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At least 361 records · Page 20
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

An imaging-based review of systemic therapies and associated toxicities in metastatic pancreatic cancer as per the 2018 ASCO guidelines: what every radiologist should know

Objective: To provide an overview of what radiologists should know about systemic agents utilized in the modern treatment of metastatic pancreatic cancer and their associated toxicities. Results: The clinical landscape of metastatic pancreatic cancer has significantly evolved in recent years, with the advent of new first- and second-line systemic therapies. As these systemic treatment options continue to expand, knowledge of their clinically relevant features is becoming critical for radiologists. While the issues of surgical resectability and tumor response evaluation of advanced stages of pancreatic cancer have been thoroughly discussed in the radiology literature, the diagnostic importance of systemic therapies has tended to be less well appreciated. In this review, we provide a primer for radiologists outlining the radiologically pertinent features of modern systemic therapies used in the treatment of metastatic pancreatic ductal adenocarcinoma. These systemic agents are discussed from the standpoint of the newly updated 2018 ( https://doi.org/10.1007/s00261-019-01954-z ) guidelines for the treatment of metastatic pancreatic cancer from the American Society of Clinical Oncology (ASCO). Understanding the radiology relevance of these modern therapeutic agents is critical, especially with regard to treatment response and toxicity assessment. Conclusion: Knowledge of the modern systemic therapies utilized in the treatment of metastatic pancreatic cancer and their associated toxicity profiles is critical in diagnostic imaging interpretation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Hepatic Toxicity After Radioembolization of the Liver Using {sup 90}Y-Microspheres: Sequential Lobar Versus Whole Liver Approach

Purpose: {sup 90}Y-radioembolization (RE) is a promising technique for delivering high doses of radiation to liver tumors but may result in compromise of liver function. To gain further perspective, we evaluated the toxicity rates of sequential lobar versus 'whole liver' {sup 90}Y-radioembolization. Methods: Thirty-four patients with liver malignancy in noncirrhotic livers were included; {sup 90}Y-radioembolization was performed as either whole liver or sequential lobar treatment in 17 patients each. Standard clinical and liver specific laboratory parameters as well as MR imaging before treatment and at follow-up (6 and 12 weeks) after radioembolization were evaluated for toxicity using the Common Terminology Criteria for Adverse Events (CTCAE). Volumetry of the liver, tumor, and spleen and measurement of portal vein diameter also were performed. Results: Three months after whole liver RE, 14 liver-related grade 3/4 events were recorded versus 2 events after sequential lobar treatment (P < 0.05). Three patients treated with whole liver RE suffered from radioembolization-induced liver disease (REILD). Pathological increases in bilirubin at 3 months were observed for the whole liver group only (52.3 vs. 18.7 {mu}mol/l, P = 0.012). Total liver volume did not change significantly in either group, but shrinkage of the initially treated hepatic lobe with compensatory hypertrophy of the subsequently treated lobe was observed in the sequential lobar group (P < 0.05). Portal vein diameter increased significantly in whole liver-treated patients only (+17% vs. +6.6%, P = 0.043). Conclusions: Noncirrhotic patients undergoing sequential lobar radioembolization had less hepatic toxicity compared to whole liver embolization. The sequential approach should be the preferred strategy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Radioembolization with {sup 90}Y Resin Microspheres of Neuroendocrine Liver Metastases: International Multicenter Study on Efficacy and Toxicity

