Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group.

BACKGROUND: Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear. METHODS: Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type. RESULTS: Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR, 1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups. CONCLUSIONS: In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients.

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.

A pilot study of low-dose anti-angiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors: A Children's Oncology Group (COG) Phase II study NCT00061893.

BACKGROUND: The aims of this study were to determine the feasibility of the combination of low dose, anti-angiogenic chemotherapy with standard therapy for patients with metastatic Ewing sarcoma (ES), and to obtain preliminary outcome data. PROCEDURES: Patients with metastatic ES were eligible. Therapy consisted of alternating cycles of ifosfamide-etoposide, and vincristine, doxorubicin, cyclophosphamide. Vinblastine and celecoxib were concomitantly administered. Surgical, radiotherapeutic, or combination local control therapy was given per institutional preference. RESULTS: Thirty-five eligible patients were enrolled. Ninety percent received at least 75% of planned vinblastine/celecoxib doses. There was no excess of neurologic, infectious, hemorrhagic, or cardiovascular toxicities. However, 7 of 21 patients who received pulmonary irradiation prior to experiencing pulmonary toxicity did develop grade 2 or greater pulmonary toxicity, including two deaths of apparent radiation pneumonitis. Fourteen of 16 patients with pelvic disease received local irradiation. Hemorrhagic cystitis developed in six patients, five of whom had received pelvic irradiation. The overall 24-month event free survival was 35% (19-51%); 71% (26-92%) for the seven with isolated pulmonary metastases, 26% (10-45%) for all others. CONCLUSION: The combination of vinblastine/celecoxib metronomic therapy with standard ES treatment was feasible according to the protocol definitions. However, excess toxicity in irradiated areas was noted and limits the usefulness of this protocol. The 24-month EFS for those with isolated pulmonary metastases is better than historical controls, although the number of patient number is small, follow up short and we are lacking contemporaneous controls.

Risk Factors Associated with COVID-19 Hospitalization and Mortality: A Large Claims-Based Analysis Among People with Type 2 Diabetes Mellitus in the United States.

INTRODUCTION: Diabetes has been identified as a high-risk comorbidity for COVID-19 hospitalization. We evaluated additional risk factors for COVID-19 hospitalization and in-hospital mortality in a nationwide US database. METHODS: This retrospective study utilized the UnitedHealth Group Clinical Discovery Database (January 1, 2019-July 15, 2020) containing de-identified nationwide administrative claims, SARS-CoV-2 laboratory test results, and COVID-19 inpatient admissions data. Logistic regression was used to understand risk factors for hospitalization and in-hospital mortality among people with type 2 diabetes (T2D) and in the overall population. Robustness of associations was further confirmed by subgroup and sensitivity analyses in the T2D population. RESULTS: A total of 36,364 people were identified who were either SARS-CoV-2+ or hospitalized for COVID-19. T2D was associated with increased COVID-19-related hospitalization and mortality. Factors associated with increased hospitalization risk were largely consistent in the overall population and the T2D subgroup, including age, male sex, and these top five comorbidities: dementia, metastatic tumor, congestive heart failure, paraplegia, and metabolic disease. Biguanides (mainly metformin) were consistently associated with lower odds of hospitalization, whereas sulfonylureas and insulins were associated with greater odds of hospitalization among people with T2D. CONCLUSION: In this nationwide US analysis, T2D was identified as an independent risk factor for COVID-19 complications. Many factors conferred similar risk of hospitalization across both populations; however, particular diabetes medications may be markers for differential risk. The insights on comorbidities and medications may inform population health initiatives, including prevention efforts for high-risk patient populations such as those with T2D.

An evaluation of the variability of tumor-shape definition derived by experienced observers from CT images of supraglottic carcinomas (ACRIN protocol 6658).

PURPOSE: Accurate target definition is considered essential for sophisticated, image-guided radiation therapy; however, relatively little information has been reported that measures our ability to identify the precise shape of targets accurately. We decided to assess the manner in which eight "experts" interpreted the size and shape of tumors based on "real-life" contrast-enhanced computed tomographic (CT) scans. METHODS AND MATERIALS: Four neuroradiologists and four radiation oncologists (the authors) with considerable experience and presumed expertise in treating head-and-neck tumors independently contoured, slice-by-slice, his/her interpretation of the precise gross tumor volume (GTV) on each of 20 sets of CT scans taken from 20 patients who previously were enrolled in Radiation Therapy Oncology Group protocol 91-11. RESULTS: The average proportion of overlap (i.e., the degree of agreement) was 0.532 (95% confidence interval 0.457 to 0.606). There was a slight tendency for the proportion of overlap to increase with increasing average GTV. CONCLUSIONS: Our work suggests that estimation of tumor shape currently is imprecise, even for experienced physicians. In consequence, there appears to be a practical limit to the current trend of smaller fields and tighter margins.

Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience.

PURPOSE: Salvage therapy for patients with unresectable colorectal liver metastases that were refractory to oxaliplatin and irinotecan was performed via radioactive microspheres. High doses of radiation were delivered to tumors from permanently implanted 90Y microspheres, delivered through the hepatic arterial vessels. METHODS AND MATERIALS: Patients from 7 institutions were selected for treatment after screening-defined vascular access to all the tumors, and imaging-confirmed microspheres would be implanted only in the liver tumors. All patients were followed with laboratory and imaging studies at regular intervals until death. Toxicities, both acute and late, were recorded, and actuarial survival determined. RESULTS: A total of 208 patients were treated from April 2002 to April 2005. Median follow-up of the 129 men and 79 women is 13 months (range, 1-42 months). Median survival is 10.5 months for responders but only 4.5 months in nonresponders. No treatment-related procedure deaths or radiation-related venoocclusive liver failures were found. Computed tomography partial response was 35%; positron emission tomography response of 91% and reduction in carcinoembryonic antigen of 70% were achieved. CONCLUSIONS: In this group of heavily pretreated patients, radioactive microspheres produced an encouraging median survival, with acceptable toxicity, and a significant objective response rate, which suggests that further investigation of this approach is warranted.

Radiation therapy for prostate cancer: external beam, brachytherapy, and salvage.

Radiation is a curative treatment for prostate cancer that is most appropriate for the older patient or the patient with significant co-morbidities. Younger patients with a greater than ten-year survival are probably best treated with surgery unless the disease is high risk. For all patients, high-risk disease is best treated with hormones and radiation. The long-term superiority of surgery over radiation, however, has not been demonstrated in randomized or retrospective studies, and the recommendation for surgery in the younger, healthy patient with favorable local disease is largely based on theoretical considerations. If chosen for appropriate indications and delivered with appropriate techniques, radiation can be delivered using external beam or brachytherapy with equal efficacy. The choice of radiation treatment is based on tumor characteristics and patient preference. Radiation can be used after prostatectomy to cure patients who are not cured with surgery. Watchful waiting may be appropriate for patients with low-risk disease.

Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group Trial 1881.

PURPOSE: From December 1988 through December 1992, the Children's Cancer Group (CCG) conducted a randomized trial (CCG-1881) designed to evaluate the impact of adding a single delayed intensification phase of therapy to standard therapy for patients with newly diagnosed low-risk acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients (n = 778) with newly diagnosed ALL, 2 to 9 years of age at diagnosis with an initial WBC count less than 10,000/microL, were eligible for this protocol. All patients received induction, consolidation, and interim maintenance phases of therapy over the first 16 weeks. At week 16, patients remaining in remission were randomly assigned to receive or not receive a single 7-week delayed intensification (DI) phase of therapy. Maintenance therapy was given in lieu of or after DI, with total duration of therapy approximately 3 years for boys and 2 years for girls. RESULTS: Patients randomized to receive DI experienced fewer relapse events in all categories. Kaplan-Meier life-table estimates for continuous complete remission (CCR) at 7 years for the randomized regimens were 77% (SE, 2.4%) for the standard regimen and 83% (SE, 2.7%) for the DI regimen (P =.072). The only prognostic factor of significance post-randomization in this selected low-risk population was the day 14 marrow response (P =.0001). CONCLUSION: The addition of a single DI phase of therapy was well tolerated and augmented 7-year CCR by 6% (SE of the difference, 3.3%), resulting in 26% fewer adverse events. Overall survival for eligible patients at 7 years is 90% (SE, 1.2%).

Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group.

PURPOSE: Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome. PATIENTS AND METHODS: This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734). RESULTS: Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar. CONCLUSION: For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.

Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study.

PURPOSE: The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue. METHODS: Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks. RESULTS: Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites. CONCLUSION: Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.

Interobserver reliability of computed tomography-derived primary tumor volume measurement in patients with supraglottic carcinoma.

