In Memoriam E. Milly Haagedoorn, MD, PhD

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Palliative Oncologic Care Curricula for Providers in Resource-Limited and Underserved Communities: a Systematic Review

Abstract

Familiarity with principles of palliative care, supportive care, and palliative oncological treatment is essential for providers caring for cancer patients, though this may be challenging in global communities where resources are limited. Herein, we describe the scope of literature on palliative oncological care curricula for providers in resource-limited settings. A systematic literature review was conducted using PubMed, Embase, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Med Ed Portal databases, and gray literature. All available prospective cohort studies, case reports, and narratives published up to July 2017 were eligible for review. Fourteen articles were identified and referenced palliative care education programs in Argentina, Uganda, Kenya, Australia, Germany, the USA, or multiple countries. The most common teaching strategy was lecture-based, followed by mentorship and experiential learning involving role play and simulation. Education topics included core principles of palliative care, pain and symptom management, and communication skills. Two programs included additional topics specific to the underserved or American Indian/Alaskan Native community. Only one program discussed supportive cancer care, and no program reported educational content on resource-stratified decision-making for palliative oncological treatment. Five programs reported positive participant satisfaction, and three programs described objective metrics of increased educational or research activity. There is scant literature on effective curricula for providers treating cancer patients in resource-limited settings. Emphasizing supportive cancer care and palliative oncologic treatments may help address gaps in education; increased outcome reporting may help define the impact of palliative care curriculum within resource-limited communities.

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In Memoriam E. Milly Haagedoorn, MD, PhD

http://ift.tt/2oUU7dj

Palliative Oncologic Care Curricula for Providers in Resource-Limited and Underserved Communities: a Systematic Review

Abstract

Familiarity with principles of palliative care, supportive care, and palliative oncological treatment is essential for providers caring for cancer patients, though this may be challenging in global communities where resources are limited. Herein, we describe the scope of literature on palliative oncological care curricula for providers in resource-limited settings. A systematic literature review was conducted using PubMed, Embase, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Med Ed Portal databases, and gray literature. All available prospective cohort studies, case reports, and narratives published up to July 2017 were eligible for review. Fourteen articles were identified and referenced palliative care education programs in Argentina, Uganda, Kenya, Australia, Germany, the USA, or multiple countries. The most common teaching strategy was lecture-based, followed by mentorship and experiential learning involving role play and simulation. Education topics included core principles of palliative care, pain and symptom management, and communication skills. Two programs included additional topics specific to the underserved or American Indian/Alaskan Native community. Only one program discussed supportive cancer care, and no program reported educational content on resource-stratified decision-making for palliative oncological treatment. Five programs reported positive participant satisfaction, and three programs described objective metrics of increased educational or research activity. There is scant literature on effective curricula for providers treating cancer patients in resource-limited settings. Emphasizing supportive cancer care and palliative oncologic treatments may help address gaps in education; increased outcome reporting may help define the impact of palliative care curriculum within resource-limited communities.

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Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis

Abstract

Purpose

Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence.

Methods

Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients.

Results

In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non-steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients.

Conclusions

Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted.

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Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma

Abstract

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single-agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression-free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti-PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors.

We identified patterns of progression that significantly correlate with further prognosis after progression on BRAF inhibitor (BRAFi) treatment. In contrast to previously published studies, we did not find a significant survival benefit for BRAFi treatment beyond progression, whereas subsequent therapies (ipilimumab, chemotherapy) had strikingly low efficacy except for PD-1 inhibitors.

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Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma

Abstract

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single-agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression-free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti-PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors.

We identified patterns of progression that significantly correlate with further prognosis after progression on BRAF inhibitor (BRAFi) treatment. In contrast to previously published studies, we did not find a significant survival benefit for BRAFi treatment beyond progression, whereas subsequent therapies (ipilimumab, chemotherapy) had strikingly low efficacy except for PD-1 inhibitors.

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Molecular Predicators of Duodenal Familial Adenomatous Polyposis Chemoprevention: Do Chemopreventive Drugs Hit Their Presumed Molecular Targets?

Patients with familial adenomatous polyposis (FAP) have an increased risk of developing duodenal adenomas and adenocarcinomas. In previous trials, sulindac (a cyclooxygenase inhibitor) alone failed to significantly suppress duodenal tumorigenesis in FAP patients, but sulindac plus the tyrosine kinase inhibitor erlotinib significantly reduced duodenal polyp burden. Delker and colleagues report in this issue (beginning on page 4) on transcriptome analyses that aimed to identify the molecular targets mediating the response to sulindac–erlotinib. Their exploratory transcriptome analyses suggested that sulindac–erlotinib suppressed duodenal polyposis via inhibiting Wnt/β-catenin, EGFR, and cyclooxygenase pathways. This perspective discusses the significance and limitations of the study. Cancer Prev Res; 11(1); 1–3. ©2017 AACR.

See related article by Delker et al., p. 4

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Clinicopathological characteristics, staging classification, and survival outcomes of primary malignant melanoma of the esophagus

Background

Primary malignant melanoma of esophagus (PMME) is a remarkably rare and highly aggressive tumor. Studies related with clinicopathological findings, staging classification, and clinical outcomes are lacking.

Methods

We reviewed 21 cases of PMME at the Tianjin Medical University Cancer Institute and Hospital from January 2002 to February 2017.

Results

Nineteen patients (90.48%) presented a history of dysphagia for months, and two (9.52%) experienced retrosternal pain. Histologically, tumors were composed of atypical melanocytes with melanocytosis surrounding the tumor. The overall survival was 1-40 months, with the median time of 10 months. The mucosal staging classification for upper aerodigestive tract showed better distribution of overall survival with different stages than that of the American Joint Commission on Cancer staging classification for esophagus, but without statistical difference. Both the clinical and pathological characteristics were not highly consistent with overall survival.

Conclusions

PMME is a considerably aggressive tumor with poor prognosis. The staging classification of mucosal melanoma of the upper aerodigestive tract may be a good option for PMME patients.

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CEA to peritoneal carcinomatosis index (PCI) ratio is prognostic in patients with colorectal cancer peritoneal carcinomatosis undergoing cytoreduction surgery and intraperitoneal chemotherapy

Background and Objectives

Serum tumor markers are prognostic in patients with colorectal cancer peritoneal carcinomatosis (CRPC) undergoing cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). Assessment of the ratio of tumor marker to volume, as depicted by peritoneal carcinomatosis index (PCI), and how this may affect overall (OS) and recurrence free survival (RFS) has not been reported.

Methods

Survival effect of this ratio was analyzed in patients with CRPC managed from 1996 to 2016 with CRS and IPC.

Results

Of 260 patients included, those with low CEA/PCI ratio (<2.3) had longer median OS (56 vs 24 months, P = 0.001) and RFS (13 vs 9 months, P = 0.02). The prognostic impact of CEA/PCI ratio was most pronounced in patients with PCI ≤ 10 (OS of 72 vs 30 months, P < 0.001; RFS of 21 vs 10 months, P = 0.002). In multivariable analysis, elevated CEA/PCI ratio was independently associated with poorer OS (adjusted HR 1.85, 95%CI 1.11-3.10, P = 0.02) and RFS (adjusted HR 1.58, 95%CI 1.04-2.41, P = 0.03).

Conclusion

CEA/PCI ratio is an independent prognostic factor for OS and RFS in CRPC. This novel approach allows both tumor activity and volume to be accounted for in one index, thus potentially providing a more accurate indication of tumor biological behavior.

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ConsensusDriver Improves upon Individual Algorithms for Predicting Driver Alterations in Different Cancer Types and Individual Patients

Existing cancer driver prediction methods are based on very different assumptions and each of them can detect only a particular subset of driver genes. Here we perform a comprehensive assessment of 18 driver prediction methods on more than 3,400 tumor samples from 15 cancer types, all to determine their suitability in guiding precision medicine efforts. We categorized these methods into five groups: functional impact on proteins in general (FI) or specific to cancer (FIC), cohort-based analysis for recurrent mutations (CBA), mutations with expression correlation (MEC), and methods that use gene interaction network-based analysis (INA). The performance of driver prediction methods varied considerably, with concordance with a gold standard varying from 9% to 68%. FI methods showed relatively poor performance (concordance <22%), while CBA methods provided conservative results but required large sample sizes for high sensitivity. INA methods, through the integration of genomic and transcriptomic data, and FIC methods, by training cancer-specific models, provided the best trade-off between sensitivity and specificity. As the methods were found to predict different subsets of driver genes, we propose a novel consensus-based approach, ConsensusDriver, which significantly improves the quality of predictions (20% increase in sensitivity) in patient subgroups or even individual patients. Consensus-based methods like ConsensusDriver promise to harness the strengths of different driver prediction paradigms.Significance: These findings assess state-of-the-art cancer driver prediction methods and develop a new and improved consensus-based approach for use in precision oncology. Cancer Res; 78(1); 1–12. ©2017 AACR.