Purpose: Radioembolization of liver metastases of neuroendocrine neoplasms (NEN) has shown promising results; however, the current literature is of limited quality. A large international, multicentre retrospective study was designed to address several shortcomings of the current literature. Materials: 244 NEN patients with different NEN grades were included. Methods: Primary outcome parameters were radiologic response 3 and 6 months after treatment according to RECIST 1.1 and mRECIST. Secondary outcome parameters included clinical response, clinical and biochemical toxicities. Results: Radioembolization resulted in CR in 2%, PR in 14%, SD in 75% and PD 9% according to RECIST 1.1 and in CR in 8%, PR in 35%, SD in 48% and PD in 9% according to mRECIST. Objective response rates improved over time in 20% and 26% according to RECIST 1.1. and mRECIST, respectively. Most common new grade 3–4 biochemical toxicity was lymphocytopenia (6.7%). No unexpected clinical toxicities occurred. Radioembolization-specific complications occurred in < 4%. In symptomatic patients, improvement and resolution of symptoms occurred in 44% and 34%, respectively. Median overall survival from first radioembolization was 3.7, 2.7 and 0.7 years for G1, G2 and G3, respectively. Objective response is independent of NEN grade or primary tumour origin. Significant prognostic factors for survival were NEN grade/Ki67 index, ≥ 75% intrahepatic tumour load, the presence of extrahepatic disease and disease control rate according to RECIST 1.1. Conclusion: Safety and efficacy of radioembolization in NEN patients was confirmed with a high disease control rate of 91% in progressive patients and alleviation of NEN-related symptoms in 79% of symptomatic patients. Level of evidence: 4.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Influence of ABCB1 polymorphisms on the pharmacokinetics and toxicity of lenalidomide in patients with multiple myeloma

Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration–time curve (AUC{sub 0–24}) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography–tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC{sub 0–24} for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC{sub 0–24} in 1236C>T and 2677G>A/T polymorphisms. AUC{sub 0–24} was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC{sub 0–24} value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC{sub 0–24} cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer’s Disease

Alzheimer’s disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule’s efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aβ42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aβ42, destabilizes preformed fibrils, and reverses Aβ42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development. .

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Evaluation of the toxic effects of celecoxib on Xenopus embryo development

Highlights: • Celecoxib is a non-steroidal anti-inflammatory drug that inhibits cyclooxygenase-2. • Celecoxib produced significant toxic and teratogenic effects in Xenopus embryos. • Embryo organ-specific pathology was consistent with gene expression changes. • Celecoxib inhibited pericyte activity and cardiovascular development. • The safety of celecoxib use in pregnant women requires careful analysis. Celecoxib is a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 and is prescribed for severe pain and inflammation. The excellent therapeutic effects of celecoxib mean that it is frequently used clinically, including for women of child-bearing age. However, the prenatal effects of this compound have not been studied extensively in vertebrates. The present study examined the developmental toxicity of celecoxib using a frog embryo teratogenic assay-Xenopus (FETAX). In addition, we examined its effects on cell migration using co-cultures of human umbilical vein endothelial cells and 10T1/2 cells. These studies revealed that celecoxib induced concentration-dependent mortality and various malformations of the Xenopus internal organs, including gut miscoiling, haemorrhage, and oedema. Celecoxib also downregulated the expression of vascular wall markers (Msr and alpha smooth muscle actin) and other organ-specific markers (Nkx2.5, Cyl104 and IFABP). In vitro co-culture studies revealed that celecoxib inhibited pericyte migration and differentiation into vascular smooth muscle cells. In conclusion, celecoxib was both toxic and teratogenic in Xenopus embryos, where it produced serious heart and vessel malformation by inhibiting vascular wall maturation and vascular network formation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A putative cyclin, SiPHO80 from root endophytic fungus Serendipita indica regulates phosphate homeostasis, salinity and heavy metal toxicity tolerance

Highlights: • SiPHO80 of S. indica gets upregulated in high Phosphate condition. • SiPHO80 restores Pi homeostasis in S. cerevisiae PHO80 mutants. • SiPHO80 rescues S. cerevisiae PHO80 mutants in salinity stress and heavy metal toxicity. Serendipita indica previously known as Piriformospora indica is an arbuscular mycorrhizal fungi (AMF) like endophytic fungus which can be cultivated axenically and colonizes an array of plants, thereby promoting their growth and confers biotic and abiotic stress tolerance to the colonized host plant. It efficiently sequestrates heavy metals and defends host plant against heavy metal-induced toxicity. In the present study, SiPHO80, a homologue of S. cerevisiae PHO80 was isolated from S. indica and functionally characterized in S. cerevisiae. SiPHO80 has conserved ‘cyclin box’ domain and closely related to negative regulator cyclin of the wood decaying fungi. In S. indica, its expression gets upregulated in phosphate-rich media. The regulation of Pi homeostasis which was disrupted in S. cerevisiae Δpho80 grown under high Pi condition was restored upon complementation with SiPHO80. Also, the expression of SiPHO80 in Δpho80 mutant restored osmotolerance and heavy metal tolerance. This is the first report of a cyclin which is involved in Pi homeostasis, salt tolerance, heavy metal toxicity tolerance in any plant growth promoting endophytic fungi.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Toxicity of Bacillus thuringiensis var. israelensis in aqueous suspension on the South American common frog Leptodactylus latrans (Anura: Leptodactylidae) tadpoles

