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PubMed | Stony Brook Cancer Center, University of Michigan, Tokyo Electron, Michigan Bone and Mineral Clinic and 10 more.
Type: Comparative Study | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2015

This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab.Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836).The overall incidence of laboratory events of hypocalcaemia grade 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 g/L [median] versus 20.77 g/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with 2 bone metastases at baseline.Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumabs greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia.

PubMed | Stony Brook Cancer Center, University of Maryland, Baltimore, Sloan Kettering Cancer Center, University of Zürich and 15 more.
Type: | Journal: Journal of neurosurgery. Spine | Year: 2016

OBJECTIVE Although postoperative stereotactic body radiation therapy (SBRT) for spinal metastases is increasingly performed, few guidelines exist for this application. The purpose of this study is to develop consensus guidelines to promote safe and effective treatment for patients with spinal metastases. METHODS Fifteen radiation oncologists and 5 neurosurgeons, representing 19 centers in 4 countries and having a collective experience of more than 1300 postoperative spine SBRT cases, completed a 19-question survey about postoperative spine SBRT practice. Responses were defined as follows: 1) consensus: selected by 75% of respondents; 2) predominant: selected by 50% of respondents or more; and 3) controversial: no single response selected by a majority of respondents. RESULTS Consensus treatment indications included: radioresistant primary, 1-2 levels of adjacent disease, and previous radiation therapy. Contraindications included: involvement of more than 3 contiguous vertebral bodies, ASIA Grade A status (complete spinal cord injury without preservation of motor or sensory function), and postoperative Bilsky Grade 3 residual (cord compression without any CSF around the cord). For treatment planning, co-registration of the preoperative MRI and postoperative T1-weighted MRI (with or without gadolinium) and delineation of the cord on the T2-weighted MRI (and/or CT myelogram in cases of significant hardware artifact) were predominant. Consensus GTV (gross tumor volume) was the postoperative residual tumor based on MRI. Predominant CTV (clinical tumor volume) practice was to include the postoperative bed defined as the entire extent of preoperative tumor, the relevant anatomical compartment and any residual disease. Consensus was achieved with respect to not including the surgical hardware and incision in the CTV. PTV (planning tumor volume) expansion was controversial, ranging from 0 to 2 mm. The spinal cord avoidance structure was predominantly the true cord. Circumferential treatment of the epidural space and margin for paraspinal extension was controversial. Prescription doses and spinal cord tolerances based on clinical scenario, neurological compromise, and prior overlapping treatments were controversial, but reasonable ranges are presented. Fifty percent of those surveyed practiced an integrated boost to areas of residual tumor and density override for hardware within the beam path. Acceptable PTV coverage was controversial, but consensus was achieved with respect to compromising coverage to meet cord constraint and fractionation to improve coverage while meeting cord constraint. CONCLUSIONS The consensus by spinal radiosurgery experts suggests that postoperative SBRT is indicated for radioresistant primary lesions, disease confined to 1-2 vertebral levels, and/or prior overlapping radiotherapy. The GTV is the postoperative residual tumor, and the CTV is the postoperative bed defined as the entire extent of preoperative tumor and anatomical compartment plus residual disease. Hardware and scar do not need to be included in CTV. While predominant agreement was reached about treatment planning and definition of organs at risk, future investigation will be critical in better understanding areas of controversy, including whether circumferential treatment of the epidural space is necessary, management of paraspinal extension, and the optimal dose fractionation schedules.

PubMed | Stony Brook Cancer Center, Monash University, University of Sheffield, Joan Karnell Cancer Center at Pennsylvania Hospital and 6 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment.This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs median versus < median based on month 3 assessments.uNTx levels the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death, 1.85; P < 0.0001). sBSAP levels median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR, 2.44; P < 0.0001). uNTx and sBSAP levels median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P < 0.0001 and HR, 1.71; P < 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P < 0.0001, respectively).BTM levels median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. Clin Cancer Res; 22(23); 5713-21. 2016 AACR.

PubMed | Stony Brook Cancer Center, Complutense University of Madrid, University of Houston, Sarah Cannon Research Institute and Tennessee Oncology and 9 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics.Patients (N=5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type.Compared with ZA, denosumab significantly reduced the risk of first SRE acrossallsubgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types.Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.