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Tenascin-C promotes tumor cell migration and metastasis through integrin {alpha}9{beta}1 -mediated YAP inhibition

Tenascin-C is an extracellular matrix molecule that drives progression of many types of human cancer but the basis for its actions remain obscure. In this study, we describe a cell-autonomous signaling mechanism explaining how tenascin-C promotes cancer cell migration in the tumor microenvironment. In a murine xenograft model of advanced human osteosarcoma, tenascin-C and its receptor integrin α9β1 were determined to be essential for lung metastasis of tumor cells. We determined that activation of this pathway also reduced tumor cell-autonomous expression of target genes for the transcription factor YAP. In clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact. Taken together, our results illuminate how tumor cell deposition of tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression. 

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Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets

The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α co-localizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSCs) are present in tumor cell lines, mouse lung tumors and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GFs) in non-transformed cells with delayed kinetics (4-6 hr), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the pro-senescence transcription factor C/EBPβ in primary MEFs undergoing senescence. Conversely, in tumor cells C/EBPβ activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBPβ.

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Inactivation of cancer-associated-fibroblasts (CAF) disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) which stimulate oncogenic signaling in TEC. In this study, we evaluated the crosstalk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mutp53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF-β signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, non-proliferative state. TEC exposed to media conditioned by drug-treated CAF exhibited a decrease in oncogenic signaling as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF-β. Given promising early clinical studies with minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma crosstalk may offer a viable strategy to treat pancreatic cancer. 

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ER stress signaling promotes the survival of cancer 'persister cells' tolerant to EGFR tyrosine kinase inhibitors

An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells which survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy,a combination previously shown to suppress drug tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response (UPR) associated with STING upregulation, promoting pro-tumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.

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The CARMA3-Bcl10-MALT1 Signalosome Drives NF-{kappa}B Activation and Promotes Aggressiveness in Angiotensin II Receptor-positive Breast Cancer.

The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NF-κB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NF-κB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration and invasion. In addition, CBM-dependent activation of NF-κB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NF-κB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NF-κB signaling pathways to improve the treatment of this breast cancer subset.

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FIH is an oxygen sensor in ovarian cancer for G9a/GLP-driven epigenetic regulation of metastasis-related genes

The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis.

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Inhibition of translesion DNA synthesis as a novel therapeutic strategy to treat brain cancer

Temozolomide is a DNA alkylating agent used to treat brain tumors but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by co-administration of an artificial nucleoside (5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate 5-NITP in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth its co-administration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacological proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.

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LSD1 stimulates cancer-associated fibrobasts to drive Notch3-dependent self-renewal of liver cancer stem-like cells

Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decreases during differentiation. LSD1 was responsible for maintaining CSC self-renewal and tumorigenicity in HCC and its overexpression was sufficient to drive self-renewal of non-CSC.Levels of acetylated LSD1 were low in CSC with high LSD1 activity, and these CSC were capable of self-renewal. Notch signaling activated LSD1 through induction of the sirtuin SIRT1, leading to deacetylation and activation of LSD1 and CSC self-renewal. Notably, we found that LSD1 expression was increased in cancer-associated fibroblasts (CAF) as an upstream driver of Notch3-mediated CSC self-renewal. In clinical specimens of HCC, the presence of CAF, LSD1 and Notch3 strongly associated with poor patient survival. Overall, our results reveal that CAF-induced expression of Notch3 is responsible for LSD1 activation in CSC, driving their self-renewal in HCC.

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Loss of RASSF4 expression in multiple myeloma promotes RAS-driven malignant progression.

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression they can also stimulate antitumor effects by activating tumor suppressive RASSF proteins. While this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2 phase cell cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways including those regulated by the kinases MST1, JNK and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.

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CXCR4 promotes neuroblastoma growth and therapeutic resistance through miR-15a/16-1 mediated ERK and BCL2/cyclin D1 pathways

CXCR4 expression in neuroblastoma (NB) tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls NB tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports NB tumorigenesis. Moreover, CXCR4 inhibition with the high affinity CXCR4 antagonist, BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the pro-apoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1 shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.

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Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms

Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors (PNET) that developed spontaneously and progress as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI). These effects were not mimicked by selective inhibition of VEGFR-2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells (Tregs) and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by co-administration of sunitinib.

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Multiply recurrent retroperitoneal liposarcoma

Retroperitoneal liposarcomas (RPLPS) are rare tumors that represent at least 50% of all retroperitoneal sarcomas. Surgical resection remains the standard of care. Unfortunately, many RPLPS patients will develop a local recurrence and subsequently die in the absence of distant metastasis. This review outlines the factors that predict local recurrence and influence the management of first and subsequent multiply recurrent RPLPS.

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Prognostic models for RPS patients—Attempting to predict patient outcomes

Retroperitoneal sarcoma (RPS) patients can have variable of outcomes after surgery. The chance to recur locally or at distant sites varies according to tumor grade, histologic subtype, and other patient- and tumor-related characteristics. The relative contribution of each prognostic variable on the oncological outcome of RPS patients can be weighted by combining them in prognostic tools such as nomograms. With this review, we critically appraise the available nomograms for RPS patients highlighting pros and cons.

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Can radical margins improve prognosis in primary and localized epithelioid sarcoma of the extremities?

Introduction

Epithelioid sarcoma (ES) has a tendency to locally recur, spread proximally, and metastasize, in particular to lymphnodes and lungs. The aim of this report is to study the role of surgery and the extent of margins required for optimal management of patients with localized epithelioid sarcoma of the extremities.

Material and Methods

We retrospectively evaluated 77 patients affected by ES of the extremities treated at two different Institutions.

Results

Twenty-two patients had metastasis at diagnosis. Estimated survival was 65.5% at 5 years and 50.9% at 10 years, with a better prognosis in patients with localized disease at diagnosis (P < 0.001). Among patients with localized disease, a significantly better survival was found in patients with primary tumors in which radical surgical margins were achieved (P = 0.043). Among 47 patients presenting with primary tumors, local recurrence-free rate was 72.9% at 5 years, and 61.9% at 10 years, with a better local control achieved in patients with radical margins were achieved (P = 0.026).

Discussion

We believe that the best approach to improve both local control and survival is to aim for radical margins in patients with primary tumors. Therefore, the best chance for cure is if the first treatment is the right treatment, which we believe to be radical margins.

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Soft tissue tumors of the pelvis: Technical and histological considerations

In this review, we first address the anatomic and technical considerations in the resection of pelvic soft tissue tumors, including the challenges unique to these tumors, such as the narrow anatomic confines of the bony pelvis, the often locally aggressive nature of these tumors, as well as the major functional deficits that may result from their resection. We then review the optimal, multidisciplinary, histology-driven treatment approach to pelvic tumors.

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5-fluorouracil combined with cisplatin and mitomycin C as an optimized regimen for hyperthermic intraperitoneal chemotherapy in gastric cancer

Background and Objectives

Optimized drug regimens for hyperthermic intraperitoneal chemotherapy (HIPEC) have not been standardized completely in patients with advanced gastric cancer (GC). We evaluated an optimized anti-tumor protocol comprising 5-fluorouracil (5-FU) combined with cisplatin (CDDP) and mitomycin C (MMC) in vitro for clinical use of HIPEC.

Methods

The sensitivities of 5-FU, CDDP, or MMC, alone or in combination, using different drug concentrations, exposure times, and hyperthermic conditions (42°C) were determined in vitro by the CD-DST method using 3 different differentiated GC cell lines.

Results

The tumor cell growth-inhibitory effect of 5-FU was concentration-dependent for all cell lines. In addition, 5-FU showed a hyperthermic sensitization effect at all drug concentrations for all cell lines. The appropriate concentration of each drug was 5-FU, 200 µg/mL; CDDP, 10 µg/mL; MMC, 2 µg/mL. Under hyperthermic conditions, most growth-inhibitory effects for each drug at 30 min was equivalent to 60 min of exposure; use of three drugs combined significantly inhibited growth compared with any of the drugs alone.

