Organ preservation in muscle-invasive urothelial bladder cancer.

PURPOSE OF REVIEW: The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies. RECENT FINDINGS: Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy. SUMMARY: MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.

Dose prescription and reporting in stereotactic body radiotherapy: A multi-institutional study.

BACKGROUND AND PURPOSE: Radiation dose prescriptions are foundational for optimizing treatment efficacy and limiting treatment-related toxicity. We sought to assess the lack of standardization of SBRT dose prescriptions across institutions. MATERIALS & METHODS: Dosimetric data from 1298 patients from 9 academic institutions treated with IMRT and VMAT were collected. Dose parameters D100, D98, D95, D50, and D2 were used to assess dosimetric variability. RESULTS: Disease sites included lung (48.3 %) followed by liver (29.7 %), prostate (7.5 %), spine (6.8 %), brain (4.1 %), and pancreas (2.5 %). The PTV volume in lung varied widely with bimodality into two main groups (22.0-28.7 cm3) and (48.0-67.1 cm3). A hot spot ranging from 120-150 % was noted in nearly half of the patients, with significant variation across institutions. A D50 ≥ 110 % was found in nearly half of the institutions. There was significant dosimetric variation across institutions. CONCLUSIONS: The SBRT prescriptions in the literature or in treatment guidelines currently lack nuance and hence there is significant variation in dose prescriptions across academic institutions. These findings add greater importance to the identification of dose parameters associated with improved clinical outcome comparisons as we move towards more hypofractionated treatments. There is a need for standardized reporting to help institutions in adapting treatment protocols based on the outcome of clinical trials. Dosimetric parameters are subsequently needed for uniformity and thereby standardizing planning guidelines to maximize efficacy, mitigate toxicity, and reduce treatment disparities are urgently needed.

Stereotactic Body Radiation Therapy for the Treatment of Locally Recurrent and Oligoprogressive Non-Small Cell Lung Cancer: A Single Institution Experience.

Objectives: To investigate the efficacy and safety of lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) including oligorecurrent and oligoprogressive disease. Methods: Single-institution retrospective analysis of 60 NSCLC patients with 62 discrete lesions treated with SBRT between 2008 and 2017. Patients were stratified into three groups, including early stage, locally recurrent, and oligoprogressive disease. Group 1 included early stage local disease with no prior local therapy. Group 2 included locally recurrent disease after local treatment of a primary lesion, and group 3 included regional or well-controlled distant metastatic disease receiving SBRT for a treatment naive lung lesion (oligoprogressive disease). Patient/tumor characteristics and adverse effects were recorded. Local failure free survival (LFFS), progression free survival (PFS), and overall survival (OS) were estimated using the Kaplan Meier method. Results: At median follow-up of 34 months, 67% of the study population remained alive. The estimated 3-year LFFS for group 1, group 2, and group 3 patients was 95% (95% CI: 86%-100%), 82%(62% - 100%), and 83% (58-100%), respectively. The estimated 3-year PFS was 59% (42-83%), 40% (21%-78%), and 33% (12%-95%), and the estimated 3-year OS was 58% (41-82%), 60% (37-96%), and 58% (31-100%)), respectively for each group. When adjusted for age and size of lesion, no significant difference in OS, LFFS, and PFS emerged between groups (p > 0.05). No patients experienced grade 3 to 5 toxicity. Eighteen patients (29%) experienced grade 1 to 2 toxicity. The most common toxicities reported were cough and fatigue. Conclusions: Our data demonstrates control rates in group 1 patients comparable to historical controls. Our study also reveals comparable clinical results for SBRT in the treatment of NSCLC by demonstrating similar rates of LFFS and OS in group 2 and group 3 patients with locally recurrent and treatment naïve lung lesion with well-controlled distant metastatic disease.

Modern Management of High-risk Soft Tissue Sarcoma With Neoadjuvant Chemoradiation: A Single-center Experience.