News Article | December 19, 2016

PORTLAND, OR - Eight years ago, results from a landmark cancer prevention trial run by SWOG showed that a daily dose of vitamin E and selenium did not prevent prostate cancer. In fact, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that vitamin E supplementation increased the risk of prostate cancer in healthy men. Now, a SWOG review of ancillary SELECT results definitively shows that these two antioxidants also don't prevent colorectal adenomas - polyps that are the premalignant precursors to most colorectal cancers. Results are published in Cancer Prevention Research. "The message to the public is this: Vitamin E and selenium will not prevent colorectal adenomas, which are surrogates for colorectal cancer," said Dr. Peter Lance, lead author of the journal article and deputy director of the University of Arizona Cancer Center. "We have no evidence that these supplements work to prevent cancer." Despite the billions spent in the United States each year on vitamin supplements, there is scant evidence they prevent cancer. According to the National Cancer Institute, which funds SWOG through its National Clinical Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP), results from nine randomized trials did not provide evidence that antioxidant supplements are beneficial in primary cancer prevention. An in-depth review conducted for the United States Preventive Services Task Force likewise found no clear evidence of benefit. "There's a whole industry that has people dosing themselves thinking that vitamins will keep them healthy," Lance said. "But we have little evidence that they protect against cancer." To arrive at their conclusions, Lance and his SWOG team used data from SELECT, a prostate cancer prevention trial that enrolled an astonishing 35,533 healthy men - 21 percent men of color - in just 33 months at 427 study sites the United States, Canada, and Puerto Rico. Men were randomized into four groups. Some took a daily dose of vitamin E, others a dose of selenium, others took both antioxidants, and the rest took a placebo only. A substantial number of SELECT participants incidentally underwent a lower endoscopy - colonoscopy or sigmoidoscopy - as part of their usual clinical care while taking part in the trial. In an ancillary study, Lance and his team went back into the SELECT data to review the lower endoscopy and pathology reports. They were able to evaluate information on 6,546 participants who received the procedure as part of SELECT, and found that 2,286 had more than one polyp detected by cameras used in the procedures. A statistical analysis showed that the occurrence of one or more premalignant polyps was about the same among men, regardless of whether men were taking selenium or vitamin E, alone or together, or double placebo. What makes these results definitive, Lance said, is that SELECT was so large and was a randomized controlled study - a design that reduces bias and is considered the gold standard in clinical research. Lance led another University of Arizona Cancer Center team that has just published similar results from a separate randomized trial of selenium and celecoxib. In December 2016, in the Journal of the National Cancer Institute, the team reported that selenium didn't prevent colorectal adenomas - and was associated with increased risk for Type 2 diabetes. Lance's SWOG study team includes: Denise Row, Dr.P.H., of the University of Arizona Mel & Enid Zuckerman College of Public Health; Dr. David Alberts, University of Arizona Cancer Center; Patricia Thompson-Carino, Ph.D., of Stony Brook Cancer Center; Liane Fales of University of Arizona Cancer Center; Fang Wang of Stony Brook Cancer Center; Jerilyn San Jose of University of Arizona Cancer Center; Elizabeth Jacobs, Ph.D. of University of Arizona Cancer Center; Phyllis Goodman of the SWOG Statistical Center at Fred Hutchinson Cancer Research Center; Amy Darke of the SWOG Statistical Center at Fred Hutchinson Cancer Research Center; Monica Yee of SWOG Statistical Center at Cancer Research And Biostatistics; Dr. Lori Minasian of the Division of Cancer Prevention at the National Cancer Institute; and Dr. Ian Thompson of the University of Texas Health Sciences Center. The work was funded by the National Institutes of Health Public Health Service, National Cancer Institute grants RO1 CA124862; U10 CA37429; and UM1 CA182883. SWOG is part of the National Cancer Institute's National Clinical Trials Network, the nation's oldest and largest cancer research network, and is a major part of the cancer research infrastructure in the U.S. and the world. SWOG has over 12,000 members in 46 states and six foreign countries who design and conduct cancer clinical trials to improve the lives of people with cancer. Founded in 1956, SWOG's 1,300 trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 2 million years of human life. Learn more at

Chahal J.,University of Arizona | Stopeck A.,Stony Brook Cancer Center | Clarke K.,Arizona Cancer Center | Livingston R.B.,Arizona Cancer Center | Chalasani P.,Arizona Cancer Center
Neurological Sciences | Year: 2015

Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood–brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution’s experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m2 every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies. © 2015, Springer-Verlag Italia.