Conclusion

An appropriate in vitro intraperitoneal chemotherapy regimen for GC was combined use of 5-FU, CDDP, and MMC at 42°C for 30 min.

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Survival in patients with medullary thyroid cancer after less than the recommended initial operation

Background and Objectives

We aimed to evaluate the disease specific-survival (DSS) of patients with Medullary Thyroid Cancer (MTC) confined to the central neck based on the extent of the initial operation.

Methods

This retrospective review of patients with MTC from the SEER registry from 2004 to 2012 excluded patients with lateral neck involvement or distant metastases.

Results

The cohort (n = 766) included 85(11%) less than total thyroidectomies (TT), 212(28%) TT alone, and 469(61%) TT with lymph node excision. Mean tumor size was similar (2.2cm for <TT, 1.9 for TT alone, and 2.2 for TT with nodes, p=0.13). Patients receiving a TT with nodal excision were more likely to have multifocal tumors (8% <TT, 22% TT alone, and 27% TT with nodes, P < 0.001), and extrathyroidal extension (1% <TT, 4% TT alone, and 9% TT with nodes, P = 0.005). Even after controlling for significant predictors of DSS, extent of the initial operation did not predict survival (HR 0.28 for <TT, 95% CI 0.26-3.11 and HR 0.62 for TT alone, 95% CI 0.17-2.22 compared to TT with nodes, P = NS for all).

Conclusion

According to population-based SEER registry data, the extent of initial resection may not significantly change DSS in patients with MTC confined to the central neck.

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Optical analysis of glioma: Fourier-transform infrared spectroscopy reveals the IDH1 mutation status.

Purpose: Somatic mutations in human cytosolic isocitrate dehydrogenase 1 (IDH1) gene cause profound changes in cell metabolism and are a common feature of gliomas with unprecedented predictive and prognostic impact. Fourier-transform infrared (FT-IR) spectroscopy addresses the molecular composition of cells and tissue and was investigated to deduct the IDH1-mutation status. Experimental Design: We tested the technique on human cell lines that were transduced with IDH1 wild-type or mutated IDH1 and on 34 human glioma samples. IR spectra were acquired at 256 positions from cell pellets or tissue cryosections. Moreover, IR spectra were obtained from fresh, unprocessed biopsies of 64 glioma patients. Results: IDH1 mutation was linked to changes in spectral bands assigned to molecular groups of lipids and proteins in cell lines and human glioma. The spectra of cryosections of brain tumor samples showed high inter-patient variability, for example bands related to calcifications at 1113 cm-1. However, supervised classification recognized relevant spectral regions at 1103, 1362, 1441, 1485 and 1553 cm-1 and assigned 88% of the tumor samples to the correct group. Similar spectral positions allowed the classification of spectra of fresh biopsies with an accuracy of 86%.  Conclusions: Here, we show that vibrational spectroscopy reveals the IDH1 genotype of glioma. Because it can provide information in seconds, an implementation into the intraoperative workflow might allow simple and rapid online diagnosis of IDH1 genotype. The intraoperative confirmation of IDH1 mutation status might guide the decision to pursue definitive neurosurgical resection and guide future in situ therapies of infiltrative gliomas.

http://ift.tt/2CGa5Ka

Long-term quality of life in inoperable non-small cell lung cancer patients treated with conventionally fractionated compared to hyperfractionated accelerated radiotherapy – Results of the randomized CHARTWEL trial

To evaluate the quality of life (QoL) of patients with inoperable non-small cell lung cancer treated with conventionally fractionated radiotherapy (CF) vs. continuous hyperfractionated accelerated radiotherapy weekend-less (CHARTWEL).

http://ift.tt/2z0gHB3

Genotype-driven phase I study of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation for locally advanced rectal cancer

We aimed to identify the maximum tolerated dose (MTD) of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation according to the UGT1A1∗28 genotype in patients with locally advanced rectal cancer.

http://ift.tt/2Bg5Att

Predicting hypoxia status using a combination of contrast-enhanced computed tomography and [18F]-Fluorodeoxyglucose positron emission tomography radiomics features

Hypoxia is a known prognostic factor in head and neck cancer. Hypoxia imaging PET radiotracers such as 18F-FMISO are promising but not widely available. The aim of this study was therefore to design a surrogate for 18F-FMISO based on 18F-FDG PET and contrast-enhanced CT radiomics features, and to study its performance in the context of hypoxia-based patient stratification.

http://ift.tt/2z0gGNv

Comparative Effectiveness of Preoperative Paravertebral Block for Post-Mastectomy Reconstruction: A Systematic Review of the Literature

Abstract

Introduction

Paravertebral block (PVB) has emerged as a viable strategy for improving postoperative outcomes in breast surgery; however, it is unclear whether these benefits extend to recipients of post-mastectomy reconstruction (PMR).

Methods

A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Library electronic databases was conducted for all studies matching the a priori inclusion criteria (inception to 1 March 2017). Independent assessment by two reviewers, in stages, of the title/abstract and full text was performed. Data relating to study design, patient characteristics, PVB medications and technique, and outcomes, including pain, opioid consumption, length of stay (LOS), postoperative nausea and vomiting (PONV), and PVB-related complications was abstracted.

Results

Of the 1243 identified articles, nine met the inclusion criteria, accounting for 936 patients (PVB, n = 518; non-PVB, n = 418) in two randomized controlled trials (RCT) and seven retrospective cohort studies. Of these studies, six described PVB for prosthetic PMR, and three described PVB for autologous PMR. Overall, there is a subtle trend towards improved pain control, less opioid requirement and shorter LOS, while PONV was largely unchanged in patients receiving PVB for PMR. In two studies, technical failure was reported at 7.4 and 10%, although no study reported a PVB-related complication. Study quality varied, and risk of bias in the included studies was high. Heterogeneity precluded a meta-analysis.

Conclusions

Although recent reports and RCTs advocate for PVB use in PMR, our review highlights significant heterogeneity and knowledge gaps that must be addressed in order for PVB to become part of the optimal anesthetic protocol in PMR.

http://ift.tt/2D8ZoRF

Comparative Effectiveness of Preoperative Paravertebral Block for Post-Mastectomy Reconstruction: A Systematic Review of the Literature

Abstract

Introduction

Paravertebral block (PVB) has emerged as a viable strategy for improving postoperative outcomes in breast surgery; however, it is unclear whether these benefits extend to recipients of post-mastectomy reconstruction (PMR).

Methods

A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Library electronic databases was conducted for all studies matching the a priori inclusion criteria (inception to 1 March 2017). Independent assessment by two reviewers, in stages, of the title/abstract and full text was performed. Data relating to study design, patient characteristics, PVB medications and technique, and outcomes, including pain, opioid consumption, length of stay (LOS), postoperative nausea and vomiting (PONV), and PVB-related complications was abstracted.

Results

Of the 1243 identified articles, nine met the inclusion criteria, accounting for 936 patients (PVB, n = 518; non-PVB, n = 418) in two randomized controlled trials (RCT) and seven retrospective cohort studies. Of these studies, six described PVB for prosthetic PMR, and three described PVB for autologous PMR. Overall, there is a subtle trend towards improved pain control, less opioid requirement and shorter LOS, while PONV was largely unchanged in patients receiving PVB for PMR. In two studies, technical failure was reported at 7.4 and 10%, although no study reported a PVB-related complication. Study quality varied, and risk of bias in the included studies was high. Heterogeneity precluded a meta-analysis.

Conclusions

Although recent reports and RCTs advocate for PVB use in PMR, our review highlights significant heterogeneity and knowledge gaps that must be addressed in order for PVB to become part of the optimal anesthetic protocol in PMR.

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Effect of postoperative radiotherapy on survival in duodenal adenocarcinoma: a propensity score-adjusted analysis of Surveillance, Epidemiology, and End Results database

Abstract

Purpose

The use of adjuvant treatment has not been sufficiently investigated in duodenal adenocarcinoma. This study evaluated the effect of postoperative radiotherapy (PORT) on survival outcomes in this rare malignancy.

Methods

We identified patients who were diagnosed between 2004 and 2013 in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and disease-specific survival (DSS) were analyzed before and after propensity score matching.