OBJECTIVE: Neoadjuvant chemoradiation (NA-CRT), followed by resection of high-risk soft tissue sarcoma (STS), may offer good disease control and toxicity outcomes. We report on a single institution's modern NA-CRT experience. MATERIALS AND METHODS: Delay to surgical resection, resection margin status, extent of necrosis, tumor cell viability, presence of hyalinization, positron emission tomography (PET)/computed tomography data, and treatment toxicities were collected. Using the Kaplan-Meier survival analysis, 5-year overall survival, disease-free survival, distant metastasis-free survival, and local control (LC) were estimated. Clinicopathologic features and PET/computed tomography avidity changes were assessed for their potential predictive impact using the log-rank test. RESULTS: From 2011 to 2018, 37 consecutive cases of localized high-risk STS were identified. Twenty-nine patients underwent ifosfamide-based NA-CRT to a median dose of 50 Gy before en bloc resection. At a median follow-up of 40.3 months, estimated 5-year overall survival was 86.1%, disease-free survival 70.2%, distant metastasis-free survival 75.2%, and LC 86.7%. Following NA-CRT, a median reduction of 54.7% was observed in tumor PET avidity; once resected, median tumor necrosis of 60.0% with no viable tumor cells was detected in 13.8% of the cases. Posttreatment resection margins were negative in all patients, with 27.6% having a margin of ≤1 mm. Delays of over 6 weeks following the end of radiation treatment to surgical resection occurred in 20.7% cases and was suggestive of inferior LC (92.8% vs. 68.6%, P=0.025). CONCLUSIONS: This single-institution series of NA-CRT demonstrates favorable disease control. Delay in surgical resection was associated with inferior LC, a finding that deserves further evaluation in a larger cohort. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Nomogram to Predict the Benefit of Intensive Treatment for Locoregionally Advanced Head and Neck Cancer.

PURPOSE: Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy. EXPERIMENTAL DESIGN: We analyzed 2,688 patients with stage III-IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat. RESULTS: Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57-0.94; P = 0.016] than those with ω score <0.80 (5-year OS, 46.7% vs. 45.3%; HR of 1.02, 95% CI: 0.92-1.14; P = 0.69; P = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression. CONCLUSIONS: Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

Dosimetric assessment of tumor control probability in intensity and volumetric modulated radiotherapy plans.

OBJECTIVE:: Radiobiological models have been used to calculate the outcomes of treatment plans based on dose-volume relationship. This study examines several radiobiological models for the calculation of tumor control probability (TCP) of intensity modulated radiotherapy plans for the treatment of lung, prostate, and head and neck (H&N) cancers. METHODS:: Dose volume histogram (DVH) data from the intensity modulated radiotherapy plans of 36 lung, 26 prostate, and 87 H&N cases were evaluated. The Poisson, Niemierko, and Marsden models were used to calculate the TCP of each disease group treatment plan. The calculated results were analyzed for correlation and discrepancy among the three models, as well as different treatment sites under study. RESULTS:: The median value of calculated TCP in lung plans was 61.9% (34.1-76.5%), 59.5% (33.5-73.9%) and 32.5% (0.0-93.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in prostate plans was 85.1% (56.4-90.9%), 81.2% (56.1-88.7%) and 62.5% (28.2-75.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in H&N plans was 94.0% (44.0-97.8%) and 94.3% (0.0-97.8%) with the Poisson and Niemierko models, respectively. There were significant differences between the calculated TCPs with the Marsden model in comparison with either the Poisson or Niemierko model (p < 0.001) for both lung and prostate plans. The TCPs calculated by the Poisson and Niemierko models were significantly correlated for all three tumor sites. CONCLUSION:: There are variations with different radiobiological models. Understanding of the correlation and limitation of a TCP model with dosimetric parameters can help develop the meaningful objective functions for plan optimization, which would lead to the implementation of outcome-based planning. More clinical data are needed to refine and consolidate the model for accuracy and robustness. ADVANCES IN KNOWLEDGE:: This study has tested three radiobiological models with varied disease sites. It is significant to compare different models with the same data set for better understanding of their clinical applicability.

Successful treatment of platinum refractory ovarian clear cell carcinoma with secondary cytoreductive surgery and implantable transponder placement to facilitate targeted volumetric arc radiation therapy.

We describe a case of the first successful treatment of platinum refractory clear cell ovarian cancer with secondary cytoreductive surgery and placement of Calypso transponders to facilitate post-operative volumetric arc radiation therapy. In the setting of both primary and recurrent disease, patients with clear cell ovarian cancer are less responsive to standard chemotherapy and those treated with radiation therapy may have improved outcomes compared to the use of other treatment modalities. Volumetric arc radiation therapy with implantable transponders is feasible, and allows for the targeted treatment of sites of metastatic disease while limiting toxicity to surrounding structures and can be considered for patients with recurrent ovarian cancer and oligometastatic disease.

Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial.