PubMed | Stony Brook Cancer Center, Arizona Cancer Center, University of Washington and University of New Mexico
Type: | Journal: Disease markers | Year: 2016

Carbonic anhydrase IX (CAIX) is a hypoxia regulated metalloenzyme integral to maintaining cellular pH. Increased CAIX expression is associated with poor prognosis in breast cancer. To explore CAIX as a biomarker for breast cancer therapies, we measured plasma CAIX levels in healthy control subjects and in breast cancer patients.In control subjects we evaluated plasma CAIX stability via commercially available ELISA. We then similarly quantified plasma CAIX levels in (1) locally advanced breast cancer (LABC) patients treated with neoadjuvant paclitaxel + sunitinib (T + S) followed by doxorubicin and cyclophosphamide (AC); (2) metastatic breast cancer (MBC) patients treated with systemic chemotherapy.Plasma CAIX levels were stable at room temperature for at least 48 hours in control subjects. Mean baseline plasma CAIX levels were lower in controls compared to patients with LABC or MBC. In LABC, CAIX levels rose significantly in response to administration of antiangiogenic therapy (T + S) (p = 0.02) but not AC (p = 0.37). In patients with MBC treated without an antiangiogenic agent CAIX levels did not change with therapy.Our results suggest that CAIX may be an easily obtained, stable measure of tumor associated hypoxia as well as a useful pharmacodynamic biomarker for antiangiogenic therapy.

PubMed | Stony Brook Cancer Center, University of Washington, Sloan Kettering Cancer Center, Johns Hopkins University and 6 more.
Type: | Journal: International journal of radiation oncology, biology, physics | Year: 2016

Todevelop consensus contouring guidelines for postoperative stereotactic body radiation therapy (SBRT) for spinal metastases.Ten spine SBRT specialists representing 10 international centers independently contoured the clinical target volume (CTV), planning target volume (PTV), spinal cord, and spinal cord planning organ at risk volume (PRV)for 10 representative clinical scenarios in postoperative spine SBRT for metastatic solid tumor malignancies. Contours were imported into the Computational Environment for Radiotherapy Research. Agreement between physicians was calculated with an expectation minimization algorithm using simultaneous truth and performance level estimation with statistics. Target volume definition guidelines were established by finding optimized confidence level consensus contours using histogram agreement analyses.Nine expert radiation oncologists and 1 neurosurgeon completed contours for all 10 cases. The mean sensitivity and specificity were 0.79 (range, 0.71-0.89) and 0.94 (range, 0.90-0.99) for the CTV and 0.79 (range, 0.70-0.95) and 0.92 (range, 0.87-0.99) for the PTV), respectively. Mean agreement, which demonstrates the probability that contours agree by chance alone, was 0.58 (range, 0.43-0.70) for CTV and 0.58 (range, 0.37-0.76) for PTV (P<.001 for all cases). Optimized consensus contours were established for all patients with 80% confidence interval. Recommendations for CTV include treatment of the entire preoperative extent of bony and epidural disease, plus immediately adjacent bony anatomic compartments at risk of microscopic disease extension. In particular, a donut-shaped CTV was consistently applied in cases of preoperative circumferential epidural extension, regardless of extent of residual epidural extension. Otherwise more conformal anatomic-based CTVs were determined and described. Spinal instrumentation was consistently excluded from the CTV.We provide consensus contouring guidelines for common scenarios in postoperative SBRT for spinal metastases. These consensus guidelines are subject to clinical validation.

Airola M.V.,State University of New York at Stony Brook | Airola M.V.,Stony Brook Cancer Center | Allen W.J.,State University of New York at Stony Brook | Pulkoski-Gross M.J.,State University of New York at Stony Brook | And 6 more authors.
Structure | Year: 2015

Summary Neutral ceramidase (nCDase) catalyzes conversion of the apoptosis-associated lipid ceramide to sphingosine, the precursor for the proliferative factor sphingosine-1-phosphate. As an enzyme regulating the balance of ceramide and sphingosine-1-phosphate, nCDase is emerging as a therapeutic target for cancer. Here, we present the 2.6-Å crystal structure of human nCDase in complex with phosphate that reveals a striking, 20-Å deep, hydrophobic active site pocket stabilized by a eukaryotic-specific subdomain not present in bacterial ceramidases. Utilizing flexible ligand docking, we predict a likely binding mode for ceramide that superimposes closely with the crystallographically observed transition state analog phosphate. Our results suggest that nCDase uses a new catalytic strategy for Zn2+-dependent amidases, and generates ceramide specificity by sterically excluding sphingolipids with bulky headgroups and specifically recognizing the small hydroxyl head group of ceramide. Together, these data provide a foundation to aid drug development and establish common themes for how proteins recognize the bioactive lipid ceramide. © 2015 Elsevier Ltd.

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