Results

Among the 701 eligible patients, 116 (17%) underwent PORT. There were no significant differences in OS and DSS according to receipt of PORT in the unmatched population (P = 0.982 and 0.496, respectively), whereas the propensity-matched analysis showed improved OS and DSS with PORT (P = 0.053 and 0.019, respectively). No receipt of PORT was an independent poor prognostic factor in multivariate analysis of both OS (P = 0.022) and DSS (P = 0.005). The potential survival benefits of PORT were observed in subgroups of T4 stage, larger tumor size, higher lymph node ratio, and total/radical resection.

Conclusions

We provide useful insights into the therapeutic role of PORT in adenocarcinoma of the duodenum. Adjuvant strategy with PORT needs to be considered in locally advanced tumors.

http://ift.tt/2oN4uQn

Effect of postoperative radiotherapy on survival in duodenal adenocarcinoma: a propensity score-adjusted analysis of Surveillance, Epidemiology, and End Results database

Abstract

Purpose

The use of adjuvant treatment has not been sufficiently investigated in duodenal adenocarcinoma. This study evaluated the effect of postoperative radiotherapy (PORT) on survival outcomes in this rare malignancy.

Methods

We identified patients who were diagnosed between 2004 and 2013 in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and disease-specific survival (DSS) were analyzed before and after propensity score matching.

Results

Among the 701 eligible patients, 116 (17%) underwent PORT. There were no significant differences in OS and DSS according to receipt of PORT in the unmatched population (P = 0.982 and 0.496, respectively), whereas the propensity-matched analysis showed improved OS and DSS with PORT (P = 0.053 and 0.019, respectively). No receipt of PORT was an independent poor prognostic factor in multivariate analysis of both OS (P = 0.022) and DSS (P = 0.005). The potential survival benefits of PORT were observed in subgroups of T4 stage, larger tumor size, higher lymph node ratio, and total/radical resection.

Conclusions

We provide useful insights into the therapeutic role of PORT in adenocarcinoma of the duodenum. Adjuvant strategy with PORT needs to be considered in locally advanced tumors.

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Preoperative Radiosurgery for Soft Tissue Sarcoma

Objectives: Preoperative radiation followed by surgical resection is a standard treatment for soft tissue sarcomas (STSs). The conventional method of radiation is 5 weeks to approximately 50 Gy. We report on our initial experience and phase II single-arm study assessing 5 fractions of stereotactic body radiotherapy (SBRT), followed by surgical resection for STS. Methods: Thirteen patients and 14 tumors were treated with preoperative SBRT; tumors were mostly poorly differentiated (5) or myxoid (5) and were located on the leg (10), arm (2) or groin (2). The median tumor size in greatest dimension was 7.6 cm (maximum 16 cm). Twelve patients received 35 Gy in 5 fractions; for 2 deeper tumors the dose was 40 Gy in 5 fractions. Ten patients were administered 0.5 cm bolus to improve the dose. Gross tumor volume was expanded 0.5 cm radially and 3 cm along the tissue plane. Treatment was to an isodose line (median 81%) and was delivered every other day. Maximum dose to the skin was 46 Gy (median 41 Gy). Results: The median follow-up period was 279 days. Surgical resection occurred a median of 37 days after completion of SBRT. Four patients had acute toxicity consisting of 2 grade 2 and 2 grade 3 skin reactions; all cases of skin toxicity resolved by the time of surgery. Percent tumor necrosis ranged from 10% to 95% (median 60%). All patients had negative margins. Planned vacuum-assisted wound closure was used in 4 patients; there were no other major wound complications. There was 1 local recurrence and 7 distant recurrences. Conclusion: This is the initial experience of radiosurgery for preoperative treatment of STSs. We have found this to be well tolerated, convenient for the patients, and a much shorter treatment course, allowing patients to undergo surgery and subsequent chemotherapy quicker. Surgical complications and control rates are satisfactory. The initial results are encouraging for further investigation.

http://ift.tt/2BIZnWD

Predictors of Hematologic Toxicity and Chemotherapy Dose Intensity in Patients Undergoing Chemoradiation for Pancreatic Cancer

Objectives: Intensity-modulated radiation therapy (IMRT) has been shown to decrease abdominal toxicity in patients undergoing chemoradiation (CRT) for pancreatic cancer. We evaluated whether IMRT impacts the rates of hematologic toxicity and chemotherapy dose intensity in patients undergoing CRT. Methods: We retrospectively reviewed patients with borderline resectable or locally advanced pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. Endpoints included total gemcitabine dose received, dose intensity, unplanned dose reductions, and hematologic toxicity (WBC, ANC, platelet, and hemoglobin). Patient/treatment factors were evaluated for their relationship to the above endpoints during CRT and within the first 3 months post-CRT. Statistical analysis was performed using the Fisher exact test and regression models. Because of the multiple comparisons in the presented analysis, a false discovery rate adjustment was performed at the 5% false discovery rate level. Results: Eighty-five patients met the inclusion criteria. Fifty-eight (68.2%) patients received treatment with IMRT, and 27 (31.8%) patients were treated with 3D-conformal radiation. During CRT, there was no relationship between radiation technique and gemcitabine dose received, dose intensity, or hematologic grade 3+ toxicity. Post-CRT, there was no relationship between radiation technique and total gemcitabine dose received, dose intensity, or dose reduction. Patients receiving IMRT were more likely to have ANC grade 3+ toxicity (P=0.007) post-CRT, although this was no longer statistically significant after correction. There were no other relationships between treatment technique and hematologic toxicity. Conclusions: IMRT technique may be associated with higher hematologic toxicity in patients undergoing CRT for pancreatic cancer. Given the expanding use of CRT, additional study is needed to identify the impact of IMRT on myelosuppression in these patients.

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Self-reported Conflicts of Interest and Trial Sponsorship of Clinical Trials in Prostate Cancer Involving Radiotherapy

Objectives: To examine the association between trial sponsorship and conflicts of interest (COI) with clinical trial conclusions for prostate cancer trials related to radiotherapy. Materials and Methods: The MEDLINE database was searched for all prostate cancer clinical trials published between 2004 and 2013 and identified 1396 studies. Two investigators independently identified trials published in the English language of ≥30 patients, and extracted relevant data. Clinical trials were classified according to trial characteristics, sponsorship source and type, COI, and study conclusion, and analyzed by univariable and multivariable logistic regression. Results: Of 240 eligible trials, 160 (67.5%) evaluated drugs without radiotherapy, 60 (25%) involved radiotherapy, and 18 (7.5%) involved procedures without radiotherapy. Of the 60 radiotherapy trials eligible for analysis, positive sponsorship and potential COI were present in 58.3% and 20% of trials, respectively. Study conclusions were positive, negative, or neutral in 78.3%, 5%, and 16.7% of trials, respectively. No association was found between positive conclusions and either industry support of potential COI. Positive conclusions were reported in 86.7% and 83.3% of trials with sponsorship and COI, respectively, as compared with 75.6% and 77.1% of those without sponsorship (P=0.37) and COI (P=0.64). Sponsorship was significantly associated with radiotherapy trials combined with drugs (odds ratio 5.5, P=0.01) and higher-risk disease (odds ratio 4.71, P=0.01). Conclusions: The presence of sponsorship was associated with radiotherapy trials involving drugs or studying higher-risk prostate cancer. However, there were no identified associations between study conclusion and sponsorship type or COI.

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Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy

Objectives: To examine the impact of positive surgical margin (PSM) laterality on failure after radical prostatectomy (RP). A PSM can influence local recurrence and outcomes after salvage radiation. Unlike intrinsic risk factors, a PSM is caused by intervention and thus iatrogenic failures may be elucidated by analyzing margin laterality as surgical approach is itself lateralized. Patients and Methods: We reviewed 226 RP patients between 1991 and 2013 with PSM. Data includes operation type, pre/postoperative PSA, surgical pathology, and margin type (location, focality, laterality). The median follow-up was 47 months. Biochemical recurrence after RP was defined as PSA≥0.1 ng/mL or 2 consecutive rises above nadir. Ninety-two patients received salvage radiation therapy (SRT). Failure after SRT was defined as any PSA≥0.2 ng/mL or greater than presalvage. Kaplan-Meier and Cox multivariate analyses compared relapse rates. Results: The majority of PSM were iatrogenic (58%). Laterality was associated with differences in median relapse: right 20 versus left 51 versus bilateral 14 months (P

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Fractionated Radiation Therapy for Benign Nonacoustic Schwannomas