Importance: Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear. Objective: To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection. Design, Setting, and Participants: Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non-small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014. Interventions: The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks. Main Outcomes and Measures: Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points. Results: Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively. Conclusions and Relevance: As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00551369.

Cost in perspective: direct assessment of American market acceptability of Co-60 in gynecologic high-dose-rate brachytherapy and contrast with experience abroad.

PURPOSE: While Ir-192 remains the mainstay isotope for gynecologic high-dose-rate (HDR) brachytherapy in the U.S., Co-60 is used abroad. Co-60 has a longer half-life than Ir-192, which may lead to long-term cost savings; however, its higher energy requires greater shielding. This study analyzes Co-60 acceptability based on a one-time expense of additional shielding and reports the financial experience of Co-60 in Peru's National Cancer Institute, which uses both isotopes. MATERIAL AND METHODS: A nationwide survey was undertaken assessing physician knowledge of Co-60 and willingness-to-pay (WTP) for additional shielding, assuming a source more cost-effective than Ir-192 was available. With 440 respondents, 280 clinicians were decision-makers and provided WTPs, with results previously reported. After completing a shielding report, we estimated costs for shielding expansion, noting acceptability to decision makers' WTP. Using activity-based costing, we note the Peruvian fiscal experience. RESULTS: Shielding estimates ranged from $173,000 to $418,000. The percentage of respondents accepting high-density modular or lead shielding (for union and non-union settings) were 17.5%, 11.4%, 3.9%, and 3.2%, respectively. Shielding acceptance was associated with greater number of radiation oncologists in a respondent's department but not time in practice or the American Brachytherapy Society membership. Peru's experience noted cost savings with Co-60 of $52,400 annually. CONCLUSIONS: By comparing the cost of additional shielding for a sample institution's HDR suite with radiation oncologists' WTP, this multi-institutional collaboration noted < 20% of clinicians would accept additional shielding. Despite low acceptability in the US, Co-60 demonstrates cost-favorability in Peru and may similarly in other locations.

A national survey of HDR source knowledge among practicing radiation oncologists and residents: Establishing a willingness-to-pay threshold for cobalt-60 usage.

PURPOSE: Ir-192 is the predominant source for high-dose-rate (HDR) brachytherapy in United States markets. Co-60, with longer half-life and fewer source exchanges, has piloted abroad with comparable clinical dosimetry but increased shielding requirements. We sought to identify practitioner knowledge of Co-60 and establish acceptable willingness-to-pay (WTP) thresholds for additional shielding requirements for use in future cost-benefit analysis. METHODS AND MATERIALS: A nationwide survey of U.S. radiation oncologists was conducted from June to July 2015, assessing knowledge of HDR sources, brachytherapy unit shielding, and factors that may influence source-selection decision-making. Self-identified decision makers in radiotherapy equipment purchase and acquisition were asked their WTP on shielding should a more cost-effective source become available. RESULTS: Four hundred forty surveys were completed and included. Forty-four percent were ABS members. Twenty percent of respondents identified Co-60 as an HDR source. Respondents who identified Co-60 were significantly more likely to be ABS members, have attended a national brachytherapy conference, and be involved in brachytherapy selection. Sixty-six percent of self-identified decision makers stated that their facility would switch to a more cost-effective source than Ir-192, if available. Cost and experience were the most common reasons provided for not switching. The most common WTP value selected by respondents was <$25,000. CONCLUSIONS: A majority of respondents were unaware of Co-60 as a commercially available HDR source. This investigation was novel in directly assessing decision makers to establish WTP for shielding costs that source change to Co-60 may require. These results will be used to establish WTP threshold for future cost-benefit analysis.

Evidence of boldenone, nandrolone, 5(10)-estrene-3ß-17α-diol and 4-estrene-3,17-dione as minor metabolites of testosterone in equine.