BACKGROUND: Prior studies have determined that macroscopic ("gross") tumor volume (GTV), as calculated from pretreatment computer tomography (CT), was capable of predicting local control in squamous cell carcinoma arising in different subsites in the head and neck in patients who were treated with nonsurgical organ-preservation therapy. The majority of these studies were single-institution, retrospective investigations. Consequently, there has been concern that GTV measurements may not be reproducible by different readers at different institutions. The objective of the current study was to measure the interobserver reliability for GTV measurements for squamous cell carcinoma of the supraglottic larynx (SGSCCA) performed by different readers at different institutions. METHODS: Eight experienced readers (4 neuroradiologists and 4 radiation oncologists) from different institutions independently measured the pretreatment GTV of 20 patients with SGSCCA. The CT scans were obtained from patients entered into the definitive radiation therapy arm of Radiation Therapy Oncology Group protocol 91-11, who had supraglottic carcinoma and underwent pretreatment CT scans of the neck. Statistical analysis focused on interobserver reliability as measured by the intraclass correlation coefficient. RESULTS: The intraclass correlation coefficient was 0.81 (95% lower confidence bound, 0.71). This value was interpreted as "excellent." CONCLUSIONS: GTV measurements were reliable and reproducible when performed by neuroradiologists and radiation oncologists who were experienced in the interpretation of CT scans of the extracranial head and neck in patients with SGSCCA. The result implied that the correlation between GTV and local control should be reproducible across institutions.

Ovarian carcinoma in an adolescent with transgenerational exposure to diethylstilbestrol.

Small cell carcinoma of the ovary is rare in adolescence. The etiology of such tumors is unknown. Several reports suggest that transgenerational exposure to diethylstilbestrol (DES) may have deleterious effects on the genitourinary tract. The authors describe a 15-year-old girl with small cell carcinoma of the ovary whose maternal grandmother had been taking DES while she was pregnant with the patient's mother. This case, while anecdotal, suggests that a transgenerational history of DES exposure should be noted, and that granddaughters with persistent abdominal pain even during childhood may need evaluation for genital tract abnormalities.

An expanded phase I/II trial of cyclophosphamide, etoposide, and carboplatin plus total body irradiation with autologous marrow or stem cell support for patients with hematologic malignancies.

The major cause for failure of autologous stem cell transplantation for hematologic malignancies is the risk of recurrent disease. As a result, new treatment regimens that include novel agents or combinations of agents and approaches are needed. The current report describes a large Phase I/II, single-center trial that includes 60 patients with a variety of hematologic malignancies. These patients received a fixed dose of carboplatin (1 g/m(2)/d x 72 hours by CI) etoposide (600 mg/m(2)/d x 3 days) and cyclophosphamide (2 g/m(2)/d x 3 days), plus escalating doses of total body irradiation (TBI) (at 1000, 1200, and 1295 cGy) over 3 days. Eleven patients received infusion of autologous marrow, 32 received peripheral blood stem cells, and 17 patients received both. The maximum tolerated dose of this regimen was a radiation dose of 1200 cGy given in 200-cGy fractions BID x 3 days. The dose-limiting toxicity was mucositis, with 97% of patients requiring narcotic analgesia for mouth pain. Overall treatment-related mortality was 6.7%, with 2 of the 4 deaths occurring in a group of 9 patients aged 60 and older. Responses were seen in all patient groups, but the most encouraging outcomes were seen in 12 patients with high-risk or advanced acute myelocytic lymphoma (AML), 7 of whom remain alive and free of disease beyond 5 years. This regimen is intensive and causes considerable mucositis but is otherwise well tolerated and has demonstrated activity in a number of hematologic malignancies, especially AML.

Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy.

OBJECTIVE: To establish outcome and optimal timing of local control for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the chest wall. METHODS: Patients < or =30 years of age with ES/PNET of the chest wall were entered in 2 consecutive protocols. Therapy included multiagent chemotherapy; local control was achieved by resection, radiotherapy, or both. We compared completeness of resection and disease-free survival in patients undergoing initial surgical resection versus those treated with neoadjuvant chemotherapy followed by resection, radiotherapy, or both. Patients with a positive surgical margin received radiotherapy. RESULTS: Ninety-eight (11.3%) of 869 patients had primary tumors of the chest wall. Median follow-up was 3.47 years and 5-year event-free survival was 56% for the chest wall lesions. Ten of 20 (50%) initial resections resulted in negative margins compared with 41 of 53 (77%) negative margins with delayed resections after chemotherapy (P = 0.043). Event-free survival did not differ by timing of surgery (P = 0.69) or type of local control (P = 0.17). Initial chemotherapy decreased the percentage of patients needing radiation therapy. Seventeen of 24 patients (70.8%) with initial surgery received radiotherapy compared with 34 of 71 patients (47.9%) who started with chemotherapy (P = 0.061). If a delayed operation was performed, excluding those patients who received only radiotherapy for local control, only 25 of 62 patients needed radiotherapy (40.3%; P = 0.016). CONCLUSION: The likelihood of complete tumor resection with a negative microscopic margin and consequent avoidance of external beam radiation and its potential complications is increased with neoadjuvant chemotherapy and delayed resection of chest wall ES/PNET.