Objectives: We analyzed the outcomes of patients with benign nonacoustic schwannomas treated with fractionated radiation therapy (RT). Methods: Between October 1987 and March 2013, 11 patients with benign nonacoustic schwannomas diagnosed radiographically (n=3) or pathologically (n=8) were treated with fractionated RT with curative intent at the University of Florida. We reviewed patients' medical records to assess outcomes and toxicities from treatment. Results: The median follow-up for all patients was 8.2 years (range, 2.2 to 22.7 y) and 8 years for all living patients (range, 2.2 to 22.7 y). Of the 11 patients included in the analysis, 8 (73%) were treated solely with RT, 1 (9%) was treated with postoperative RT after subtotal resection, and 2 (18%) were treated with postoperative RT after recurrence following initial surgical resection. The 5-year overall survival, disease-free survival, and local control rates were 100%. There were no grade 2 to 5 treatment toxicities. Conclusions: RT for benign nonacoustic schwannoma may be effective when used alone or in addition to surgery. Irradiation should be considered in patients for whom resection is likely to result in one or more neurological deficits. Fractionated RT to a total dose of 50 Gy provides excellent local control and minimal morbidity.

http://ift.tt/2BKGaDS

Chronological Age and Risk of Chemotherapy Nonfeasibility: A Real-Life Cohort Study of 153 Stage II or III Colorectal Cancer Patients Given Adjuvant-modified FOLFOX6

Objectives: To assess nonfeasibility of adjuvant-modified FOLFOX6 chemotherapy in patients with stage II or III colorectal cancer. Methods: Consecutive patients managed between 2009 and 2013 in 2 teaching hospitals in the Paris urban area were included in the CORSAGE (COlorectal canceR, AGe, and chemotherapy fEasability study) cohort study. Nonfeasibility was defined by the frequencies of empirical first-cycle dose reduction (>15%), early discontinuation (

http://ift.tt/2BITVTH

Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma

Objective: This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. Materials and Methods: The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). Results: The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

http://ift.tt/2BLd1Zb

Concurrent Radiotherapy With Cetuximab or Platinum-based Chemotherapy for Locally Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck

Objectives: The management of high-risk cutaneous squamous cell carcinoma of the head and neck (SCCHN) is not well defined. We review outcomes in patients with locally advanced cutaneous SCCHN treated with radiation and concomitant platinum (Pt)-based chemotherapy or cetuximab (Cx). Methods: We identified 23 patients treated at our institution from 2007 to 2014. Systemic therapy consisted of Pt-based chemotherapy for 15 (65%) patients and Cx for 8 (35%) patients. Treatment intent was definitive for 48% and adjuvant for 52% of the cases. Results: The majority (87%) of patients had stage III/IV disease and 9 (39%) patients had unresectable disease. All patients were being treated for recurrent disease. Aside from median age (59 Pt vs. 71 Cx, P=0.04), there were no significant differences in patient and tumor characteristics between those receiving Pt versus Cx therapy. At mean follow-up of 24 months, locoregional recurrence and distant failure were observed in 52% and 17% of all patients, respectively. Estimated 2-year disease-free survival and overall survival in the Cx versus Pt groups were: 50% versus 30% (P=0.25), and 73% versus 40% (P=0.32), respectively. Conclusions: Radiotherapy with either concurrent Pt or Cx appears to offer similar clinical outcomes in patients with locally advanced cutaneous SCCHN.

http://ift.tt/2BK17Pg

Primary Pulmonary Carcinoid Tumor: A Long-term Single Institution Experience

Objectives: Primary carcinoid tumors of the lung are rare tumors which comprise approximately 0.5% to 5% of all lung malignancies in adults and roughly 20% to 30% of all carcinoid tumors. The purpose of this retrospective, descriptive study was to describe the incidence, characteristics, and outcomes of patients treated for primary pulmonary carcinoid tumor at a single institution. Materials and Methods: All patients with a diagnosis of primary pulmonary carcinoid tumor treated from 1989 to 2009 were reviewed. Data collected included demographics, pathology, tobacco use, clinical presentation, tumor location, tumor spread, treatment, and survival. Results: There were 59 cases of pulmonary carcinoid tumors: 47 typical (80%) and 12 atypical (20%). All but 4 patients underwent surgery, including 54 (92%) lung-sparing resections and 1 pneumonectomy. Five of 55 patients received concurrent adjuvant chemoradiation therapy; 4 patients with atypical and 1 with typical histology. Three additional patients with atypical carcinoid were treated only with adjuvant radiotherapy, palliative radiotherapy, or palliative chemotherapy, respectively. The Kaplan-Meier 5- and 10-year overall survivals were both 80% within the entire population. In the 88% of patients who achieved complete remission, disease-free survival was 98%. A review of a large series from the literature is also presented. Conclusions: Surgical resection was primary and adequate therapy for most typical carcinoid tumors with high overall survival and disease-free survival. Adjuvant chemotherapy or radiotherapy might be considered for patients with atypical carcinoid tumors who present with adverse pathologic findings.

http://ift.tt/2BN8AwQ

Stereotactic Body Radiotherapy for Lung Metastases from Colorectal Cancer: Prognostic Factors for Disease Control and Survival

Objectives: To evaluate disease control and survival after stereotactic body radiotherapy (SBRT) for lung metastases from colorectal cancer and to identify prognostic factors after treatment. Methods: Patients with metastatic colorectal cancer to the lungs treated with SBRT from 2002 to 2013 were identified from a prospectively maintained database. Patients may have received prior systemic therapy, radiotherapy to nonthoracic sites and/or resection of thoracic and/or nonthoracic metastases. Endpoints were timed from end of SBRT and included overall survival (OS), progression-free survival, distant metastases-free survival, and local failure-free survival. Univariate and multivariate analysis using Cox proportional hazard modeling was used to identify prognostic factors. Results: Sixty-five patients were identified. Before SBRT, 69.2% and 33.8% of patients received systemic therapy and lung-directed local therapy, respectively, for metastatic disease. At the time of SBRT, 64.6% had lung-only involvement. Median survivals were: OS of 20.3 months (95% confidence intervals [CI], 15.9-27.0 mo), progression-free survival of 5.7 months (95% CI, 3.2-7.0 mo), distant metastases-free survival of 5.8 months (95% CI, 3.2-7.6 mo), and local failure-free survival of 15.4 months (95% CI, 8.5-21.1 mo). Nearly all (98%) patients developed distant progression. Extra lung and liver involvement at the time of initial metastases (hazard ratios [HR] 2.10) and extra lung involvement at SBRT (HR 2.67) were the only independent predictors of OS. Net gross target volume of >14.1 mL (HR 2.49) was the only independent predictor of local failure-free survival. Conclusions: Reasonable survival and local control can be achieved with SBRT. We identified several prognostic factors testable in future prospective trials that may help improve patient selection.

http://ift.tt/2BN8Agk

Trimodality Treatment of Malignant Pleural Mesothelioma: An Institutional Review

Objective: Malignant pleural mesothelioma (MPM) is a deadly disease with varying treatment options. This study retrospectively describes treatment practices at the University of Washington Medical System from 1980 to 2011, and evaluates the impact of trimodality therapy and radiation (photon and neutron) on survival. Methods: A retrospective study was conducted on patients treated for MPM. Univariate and multivariate methods were utilized to evaluate potential factors associated with survival. Treatments received and baseline characteristics were included. Survival analysis of trimodality therapy was performed using a propensity score method to control for baseline characteristics. Results: Among 78 eligible patients, the median age at diagnosis was 59 years and the median survival was 13.7 months. On multivariate analysis, the significant predictors of improved survival were age, smoking history, location, and receipt of radiation therapy or chemotherapy. In the 48 patients receiving radiation therapy, the difference in survival between neutron therapy and non-neutron therapy patients was not statistically significant: hazard ratio, 1.20 (95% confidence interval, 0.68-2.13), P=0.52. Patients receiving trimodality therapy were more likely to have early-stage disease (60% vs. 30%) and epithelioid histology (86% vs. 58%). In a propensity score-weighted Cox proportional hazards model, trimodality therapy patients had improved overall survival, hazard ratio 0.45, P=0.004, median 14.6 versus 8.6 months. Conclusions: Trimodality therapy was significantly associated with prolonged survival in patients with MPM, even when adjusting for baseline patient factors. Radiation therapy was associated with improved survival, but the modality of radiation therapy used was not associated with outcome.