The detection of boldenone, nandrolone, 5(10)-estrene-3ß,17α-diol, and 4-estrene-3,17-dione in a urine sample collected from a gelding having been treated with testosterone (500 mg 'Testosterone Suspension 100', single dose, injected intramuscularly) in 2009 led the authors' laboratory to suspect that these 'testicular' steroids could be minor metabolites of testosterone in geldings. Administration trials on six castrated horses with Testosterone Suspension 100 confirmed that low levels of boldenone, nandrolone, 5(10)-estrene-3ß,17α-diol, and 4-estrene-3,17-dione could indeed be detected and confirmed in the early post-administration urine samples from all six geldings. Although boldenone has been reported to be present in urine after testosterone administration, there has been no direct evidence reported that boldenone, nandrolone, 5(10)-estrene-3ß,17α-diol, and 4-estrene-3,17-dione are metabolites of testosterone in geldings. Subsequent in vitro experiments involving the incubation of testosterone with horse liver microsomes, liver, adipose and muscle tissues, and adrenal cortex homogenates failed to provide evidence that these four substances are minor metabolites of testosterone. An administration trial using 'Testosterone Suspension 100' supplemented with 13 C-labelled testosterone (500 mg, 1:1 ratio, injected intramuscularly) was performed. The similarities of the excretion curves of 12 C-testosterone and 13 C-testosterone in urine suggest that there was minimal kinetic isotope effect. 13 C-Labelled boldenone, nandrolone and 4-estrene-3,17-dione were detected but not 5(10)-estrene-3ß,17α-diol and its 13 C-counterpart. This is the first unequivocal evidence of boldenone, nandrolone and 4-estrene-3,17-dione being metabolites of testosterone in geldings. In view of these results, caution should be exercised when interpreting findings of boldenone, nandrolone and/or 4-estrene-3,17-dione together with a relatively high level of testosterone in gelding urine. Copyright © 2017 John Wiley & Sons, Ltd.

Adult Primary Spinal Epidural Extraosseous Ewing's Sarcoma: A Case Report and Review of the Literature.

Background. Extraosseous Ewing's sarcoma in the spinal epidural space is a rare malignancy, especially in adults. Case Presentation. A 40-year-old male presented with back pain and urinary hesitancy. MRI revealed a thoracic extradural mass with no osseous involvement. He underwent surgery for gross total resection of the mass, which was diagnosed as Ewing's sarcoma. He was subsequently treated with chemoradiotherapy. He remains disease-free 1 year after surgery. Review of the literature indicated only 45 previously reported cases of spinal epidural extraosseous Ewing's sarcoma in adults. Conclusions. Extraosseous Ewing's sarcoma in the spinal epidural space is a rare clinical entity that should be included in the differential for spinal epidural masses. Its treatment is multidisciplinary but frequently requires surgical intervention due to compressive neurologic symptoms. Gross total resection appears to correlate with improved outcomes.

Use of a Flexible Inflatable Multi-Channel Applicator for Vaginal Brachytherapy in the Management of Gynecologic Cancer.

INTRODUCTION: Evaluate use of novel multi-channel applicator (MC) Capri™ to improve vaginal disease coverage achievable by single-channel applicator (SC) and comparable to Syed plan simulation. MATERIALS AND METHODS: Twenty-eight plans were evaluated from four patients with primary or recurrent gynecologic cancer in the vagina. Each received whole pelvis radiation, followed by three weekly treatments using HDR brachytherapy with a 13-channel MC. Upper vagina was treated to 5 mm depth to 1500 cGy/3 fractions with a simultaneous integrated boost totaling 2100 cGy/3 fractions to tumor. Modeling of SC and Syed plans was performed using MC scans for each patient. Dosimetry for MC and SC plans was evaluated for PTV700 cGy coverage, maximum dose to 2 cm(3) to bladder, rectum, as well as mucosal surface points. Dosimetry for Syed plans was calculated for PTV700 cGy coverage. Patients were followed for treatment response and toxicity. RESULTS: Dosimetric analysis between MC and SC plans demonstrated increased tumor coverage (PTV700 cGy), with decreased rectal, bladder, and contralateral vaginal mucosa dose in favor of MC. These differences were significant (p < 0.05). Comparison of MC and Syed plans demonstrated increased tumor coverage in favor of Syed plans which were not significant (p = 0.71). Patients treated with MC had no cancer recurrence or ≥grade 3 toxicity. CONCLUSION: Use of MC was efficacious and safe, providing superior coverage of tumor volumes ≤1 cm depth compared to SC and comparable to Syed implant. MC avoids excess dose to surrounding organs compared to SC, and potentially less morbidity than Syed implants. For tumors extending ≤1 cm depth, use of MC represents an alternative to an interstitial implant.

Metabolic study of androsta-1,4,6-triene-3,17-dione in horses using liquid chromatography/high resolution mass spectrometry.