The effects of commercial formulations of Bacillus thuringiensisvar.israelensis (Bti) on non-target organisms are still a matter of debate; in amphibians, the risks of Bti are little known. To evaluate the toxicity of a commercial liquid (aqueous suspension, AS) formulation of Bti (Introban{sup ®}) on Leptodactylus latrans tadpoles, including median lethal concentration (LC{sub 50}) and no-and lowest–observed-effect concentrations (NOEC and LOEC, respectively), as well as the possible effects of Bti on oxidative responses, erythrocytes genotoxicity, and histology of the intestines. In the laboratory, tadpoles were exposed to nominal concentrations of 0 (control), 2.5, 5, 10, 20 and 40 mg/L of formulated Bti-AS. Glutathione S-transferase (GST) and catalase (CAT) activities, as well as formation of erythrocyte nuclear abnormalities (ENAs), and histological effect were measured in tadpoles displaying survival rates >85%. L. latrans tadpoles were sensitive to exposure to Bti-AS, reaching 100% mortality after 48 h of exposure at the highest concentration. Bti-AS induced GST and CAT enzymes and genotoxicity (erythrocyte's nuclear abnormalities), and caused intestine's histopathology. Our results demonstrate that toxicity of Bti-AS is dose-dependent for L. latrans tadpoles and that sublethal exposure alters enzymes of oxidative stress, induces genotoxicity, and causes intestine damage. Further research is needed to evaluate the ecotoxicological risk of the massive use of Bti formulations on amphibian populations that commonly used suburban wastewater or urban waterbodies to reproduce and where this biopesticide is frequently applied. - Highlights: • An ecotoxicological evaluation of a Bti formulation on amphibian was conducted. • Toxicity of Bti-AS was dose-dependent for Leptodactylus latrans tadpoles. • Sublethal exposure altered the enzymes of oxidative stress (GST and CAT). • Bti-AS was genotoxic because increased MN frequencies (CO: 0.82–2.74‰). • Bti-AS caused the inflammatory infiltration in the lamina propria of intestine.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Comparison of distribution and toxicity following repeated oral dosing of different vanadium oxide nanoparticles in mice