http://ift.tt/2CFTLsQ

Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States

Purpose: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). Materials and Methods: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. Results: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. Conclusions: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

http://ift.tt/2CF35NJ

Brain Metastases at Presentation in Patients With Non–Small Cell Lung Cancer

Objective: We used brain radiotherapy as a surrogate for the presence of brain metastases in patients with non–small cell lung cancer (NSCLC) to determine the prevalence of brain metastases using the Surveillance Epidemiology and End Results database. Methods: Patients with NSCLC diagnosed between 1988 and 1997 were subdivided according to brain radiotherapy status at presentation into: "none" or "radiation therapy indicated." We calculated the frequency of brain radiotherapy use in all patients. Odds ratios (ORs) for the indication of brain radiotherapy were calculated for individual prespecified covariates of interest. All statistical tests were 2-sided and P3 cm (3.1 to 5 cm OR, 1.22; 95% CI: 1.14, 1.30 and >5 cm OR, 1.25; 95% CI: 1.17, 1.33); tumor grade >II (grade III OR, 1.82; 95% CI: 1.69, 1.95 and grade IV OR, 1.91; 95% CI: 1.73, 2.11); and nodal involvement N1 (OR, 1.33; 95% CI: 1.20, 1.47), N2 (OR, 2.24; 95% CI: 2.10, 2.40), and N3 (OR, 2.39; 95% CI: 2.19, 2.60). Conclusions: Brain radiotherapy is indicated in over 8% of patients with NSCLC at presentation. We demonstrated that the risk of brain metastasis at presentation may be stratified with the use of 6 clinical factors.

http://ift.tt/2CH8WCh

Soft Tissue Solitary Fibrous Tumor: Combined Surgery and Radiation Therapy Results in Excellent Local Control

Purpose: To report survival outcomes and local control in patients with solitary fibrous tumors (SFT) treated using surgery and radiation therapy (RT). Methods: We reviewed the medical records of 31 consecutive patients definitively treated for SFT with surgery and RT between 1982 and 2012. The median age was 51 years (range, 23 to 88 y) and tumors were evenly distributed between the head and neck (n=9, 29%), trunk (n=10, 32%), and lower extremities (n=9, 29%). The majority of tumors were large (>5 cm) (n=23, 72%). Specimens had a median of 2 mitoses/10 HPF (range, 0 to 8). Nearly half the cases were treated with postoperative RT (n=14, 45%; median dose, 58 Gy) and the other 17 patients (55%) received preoperative RT (median dose, 50 Gy). Results: Median follow-up time was 59 months (range, 18 to 349 mo). The 5-year rates of local control, overall survival, and distant metastatic-free survival were 100%, 95%, and 92%, respectively. There were no local or nodal relapses and the 10-year complication rate was 6% (n=2). Conclusions: Treatment of soft tissue SFT using combined surgery and RT results in excellent local control.

http://ift.tt/2CFKFfH

Risk Analysis of Pneumonitis in Taxane Therapy After Chemoradiotherapy for Patients With Metastatic or Recurrent Esophageal Cancer

Objectives: Taxane chemotherapy for esophageal cancer causes pneumonitis, not only by itself but also by radiation recall. This study aimed to clarify the risk of pneumonitis in patients with esophageal cancer who receive taxane therapy after chemoradiotherapy. Methods: The data of 129 patients with metastatic or recurrent esophageal cancer who initiated taxane therapy between September 2002 and June 2013 were retrospectively analyzed. Patient selection criteria were as follows: performance status ≤2, preserved organ functions, previous chemoradiotherapy with a radiation dose of ≥50 Gy, grade 0 or 1 pneumonitis at taxane initiation, and no concomitant malignancy. Logistic regression analysis was performed to identify risk factors for pneumonitis. Results: Patient characteristics were as follows: males/females, 116/13; median age, 63 years (range, 44 to 80 y); performance status of 0/1/2, 61/60/8; smoking history, 112 (88%); location of the primary tumor Ce/Ut/Mt/Lt/Ae 12/30/66/20/1; median radiation dose, 60 Gy; history of radiation pneumonitis, 39 (30%); history of other pulmonary disease, 4 (3%); and median duration between the last radiation therapy (RT) exposure and taxane initiation, 6.1 months (range, 1.0 to 71 mo). During the median observation period of 7.8 months from taxane initiation, the incidence of grade 2 and 3 pneumonitis was observed in 7 (5.4%) and 3 (2.3%) patients, respectively. No patient died of pneumonitis. The only independent risk factor for pneumonitis was a ≤4-month period between the last RT exposure and taxane initiation (P=0.03). Conclusions: A short period between the last RT exposure and taxane initiation is an independent risk factor for pneumonitis development.

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Primary Tumor Thickness is a Prognostic Factor in Stage IV Melanoma: A Retrospective Study of Primary Tumor Characteristics

Introduction: Stage IV melanoma exhibits a diverse range of tumor biology from indolent to aggressive disease. Many important prognostic factors have already been identified. Despite this, the behavior of metastatic melanoma remains difficult to predict. We sought to determine if any primary tumor characteristics affect survival following the diagnosis of stage IV melanoma. Methods: All patients diagnosed with stage IV melanoma between January 2003 and December 2012 were identified from the Victorian Melanoma Service database. Retrospective chart review was performed to collect data on primary tumor characteristics (thickness, ulceration, mitotic rate, melanoma subtype, or occult primary). Known and suspected prognostic factors were additionally collected (time to diagnosis of stage IV disease, age, sex, stage, receipt of chemotherapy, and era of recurrence). The effect of primary tumor characteristics on overall survival from the date of diagnosis of stage IV disease was assessed. Results: A total of 227 patients with a median follow-up of 5 years from diagnosis of stage IV disease were identified. Median overall survival of the cohort was 250 days. Of the primary tumor characteristics assessed, only tumor thickness affected survival from diagnosis of stage IV disease, hazard ratio=1.09 (1.02 to 1.16), P=0.008. This remained significant in multivariate analysis, P=0.007. Other primary tumor characteristics did not significantly influence survival. Conclusions: Primary tumor thickness is a significant prognostic factor in stage IV melanoma. Our data suggest that the biology of the primary melanoma may persist to influence the behavior of metastatic disease.

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Prognostic Factors as a Function of Disease-free Interval After Definitive (Chemo)radiation for Non–Small Cell Lung Cancer Using Conditional Survival Analysis

Purpose: We analyzed overall and disease-free survival (OS and DFS) after definitive (chemo)radiation for stage III non–small cell lung cancer with 2 statistical methods: Kaplan-Meier (KM) analysis, with diagnosis as index date, and conditional survival (CS) analysis, with a variety of disease-free index dates, and determined whether prognostic factors varied based on the reference date. Materials and Methods: All 651 patients analyzed received definitive (chemo)radiotherapy for stage III non–small cell lung cancer in November 1998 to December 2010 at a single institution; all had Karnofsky performance status scores ≥60 and received ≥60 Gy. OS and DFS were first calculated with the KM method, and then CS was used to calculate 2 outcomes: OS conditioned on DFS time (OS|DFS) and DFS conditioned on DFS time (DFS|DFS). Factors predicting OS and DFS conditioned on 1-, 2-, and 3-year DFS were sought in univariate and multivariate analyses. Results: KM analysis produced 1-, 2-, and 3-year DFS rates of 48%, 30%, and 26%; OS rates were 64%, 41%, and 29%. By CS analysis, both OS|DFS and DFS|DFS showed an increase in 5-year OS after 6 months, and CS after 30 months approached 100%. On multivariate analyses, age and concurrent chemoradiation predicted OS|DFS; age, smoking history, tumor histology, disease stage, and radiation dose predicted DFS|DFS. Conclusions: CS analysis showed that the probability of long-term survival increases sharply after 6 months with no evidence of disease; factors predicting survival differed based on the method and endpoint used.

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Radiotherapy in the Management of Orbital Lymphoma: A Single Institution’s Experience Over 4 Decades

Purpose: To report our institution's treatment techniques, disease outcomes, and complication rates after radiotherapy for the management of lymphoma involving the orbits. Patients and Methods: We retrospectively reviewed the medical records of 44 patients curatively treated with radiotherapy for stage IAE (75%) or stage IIAE (25%) orbital lymphoma between 1969 and 2013. Median follow-up was 4.9 years. Thirty-eight patients (86%) had low-grade lymphoma and 6 (14%) had high-grade lymphoma. Radiation was delivered with either a wedge-pair (61%), single-anterior (34%), or anterior with bilateral wedges (5%) technique. The median radiation dose was 25.5 Gy (range, 15 to 47.5 Gy). Lens shielding was performed when possible. Cause-specific survival and freedom from distant relapse were calculated using the Kaplan-Meier method. Results: The 5-year local control rate was 98%. Control of disease in the orbit was achieved in all but 1 patient who developed an out-of-field recurrence after irradiation of a lacrimal tumor. The 5-year regional control rate was 91% (3 patients failed in the contralateral orbit and 1 patient failed in the ipsilateral parotid). Freedom from disease, cause-specific survival, and overall survival rates at 5 and 10 years were 70% and 55%, 89% and 89%, and 76% and 61%, respectively. Acute toxicity was minimal. Ten patients (23%) reported worsened vision following radiotherapy, and cataracts developed in 17 patients. Cataracts developed in 13 of 28 patients treated without lens shielding (46%) and 4 of 16 patients (25%) treated with lens shielding. Conclusion: Radiotherapy is a safe and effective local treatment in the management of orbital lymphoma.