Androsta-1,4,6-triene-3,17-dione (ATD) is an irreversible steroidal aromatase inhibitor and is marketed as a supplement. It has been reported to effectively reduce estrogen biosynthesis and significantly increase the levels of endogenous steroids such as dihydrotestosterone and testosterone in human. ATD abuses have been reported in human sports. Its metabolism in human has been studied, and the in vitro metabolic study of ATD in horses has been reported, however, little is known about its biotransformation and elimination in horses. This paper describes the in vitro and in vivo metabolism studies of ATD in horses, with an objective of identifying the target metabolites with the longest detection time for controlling ATD abuse. In vitro metabolism studies of ATD were performed using homogenized horse liver. ATD was found to be extensively metabolized, and its metabolites could not be easily characterized by gas chromatography/mass spectrometry (GC/MS) due to insufficient sensitivity. Liquid chromatography/high resolution mass spectrometry (LC/HRMS) was therefore employed for the identification of in vitro metabolites. The major biotransformations observed were combinations of reduction of the olefin groups and/or the keto group at either C3 or C17 position. In addition, mono-hydroxylation in the D-ring was observed along with reduction of the olefin groups and/or the keto group at C17 position. Fourteen in vitro metabolites, including two epimers of androsta-1,4,6-trien-17-ol-3-one (M1a, M1b), androsta-4,6-diene-3,17-dione (M2), boldione (M3), androsta-4,6-diene-17ß-ol-3-one (M4), androsta-4,6-diene-3-ol-17-one (M5), boldenone and epi-boldenone (M6a, M6b), four stereoisomers of hydroxylated androsta-1,4,6-trien-17-ol-3-one (M7a to M7d), and two epimers of androsta-1,4-diene-16α,17-diol (M8a, M8b), were identified. The identities of all metabolites, except M1a, M5, M7a to M7d, were confirmed by matching with authentic reference standards using LC/HRMS. For the in vivo metabolism studies, two thoroughbred geldings were each administered with 800 mg of ATD by stomach tubing. ATD, and twelve out of the fourteen in vitro metabolites, including M1a, M1b, M2, M4, M5, M6, M7a to M7d, M8a and M8b, were detected in post-administration urine. Two additional urinary metabolites, namely stereoisomers of hydroxylated androsta-4,6-dien-17-ol-3-one (M9a, M9b), were tentatively identified by mass spectral interpretation. Elevated level of testosterone was also observed. In post-administration blood samples, only the parent drug, M1b and M2 were identified. This study showed that the detection of ATD administration would be best achieved by either monitoring the metabolites M1b (androsta-1,4,6-trien-17ß-ol-3-one) or M4 (both excreted as sulfate conjugates) in urine, which could be detected for up to a maximum of 77 h post-administration. The analyte of choice for plasma is M1b, which could be detected for up to 28 h post administration.

Surveillance epidemiology and end results analysis demonstrates improvement in overall survival for cervical cancer patients treated in the era of concurrent chemoradiotherapy.

BACKGROUND: In February 1999, the National Cancer Institute (NCI) issued a clinical alert based on five randomized trials that reported better overall survival (OS) with concurrent chemoradiotherapy (CCRT) than with surgery or radiation alone for locoregional cervical cancer. This study analyzes data from the surveillance epidemiology and end results (SEER) program to evaluate the improvement in survival in the era of CCRT. METHODS: The SEER database was queried for FIGO stages IB2-IVA cervical cancer patients treated with radiotherapy between 1995 and 2002. Patients diagnosed between 1999 and 2002 (CCRT era) were assumed to have received CCRT more frequently than patients diagnosed between 1995 and 1998 (RT era). Cases were stratified by period of diagnosis, age, and SEER region. OS and cause specific survival (CSS) were compared between the two time periods with chi-square log-rank tests. Multivariable Cox models were also used to compare OS and CSS between the two time periods, with adjustment for stratification variables and other covariates. RESULTS: The study included 3517 patients. Unadjusted OS and CSS were significantly improved in 1999-2002 compared with 1995-1998 (OS: p < 0.001, hazard ratio (HR): 0.81; CSS: p < 0.001, HR: 0.79). Significant improvements in OS and CSS were retained after adjustment for multiple variables (multivariable OS HR 0.78; CSS HR 0.76). CONCLUSION: Cervical cancer patients treated with radiotherapy after 1999 had improved OS and CSS compared with patients treated before 1999, likely reflecting increased usage of CCRT. This study adds to the population-level evidence supporting the adoption of CCRT as the standard of care for locoregional cervical cancer.

Taxanes as radiosensitizers.