Vanadium is an important ultra-trace element derived from fuel product combustion. With the development of nanotechnology, vanadium oxide nanoparticles (VO NPs) have been considered for application in various fields, thus the possibility of release into the environment and human exposure is also increasing. Considering that verification of bioaccumulation and relevant biological responses are essential for safe application of products, in this study, we aimed to identify the physicochemical properties that determine their health effects by comparing the biological effects and tissue distribution of different types of VO NPs in mice. For this, we prepared five types of VO NPs, commercial (C)-VO{sub 2} and -V{sub 2}O{sub 5} NPs and synthetic (S)-VO{sub 2}, -V{sub 2}O{sub 3,} and -V{sub 2}O{sub 5} NPs. While the hydrodynamic diameter of the two types of C-VO NPs was irregular and impossible to measure, those of the three types of S-VO NPs was in the range of 125–170 nm. The S- and C-V{sub 2}O{sub 5} NPs showed higher dissolution rates compared to other VO NPs. We orally dosed the five types of VO NPs (70 and 210 μg/mouse, approximately 2 and 6 mg/kg) to mice for 28 days and compared their biodistribution and toxic effects. We found that S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs more accumulated in tissues compared to other three types of VO NPs, and the accumulated level was in order of heart>liver>kidney>spleen. Additionally, tissue levels of redox reaction-related elements and electrolytes (Na{sup +}, K{sup +}, and Ca{sup 2+}) were most clearly altered in the heart of treated mice. Notably, all S- and C-VO NPs decreased the number of WBCs at the higher dose, while total protein and albumin levels were reduced at the higher dose of S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs. Taken together, we conclude that the biodistribution and toxic effects of VO NPs depend on their dissolution rates and size (surface area). Additionally, we suggest that further studies are needed to clarify effects of VO NPs on functions of the heart and the immune system. - Highlights: • We used commercial (C)-VO{sub 2} and -V{sub 2}O{sub 5} and synthetic (S)-VO{sub 2}, -V{sub 2}O{sub 3,} and -V{sub 2}O{sub 5} NPs. • The S- and C-V{sub 2}O{sub 5} NPs showed higher dissolution rates compared to other VO NPs. • S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs more accumulated in tissues compared to other types of VO NPs. • Redox reaction-related elements and electrolytes were clearly altered in the heart. • With decreased body weight, immune and blood-related factors influence by all VO NPs. • Biodistribution and toxicity of VO NPs depend on their dissolution rates and size.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Modeling and MANOVA studies on toxicity and endocrine potential of packaging materials exposed to different extraction schemes

Highlights: • Simultaneous assessment of the impact of treatment conditions on packages ecotoxicity. • Checking of the impact of temperature and extracting solvents on endocrine potential of packages. • Comparison of the package lining spectra before and after extraction. • Ecotoxicity parameters as a tool in packages lining stability assessment. The stability of the linings of packaging that is in contact with the goods stored has been of major concern during decades of the development of packaging materials. In this work, an attempt was undertaken to assess the applicability of using two bioassays (Microtox® and XenoScreen YES/YAS) in estimating the stability of packaging (cans, caps, multilayer material) and the impact of their degradation on the toxicity of some simulated media. The assessment of the impact of packaging storage conditions (temperature, disinfection, preservation, extracting and washing solvents) was planned and performed with i) regression modeling of the experimental effects on the ecotoxicity readings, ii) ANOVA and MANOVA estimation of the experimental conditions as significant factors affecting the toxicity results and iii) FTIR analysis of the packages. It is shown that the effects of temperature and extraction solvents could be quantitatively assessed by the agreement between all methods applied. It can be stated that temperature and acidity as well as the alcohol content in the sensitive media have the greatest impact on the toxicity of the extract and thus on the stability of the internal lining and the extractability of xenobiotics.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Chronic toxicity of nanodiamonds can disturb development and reproduction of Acheta domesticus L

Highlights: • The in vivo toxicity of ND was measured in A. domesticus after long-term exposure. • Organism-level end-point indices revealed adverse changes in the treated crickets. • EPR analysis showed increase of radical signal in the faeces of ND-fed crickets. • Adverse effects of NDs in crickets seem to be limited to the exposed generation only. The use of nanodiamonds in numerous materials designed for industry and medicine is growing rapidly. Consequently health and environmental risks associated with the exposure of humans and other biota to nanodiamonds-based materials are of the utmost importance. Scarcity of toxicological data for these particles led us to examine the potentially deleterious effects of nanodiamonds in model insect species, Acheta domesticus (Orthoptera) chronically exposed to ND in its diet. Organism-level end-point indices (lifespan, body weight, consumption, caloric value of faeces, reproduction) revealed adverse changes in the treated crickets in comparison with the control. Preliminary studies of oxidative stress level in the offspring of ND-treated crickets suggest toxicity of these particles limited to the exposed individuals. EPR analysis showing increase of radical signal in the faeces of ND-fed crickets led us to propose novel mechanism of nanodiamonds toxicity that is discussed in the light of literature data.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2012

Dose-Painted Intensity-Modulated Radiation Therapy for Anal Cancer: A Multi-Institutional Report of Acute Toxicity and Response to Therapy