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Concurrent Radiotherapy With Cetuximab or Platinum-based Chemotherapy for Locally Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck

Objectives: The management of high-risk cutaneous squamous cell carcinoma of the head and neck (SCCHN) is not well defined. We review outcomes in patients with locally advanced cutaneous SCCHN treated with radiation and concomitant platinum (Pt)-based chemotherapy or cetuximab (Cx). Methods: We identified 23 patients treated at our institution from 2007 to 2014. Systemic therapy consisted of Pt-based chemotherapy for 15 (65%) patients and Cx for 8 (35%) patients. Treatment intent was definitive for 48% and adjuvant for 52% of the cases. Results: The majority (87%) of patients had stage III/IV disease and 9 (39%) patients had unresectable disease. All patients were being treated for recurrent disease. Aside from median age (59 Pt vs. 71 Cx, P=0.04), there were no significant differences in patient and tumor characteristics between those receiving Pt versus Cx therapy. At mean follow-up of 24 months, locoregional recurrence and distant failure were observed in 52% and 17% of all patients, respectively. Estimated 2-year disease-free survival and overall survival in the Cx versus Pt groups were: 50% versus 30% (P=0.25), and 73% versus 40% (P=0.32), respectively. Conclusions: Radiotherapy with either concurrent Pt or Cx appears to offer similar clinical outcomes in patients with locally advanced cutaneous SCCHN.

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Preoperative Radiosurgery for Soft Tissue Sarcoma

Objectives: Preoperative radiation followed by surgical resection is a standard treatment for soft tissue sarcomas (STSs). The conventional method of radiation is 5 weeks to approximately 50 Gy. We report on our initial experience and phase II single-arm study assessing 5 fractions of stereotactic body radiotherapy (SBRT), followed by surgical resection for STS. Methods: Thirteen patients and 14 tumors were treated with preoperative SBRT; tumors were mostly poorly differentiated (5) or myxoid (5) and were located on the leg (10), arm (2) or groin (2). The median tumor size in greatest dimension was 7.6 cm (maximum 16 cm). Twelve patients received 35 Gy in 5 fractions; for 2 deeper tumors the dose was 40 Gy in 5 fractions. Ten patients were administered 0.5 cm bolus to improve the dose. Gross tumor volume was expanded 0.5 cm radially and 3 cm along the tissue plane. Treatment was to an isodose line (median 81%) and was delivered every other day. Maximum dose to the skin was 46 Gy (median 41 Gy). Results: The median follow-up period was 279 days. Surgical resection occurred a median of 37 days after completion of SBRT. Four patients had acute toxicity consisting of 2 grade 2 and 2 grade 3 skin reactions; all cases of skin toxicity resolved by the time of surgery. Percent tumor necrosis ranged from 10% to 95% (median 60%). All patients had negative margins. Planned vacuum-assisted wound closure was used in 4 patients; there were no other major wound complications. There was 1 local recurrence and 7 distant recurrences. Conclusion: This is the initial experience of radiosurgery for preoperative treatment of STSs. We have found this to be well tolerated, convenient for the patients, and a much shorter treatment course, allowing patients to undergo surgery and subsequent chemotherapy quicker. Surgical complications and control rates are satisfactory. The initial results are encouraging for further investigation.

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Predictors of Hematologic Toxicity and Chemotherapy Dose Intensity in Patients Undergoing Chemoradiation for Pancreatic Cancer

Objectives: Intensity-modulated radiation therapy (IMRT) has been shown to decrease abdominal toxicity in patients undergoing chemoradiation (CRT) for pancreatic cancer. We evaluated whether IMRT impacts the rates of hematologic toxicity and chemotherapy dose intensity in patients undergoing CRT. Methods: We retrospectively reviewed patients with borderline resectable or locally advanced pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. Endpoints included total gemcitabine dose received, dose intensity, unplanned dose reductions, and hematologic toxicity (WBC, ANC, platelet, and hemoglobin). Patient/treatment factors were evaluated for their relationship to the above endpoints during CRT and within the first 3 months post-CRT. Statistical analysis was performed using the Fisher exact test and regression models. Because of the multiple comparisons in the presented analysis, a false discovery rate adjustment was performed at the 5% false discovery rate level. Results: Eighty-five patients met the inclusion criteria. Fifty-eight (68.2%) patients received treatment with IMRT, and 27 (31.8%) patients were treated with 3D-conformal radiation. During CRT, there was no relationship between radiation technique and gemcitabine dose received, dose intensity, or hematologic grade 3+ toxicity. Post-CRT, there was no relationship between radiation technique and total gemcitabine dose received, dose intensity, or dose reduction. Patients receiving IMRT were more likely to have ANC grade 3+ toxicity (P=0.007) post-CRT, although this was no longer statistically significant after correction. There were no other relationships between treatment technique and hematologic toxicity. Conclusions: IMRT technique may be associated with higher hematologic toxicity in patients undergoing CRT for pancreatic cancer. Given the expanding use of CRT, additional study is needed to identify the impact of IMRT on myelosuppression in these patients.

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Self-reported Conflicts of Interest and Trial Sponsorship of Clinical Trials in Prostate Cancer Involving Radiotherapy

Objectives: To examine the association between trial sponsorship and conflicts of interest (COI) with clinical trial conclusions for prostate cancer trials related to radiotherapy. Materials and Methods: The MEDLINE database was searched for all prostate cancer clinical trials published between 2004 and 2013 and identified 1396 studies. Two investigators independently identified trials published in the English language of ≥30 patients, and extracted relevant data. Clinical trials were classified according to trial characteristics, sponsorship source and type, COI, and study conclusion, and analyzed by univariable and multivariable logistic regression. Results: Of 240 eligible trials, 160 (67.5%) evaluated drugs without radiotherapy, 60 (25%) involved radiotherapy, and 18 (7.5%) involved procedures without radiotherapy. Of the 60 radiotherapy trials eligible for analysis, positive sponsorship and potential COI were present in 58.3% and 20% of trials, respectively. Study conclusions were positive, negative, or neutral in 78.3%, 5%, and 16.7% of trials, respectively. No association was found between positive conclusions and either industry support of potential COI. Positive conclusions were reported in 86.7% and 83.3% of trials with sponsorship and COI, respectively, as compared with 75.6% and 77.1% of those without sponsorship (P=0.37) and COI (P=0.64). Sponsorship was significantly associated with radiotherapy trials combined with drugs (odds ratio 5.5, P=0.01) and higher-risk disease (odds ratio 4.71, P=0.01). Conclusions: The presence of sponsorship was associated with radiotherapy trials involving drugs or studying higher-risk prostate cancer. However, there were no identified associations between study conclusion and sponsorship type or COI.

