and infection) were significantly worse among patients who received the combination of chemotherapy and radiotherapy. We conclude that most children with localized non-Hodgkin's lymphoma can be cured by a chemotherapy regimen of reduced intensity and duration. Radiotherapy can be safely omitted from the therapy of such children without substantially jeopardizing their excellent chance of cure.

Prior to 1960, Hodgkin lymphoma was considered a uniformly fatal cancer. Hodgkin described the disease in 1832, but most attributed its pathophysiology to an infl ammatory condition. Sternberg and Reed are credited for the fi rst defi nitive description of the histopathology (Reed 1902; Sternberg 1898). Fox later refi ned the defi nition, and noted the occurrence of this entity in young patients (Fox 1926). However, little was known about its etiology and/or epidemiology. Th ere was neither a uniform histopathologic classifi cation, nor consistently used workup or staging system. Th e clinical assessment, largely by observation and palpation, was gradually supplemented by laboratory studies that characterized specifi c abnormalities. Imaging studies lacked precision, and staging was not precise. Th erapy was largely symptomatic. Early aft er Roentgen’s discovery of the X-ray in 1896, Pusey fi rst used X-rays to treat a young man with a presumed lymphoma; he noted dramatic shrinkage of enlarged neck adenopathy aft er 21 exposures to the X-rays (Pusey 1902). He soon used the X-ray treatment on a 4-year-old boy with bilateral cervical swelling from Hodgkin lymphoma and reported the swollen glands were “reduced to the size of an almond” within 2 months. During the time period from 1920 to 1940, there was some interest in the use of radical surgery followed by postoperative radiotherapy for the treatment of localized lymphoma. Th e good results from the X-ray treatment, and the cosmetic disfi gurement from the extensive surgery, led most surgeons to consider that radical surgery was not indicated in the treatment of this disease. As a byproduct of the World War II development of mustard gases, investigators observed nitrogen musIntroduction and Historical Background: Pediatric Hodgkin Lymphoma

PURPOSE: To evaluate the impact of craniospinal irradiation (CSI) dose and molecular sub-type on medulloblastoma relapse rates. METHODS: 115 medulloblastoma patients were treated with 18- ≥ 36 Gy CSI. Molecular subtyping data was done by nanostring assay [WNT, SHH, and Group 3/4 non-WNT/non-SHH (NWNS)]. A CSI dose schema based on prognostic implications of molecular subtype was devised: ≥36 Gy for M+ or Group 3; ≤18 Gy for non-disseminated WNT; 23.4 Gy all others. Relapse rates were assessed and correlated with CSI dose. RESULTS: After excluding patients with incomplete data, the final cohort included 36 subjects with median age 8.7 years (range 3.3–16.9) and median follow-up 4.1 years (0.2-3.7). Molecular subtypes were as follows: 2-WNT, 6-SHH, 28-NWNS. CSI dose was 18 Gy(11 cases), 23.4 Gy(9), and ≥36 Gy(16). CSI dose was divergent from the proposed schema in 18 cases (14-lower, 4-higher). There were 14 relapses (by molecular subtype: 0-WNT, 1-SHH, 13-NWNS; by histology: 8-classic, 5-LC/A, 1-EN), with median time to relapse 18.5 months (0.43-62). Seven of 14 tumors treated to a lower dose relapsed (1 SHH; 6 NWNS); only 1 (NWNS) of 4 patients with higher divergent dose relapsed. Six of 18 patients treated to similar dose relapsed; all were NWNS, and 4/6 had M3 disease. Eleven of 14 patients who relapsed died. CONCLUSION: Molecular subtyping may help avoid under-treating some NWNS tumors but innovative strategies for metastatic NWNS are needed. We confirm that histological subtypes may hold some predictive value as 5/7 LC/A relapsed and no desmoplastic tumors relapsed. In this small sample, no WNT relapse occurred and only 1 SHH relapsed, suggesting that dose de-escalation can be cautiously explored for these subtypes. Future research directions include applying an MRI image-based algorithm to subtype the entire cohort, and combining molecular data with other institutions to examine relapse patterns by subtype.

Background: 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 defi ned. Methods: 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 – specifi c 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% confi dence 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. Results: Subsequent CNS primary neoplasms were identifi ed 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. Conclusions: 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 refl ect greater susceptibility of the developing brain to radiation. [J Natl Cancer Inst 2006;98: 1528 – 37 ]

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.