In parallel with the discovery of the taxanes, our understanding of the molecular underpinnings that comprise the classic biologic principles of fractionated radiotherapy has rapidly evolved over the past half century. Early studies have implicated DNA as the primary target for radiation-induced lethality. More recently, however, the molecular biology involved in radiosensitization of tumor cells has been unveiled. Specifically, factors associated with DNA damage and cell killing, collectively known as the 'four Rs' of radiobiology, including (r)eassortment of tumor cells into the radiosensitive phases of the cell cycle (G2/M), (r)eoxygenation of hypoxic areas within a tumor, (r)epair of sublethal DNA damage, and (r)epopulation of surviving tumor cells, have been elucidated, and upon manipulation of each factor or a combination of factors a significant impact on radiation-associated tumor control probabilities was found. Not only does spatial cooperation have a theoretical benefit in patients with undetectable micrometastatic disease at presentation, but the manipulation of either of the 'four Rs' using taxanes provokes further local radiation-associated tumor cell killing with an associated improvement in clinical responses. Numerous studies have shown that taxanes radiosensitize tumor cells directly and/or indirectly by perturbing the tumor microenvironment in a time-dependent and dose-dependent manner. Herein, the impact of taxanes on radiobiological tenets as a mode of radiosensitizing tumor cells and their clinical implications are reviewed.

Detection of volatile biomarkers of therapeutic radiation in breath.

Breath testing could provide a rational tool for radiation biodosimetry because radiation causes distinct stress-producing molecular damage, notably an increased production of reactive oxygen species. The resulting oxidative stress accelerates lipid peroxidation of polyunsaturated fatty acids, liberating alkanes and alkane metabolites that are excreted in the breath as volatile organic compounds (VOCs). Breath tests were performed before and after radiation therapy over five days in 31 subjects receiving daily fractionated doses: 180-400 cGy d(-1) standard radiotherapy (n = 26), or 700-1200 cGy d(-1) high-dose stereotactic body radiotherapy (n = 5). Breath VOCs were assayed using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Multiple Monte Carlo simulations identified approximately 50 VOCs as greater-than-chance biomarkers of radiation on all five days of the study. A consistent subset of 15 VOCs was observed at all time points. A radiation response function was built by combining these biomarkers and the resulting dose-effect curve was significantly elevated at all exposures ⩾1.8 Gy. Cross-validated binary algorithms identified radiation exposures ⩾1.8 Gy with 99% accuracy, and ⩾5 Gy with 78% accuracy. In this proof of principal study of breath VOCs, we built a preliminary radiation response function based on 15 VOCs that appears to identify exposure to localized doses of 1.8 Gy and higher. VOC breath testing could provide a new tool for rapid and non-invasive radiation biodosimetry.

Is there a role for an external beam boost in cervical cancer radiotherapy?

OBJECTIVES: Some patients are medically unfit for or averse to undergoing a brachytherapy boost as part of cervical cancer radiotherapy. In order to be able to definitively treat these patients, we assessed whether we could achieve a boost plan that would mimic our brachytherapy plans using external beam radiotherapy. METHODS: High dose rate brachytherapy plans of 20 patients with stage IIB cervical cancer treated with definitive chemoradiotherapy were included in this study. Patients had undergone computer tomography (CT) simulations with tandem and ovoids in place. Point "A" dose was 600-700 cGy. We attempted to replicate the boost dose distribution from brachytherapy plans using intensity-modulated radiotherapy (Varian Medical Systems, Palo Alto, CA, USA), volumetric modulated arc therapy (Rapid Arc, Varian Medical Systems, Palo Alto, CA, USA), or TomoTherapy (Accuray, Inc., Sunnyvale, CA, USA) with the brachytherapy 100% isodose line as our target. Target coverage, normal tissue dose, and brachytherapy point doses were compared with ANOVA. Two-sided p-values ≤0.05 were considered significant. RESULTS: External beam plans had excellent planning target volume (PTV) coverage, with no difference in mean PTV V95% among planning techniques (range 98-100%). External beam plans had lower bladder Dmax, small intestine Dmax, and vaginal mucosal point dose than brachytherapy plans, with no difference in bladder point dose, mean bladder dose, mean small intestine dose, or rectal dose. Femoral head dose, parametria point dose, and pelvic sidewall point dose were higher with external beam techniques than brachytherapy. CONCLUSIONS: External beam plans had comparable target coverage and potential for improved sparing of most normal tissues compared to tandem and ovoid brachytherapy.