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Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy

Objectives: To examine the impact of positive surgical margin (PSM) laterality on failure after radical prostatectomy (RP). A PSM can influence local recurrence and outcomes after salvage radiation. Unlike intrinsic risk factors, a PSM is caused by intervention and thus iatrogenic failures may be elucidated by analyzing margin laterality as surgical approach is itself lateralized. Patients and Methods: We reviewed 226 RP patients between 1991 and 2013 with PSM. Data includes operation type, pre/postoperative PSA, surgical pathology, and margin type (location, focality, laterality). The median follow-up was 47 months. Biochemical recurrence after RP was defined as PSA≥0.1 ng/mL or 2 consecutive rises above nadir. Ninety-two patients received salvage radiation therapy (SRT). Failure after SRT was defined as any PSA≥0.2 ng/mL or greater than presalvage. Kaplan-Meier and Cox multivariate analyses compared relapse rates. Results: The majority of PSM were iatrogenic (58%). Laterality was associated with differences in median relapse: right 20 versus left 51 versus bilateral 14 months (P

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Fractionated Radiation Therapy for Benign Nonacoustic Schwannomas

Objectives: We analyzed the outcomes of patients with benign nonacoustic schwannomas treated with fractionated radiation therapy (RT). Methods: Between October 1987 and March 2013, 11 patients with benign nonacoustic schwannomas diagnosed radiographically (n=3) or pathologically (n=8) were treated with fractionated RT with curative intent at the University of Florida. We reviewed patients' medical records to assess outcomes and toxicities from treatment. Results: The median follow-up for all patients was 8.2 years (range, 2.2 to 22.7 y) and 8 years for all living patients (range, 2.2 to 22.7 y). Of the 11 patients included in the analysis, 8 (73%) were treated solely with RT, 1 (9%) was treated with postoperative RT after subtotal resection, and 2 (18%) were treated with postoperative RT after recurrence following initial surgical resection. The 5-year overall survival, disease-free survival, and local control rates were 100%. There were no grade 2 to 5 treatment toxicities. Conclusions: RT for benign nonacoustic schwannoma may be effective when used alone or in addition to surgery. Irradiation should be considered in patients for whom resection is likely to result in one or more neurological deficits. Fractionated RT to a total dose of 50 Gy provides excellent local control and minimal morbidity.

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Chronological Age and Risk of Chemotherapy Nonfeasibility: A Real-Life Cohort Study of 153 Stage II or III Colorectal Cancer Patients Given Adjuvant-modified FOLFOX6

Objectives: To assess nonfeasibility of adjuvant-modified FOLFOX6 chemotherapy in patients with stage II or III colorectal cancer. Methods: Consecutive patients managed between 2009 and 2013 in 2 teaching hospitals in the Paris urban area were included in the CORSAGE (COlorectal canceR, AGe, and chemotherapy fEasability study) cohort study. Nonfeasibility was defined by the frequencies of empirical first-cycle dose reduction (>15%), early discontinuation (

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Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma

Objective: This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. Materials and Methods: The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). Results: The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

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Primary Pulmonary Carcinoid Tumor: A Long-term Single Institution Experience

Objectives: Primary carcinoid tumors of the lung are rare tumors which comprise approximately 0.5% to 5% of all lung malignancies in adults and roughly 20% to 30% of all carcinoid tumors. The purpose of this retrospective, descriptive study was to describe the incidence, characteristics, and outcomes of patients treated for primary pulmonary carcinoid tumor at a single institution. Materials and Methods: All patients with a diagnosis of primary pulmonary carcinoid tumor treated from 1989 to 2009 were reviewed. Data collected included demographics, pathology, tobacco use, clinical presentation, tumor location, tumor spread, treatment, and survival. Results: There were 59 cases of pulmonary carcinoid tumors: 47 typical (80%) and 12 atypical (20%). All but 4 patients underwent surgery, including 54 (92%) lung-sparing resections and 1 pneumonectomy. Five of 55 patients received concurrent adjuvant chemoradiation therapy; 4 patients with atypical and 1 with typical histology. Three additional patients with atypical carcinoid were treated only with adjuvant radiotherapy, palliative radiotherapy, or palliative chemotherapy, respectively. The Kaplan-Meier 5- and 10-year overall survivals were both 80% within the entire population. In the 88% of patients who achieved complete remission, disease-free survival was 98%. A review of a large series from the literature is also presented. Conclusions: Surgical resection was primary and adequate therapy for most typical carcinoid tumors with high overall survival and disease-free survival. Adjuvant chemotherapy or radiotherapy might be considered for patients with atypical carcinoid tumors who present with adverse pathologic findings.

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Stereotactic Body Radiotherapy for Lung Metastases from Colorectal Cancer: Prognostic Factors for Disease Control and Survival

Objectives: To evaluate disease control and survival after stereotactic body radiotherapy (SBRT) for lung metastases from colorectal cancer and to identify prognostic factors after treatment. Methods: Patients with metastatic colorectal cancer to the lungs treated with SBRT from 2002 to 2013 were identified from a prospectively maintained database. Patients may have received prior systemic therapy, radiotherapy to nonthoracic sites and/or resection of thoracic and/or nonthoracic metastases. Endpoints were timed from end of SBRT and included overall survival (OS), progression-free survival, distant metastases-free survival, and local failure-free survival. Univariate and multivariate analysis using Cox proportional hazard modeling was used to identify prognostic factors. Results: Sixty-five patients were identified. Before SBRT, 69.2% and 33.8% of patients received systemic therapy and lung-directed local therapy, respectively, for metastatic disease. At the time of SBRT, 64.6% had lung-only involvement. Median survivals were: OS of 20.3 months (95% confidence intervals [CI], 15.9-27.0 mo), progression-free survival of 5.7 months (95% CI, 3.2-7.0 mo), distant metastases-free survival of 5.8 months (95% CI, 3.2-7.6 mo), and local failure-free survival of 15.4 months (95% CI, 8.5-21.1 mo). Nearly all (98%) patients developed distant progression. Extra lung and liver involvement at the time of initial metastases (hazard ratios [HR] 2.10) and extra lung involvement at SBRT (HR 2.67) were the only independent predictors of OS. Net gross target volume of >14.1 mL (HR 2.49) was the only independent predictor of local failure-free survival. Conclusions: Reasonable survival and local control can be achieved with SBRT. We identified several prognostic factors testable in future prospective trials that may help improve patient selection.

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Trimodality Treatment of Malignant Pleural Mesothelioma: An Institutional Review

Objective: Malignant pleural mesothelioma (MPM) is a deadly disease with varying treatment options. This study retrospectively describes treatment practices at the University of Washington Medical System from 1980 to 2011, and evaluates the impact of trimodality therapy and radiation (photon and neutron) on survival. Methods: A retrospective study was conducted on patients treated for MPM. Univariate and multivariate methods were utilized to evaluate potential factors associated with survival. Treatments received and baseline characteristics were included. Survival analysis of trimodality therapy was performed using a propensity score method to control for baseline characteristics. Results: Among 78 eligible patients, the median age at diagnosis was 59 years and the median survival was 13.7 months. On multivariate analysis, the significant predictors of improved survival were age, smoking history, location, and receipt of radiation therapy or chemotherapy. In the 48 patients receiving radiation therapy, the difference in survival between neutron therapy and non-neutron therapy patients was not statistically significant: hazard ratio, 1.20 (95% confidence interval, 0.68-2.13), P=0.52. Patients receiving trimodality therapy were more likely to have early-stage disease (60% vs. 30%) and epithelioid histology (86% vs. 58%). In a propensity score-weighted Cox proportional hazards model, trimodality therapy patients had improved overall survival, hazard ratio 0.45, P=0.004, median 14.6 versus 8.6 months. Conclusions: Trimodality therapy was significantly associated with prolonged survival in patients with MPM, even when adjusting for baseline patient factors. Radiation therapy was associated with improved survival, but the modality of radiation therapy used was not associated with outcome.

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Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States

Purpose: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). Materials and Methods: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. Results: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. Conclusions: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

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Brain Metastases at Presentation in Patients With Non–Small Cell Lung Cancer

Objective: We used brain radiotherapy as a surrogate for the presence of brain metastases in patients with non–small cell lung cancer (NSCLC) to determine the prevalence of brain metastases using the Surveillance Epidemiology and End Results database. Methods: Patients with NSCLC diagnosed between 1988 and 1997 were subdivided according to brain radiotherapy status at presentation into: "none" or "radiation therapy indicated." We calculated the frequency of brain radiotherapy use in all patients. Odds ratios (ORs) for the indication of brain radiotherapy were calculated for individual prespecified covariates of interest. All statistical tests were 2-sided and P3 cm (3.1 to 5 cm OR, 1.22; 95% CI: 1.14, 1.30 and >5 cm OR, 1.25; 95% CI: 1.17, 1.33); tumor grade >II (grade III OR, 1.82; 95% CI: 1.69, 1.95 and grade IV OR, 1.91; 95% CI: 1.73, 2.11); and nodal involvement N1 (OR, 1.33; 95% CI: 1.20, 1.47), N2 (OR, 2.24; 95% CI: 2.10, 2.40), and N3 (OR, 2.39; 95% CI: 2.19, 2.60). Conclusions: Brain radiotherapy is indicated in over 8% of patients with NSCLC at presentation. We demonstrated that the risk of brain metastasis at presentation may be stratified with the use of 6 clinical factors.

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