Purpose: Chemoradiation for anal cancer yields effective tumor control, but is associated with significant acute toxicity. We report our multi-institutional experience using dose-painted IMRT (DP-IMRT). Patients and Methods: Between August 2005 and May 2009, 43 patients were treated with DP-IMRT and concurrent chemotherapy for biopsy-proven, squamous cell carcinoma of the anal canal at two academic medical centers. DP-IMRT was prescribed as follows: T2N0: 42 Gy, 1.5 Gy/fraction (fx) to elective nodal planning target volume (PTV) and 50.4 Gy, 1.8 Gy/fx to anal tumor PTV; T3-4N0-3: 45 Gy, 1.5 Gy/fx to elective nodal PTV, and 54 Gy, 1.8 Gy/fx to the anal tumor and metastatic nodal PTV >3 cm with 50.4 Gy, 1.68 Gy/fx to nodal PTVs {<=}3 cm in size. Acute and late toxicity was reported by the treating physician. Actuarial analysis was performed using the Kaplan-Meier method. Results: Median age was 58 years; 67% female; 16% Stage I, 37% II; 42% III; 5% IV. Fourteen patients were immunocompromised: 21% HIV-positive and 12% on chronic immunosuppression. Median follow-up was 24 months (range, 0.6-43.5 months). Sixty percent completed chemoradiation without treatment interruption; median duration of treatment interruption was 2 days (range, 2-24 days). Acute Grade 3+ toxicity included: hematologic 51%, dermatologic 10%, gastrointestinal 7%, and genitourinary 7%. Two-year local control, overall survival, colostomy-free survival, and metastasis-free survival were 95%, 94%, 90%, and 92%, respectively. Conclusions: Dose-painted IMRT appears effective and well-tolerated as part of a chemoradiation therapy regimen for the treatment of anal canal cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Acute Toxicity Profile and Compliance to Accelerated Radiotherapy Plus Carbogen and Nicotinamide for Clinical Stage T2-4 Laryngeal Cancer: Results of a Phase III Randomized Trial

Purpose: To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. Methods and Materials: From April 2001 to February 2008, 345 patients with cT2-4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2-4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. Results: Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moist desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. Conclusion: With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2-4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Mild Toxicity and Favorable Prognosis of High-Dose and Extended Involved-Field Intensity-Modulated Radiotherapy for Patients With Early-Stage Nasal NK/T-Cell Lymphoma

Purpose: The value of intensity-modulated radiotherapy (IMRT) for early-stage nasal NK/T-cell lymphoma has not been previously reported. The aim of the present study was to assess the dosimetric parameters, toxicity, and treatment outcomes of patients with nasal NK/T-cell lymphoma. Methods and Materials: Between 2003 and 2008, 42 patients with early-stage nasal NK/T-cell lymphoma underwent definitive high-dose and extended involved-field IMRT with or without combination chemotherapy. The median radiation dose to the primary tumor was 50 Gy. The dose-volume histograms of the target volume and critical normal structures were evaluated in all patients. The locoregional control, overall survival, and progression-free survival were calculated using the Kaplan-Meier method. Results: The average mean dose delivered to the planning target volume was 55.5 Gy. Only 1.3% and 2.5% of the planning target volume received <90% and 95% of the prescribed dose, respectively, indicating excellent planning target volume coverage. The mean dose and average dose to the parotid glands was 15 Gy and 14 Gy, respectively. With a median follow-up time of 27 months, the 2-year locoregional control, overall survival, and progression-free survivalrate was 93%, 78%, and 74%, respectively. No Grade 4 or 5 acute or late toxicity was reported. Conclusions: High-dose and extended involved-field IMRT for patients with early-stage nasal NK/T-cell lymphoma showed favorable locoregional control, overall survival, and progression-free survival, with mild toxicity. The dose constraints of IMRT for the parotid glands can be limited to <20 Gy in these patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Determinants of Toxicity, Patterns of Failure, and Outcome Among Adult Patients With Soft Tissue Sarcomas of the Extremity and Superficial Trunk Treated With Greater Than Conventional Doses of Perioperative High-Dose-Rate Brachytherapy and External Beam Radiotherapy

Purpose: The present study was undertaken to determine factors predictive of toxicity, patterns of failure, and survival in 60 adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with combined perioperative high-dose-rate brachytherapy and external beam radiotherapy. Methods and Materials: The patients were treated with surgical resection and perioperative high-dose-rate brachytherapy (16 or 24 Gy) for negative and close/microscopically positive resection margins, respectively. External beam radiotherapy (45 Gy) was added postoperatively to reach a 2-Gy equivalent dose of 62.9 and 72.3 Gy, respectively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with advanced high-grade tumors. Results: Grade 3 toxic events were observed in 18 patients (30%) and Grade 4 events in 6 patients (10%). No Grade 5 events were observed. A location in the lower limb was significant for Grade 3 or greater toxic events on multivariate analysis (p = .013), and the tissue volume encompassed by the 150% isodose line showed a trend toward statistical significance (p = .086). The local control, locoregional control, and distant control rate at 9 years was 77.4%, 69.5%, and 63.8%, respectively. On multivariate analysis, microscopically involved margins correlated with local control (p = .036) and locoregional control (p = .007) and tumor size correlated with distant metastases (p = .004). The 9-year disease-free survival and overall survival rate was 47.0% and 61.5%, respectively. Multivariate analysis showed poorer disease-free survival rates for patients with tumors >6 cm (p = .005) and microscopically involved margins (p = .043), and overall survival rates decreased with increasing tumor size (p = .011). Conclusions: Grade 3 or greater wound complications can probably be decreased using meticulous treatment planning to decrease the tissue volume encompassed by the 150% isodose line, especially in lower limb locations. Microscopically involved margins remain a predictor of local and locoregional failure, despite radiation doses >70 Gy. Patients with tumors {>=}6 cm and microscopically involved margins are at high risk of treatment failure and death from the development of distant metastases.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Correlation Between Radiation Dose to {sup 18}F-FDG-PET Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Cervical Cancer Patients Treated With Chemoradiotherapy

Purpose: To test the hypothesis that radiation dose to {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG-PET)-defined active bone marrow (BM{sub ACT}) subregions is correlated with hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Methods and Materials: The conditions of 26 women with cervical cancer who underwent {sup 18}F-FDG-PET before treatment with concurrent cisplatin and intensity-modulated radiation therapy were analyzed. BM{sub ACT} was defined as the subregion of total bone marrow (BM{sub TOT}) with a standardized uptake value (SUV) equal to or above the mean for that individual. Inactive bone marrow (BM{sub INACT}) was defined as BM{sub TOT} - BM{sub ACT}. Generalized linear modeling was used to test the correlation between BM{sub ACT} and BM{sub INACT} dose-volume metrics and hematologic nadirs, particularly white blood cell count (WBC) and absolute neutrophil count (ANC). Results: Increased BM{sub ACT} mean dose was significantly associated with decreased log(WBC) nadir ({beta} = -0.04; 95% CI, -0.07to -0.01; p = 0.009), decreased log(ANC) nadir ({beta} = -0.05; 95% CI, -0.08 to -0.02; p = 0.006), decreased hemoglobin nadir ({beta} = -0.16; 95% CI, -0.27 to -0.05; p = 0.010), and decreased platelet nadir ({beta} = -6.16; 95% CI, -9.37 to -2.96; p < 0.001). By contrast, there was no association between BM{sub INACT} mean dose and log(WBC) nadir ({beta} = -0.01; 95% CI, -0.06 to 0.05; p = 0.84), log(ANC) nadir ({beta} = -0.03; 95% CI, -0.10 to 0.04; p = 0.40), hemoglobin nadir ({beta} = -0.09; 95% CI, -0.31 to 0.14; p = 0.452), or platelet nadir ({beta} = -3.47; 95% CI, -10.44 to 3.50; p = 0.339). Conclusions: Irradiation of BM subregions with higher {sup 18}F-FDG-PET activity was associated with hematologic toxicity, supporting the hypothesis that reducing dose to BM{sub ACT} subregions could mitigate hematologic toxicity. Future investigation should seek to confirm these findings and to identify optimal SUV thresholds to define BM{sub ACT}.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Randomized Control Trial: Evaluating Aluminum-Based Antiperspirant Use, Axilla Skin Toxicity, and Reported Quality of Life in Women Receiving External Beam Radiotherapy for Treatment of Stage 0, I, and II Breast Cancer

Purpose: Standard skin care instructions regarding the use of antiperspirants during radiotherapy to the breast varies across North America. Women have articulated that when instructed to not use antiperspirant, the potential for body odor is distressing. Historical practices and individual opinions have often guided practice in this field. The present study had 2 purposes. To evaluate whether the use of aluminum-based antiperspirant while receiving external beam radiotherapy for stage 0, I, or II breast cancer will increase axilla skin toxicity and to evaluate whether the use of antiperspirant during external beam radiotherapy improves quality of life. Methods: A total of 198 participants were randomized to either the experimental group (antiperspirant) or control group (standard care-wash only). The skin reactions in both groups were measured weekly and 2 weeks after treatment using the National Cancer Institute Common Toxicity Criteria Adverse Events, version 3, toxicity grading criteria. Both groups completed the Functional Assessment for Chronic Illness Therapy's questionnaire for the breast population quality of life assessment tool, with additional questions evaluating the effect of underarm antiperspirant use on quality of life before treatment, immediately after treatment, and 2 weeks after treatment during the study. Results: The skin reaction data were analyzed using the generalized estimating equation. No statistically significant difference was seen in the skin reaction between the 2 groups over time. The quality of life data also revealed no statistically significant difference between the 2 groups over time. Conclusions: Data analysis indicates that using antiperspirant routinely during external beam radiotherapy for Stage 0, I, or II breast cancer does not affect the intensity of the skin reaction or the self-reported quality of life. This evidence supports that in this particular population, there is no purpose to restrict these women from using antiperspirants during their treatment, and the decision to use an antiperspirant or not in this setting should be left to the discretion of the patient.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Local Control, Toxicity, and Cosmesis in Women >70 Years Enrolled in the American Society of Breast Surgeons Accelerated Partial Breast Irradiation Registry Trial

Purpose: The American Society of Breast Surgeons enrolled women in a registry trial to prospectively study patients treated with the MammoSite Radiation Therapy System breast brachytherapy device. The present report examined the outcomes in women aged >70 years enrolled in the trial. Methods and Materials: A total of 1,449 primary early stage breast cancers were treated in 1,440 women. Of these, 537 occurred in women >70 years old. Fisher's exact test was performed to correlate age ({<=}70 vs. >70 years) with toxicity and with cosmesis. The association of age with local recurrence (LR) failure times was investigated by fitting a parametric model. Results: Older women were less likely to develop telangiectasias than younger women (7.9% vs. 12.4%, p = 0.0083). The incidence of other toxicities was similar. Cosmesis was good or excellent in 92% of the women >70 years old. No significant difference was found in LR as a function of age. The 5-year actuarial LR rate with invasive disease for the older vs. younger population was 2.79% and 2.92%, respectively (p = 0.5780). In women >70 years with hormone-sensitive tumors {<=}2 cm who received hormonal therapy (n = 195), the 5-year actuarial rate of LR, overall survival, disease-free survival, and cause-specific survival was 2.06%, 89.3%, 87%, and 97.5%, respectively. These outcomes were similar in women who did not receive hormonal therapy. Women with small, estrogen receptor-negative disease had worse LR, overall survival, and disease-free survival compared with receptor-positive patients. Conclusions: Accelerated partial breast irradiation with the MammoSite radiation therapy system resulted in low toxicity and produced similar cosmesis and local control at 5 years in women >70 years compared with younger women. This treatment should be considered as an alternative to omitting adjuvant radiotherapy for older women with small-volume, early-stage breast cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