tbuckley/cabot-search huggingface dataset:
A phase II study of erlotinib plus capecitabine (XEL) as first-line treatment for elderly patients (pts) with advanced adenocarcinoma of lung (ML 22206 study).
Authors: H. Zhao, G. Chen, J. Feng, Y. Chen, Y. Zhang, X. Song, Y. Huang, L. Zhang
Journal: Journal of Clinical Oncology (2010)

e18016 Background: For adenocarcinoma of lung, anti-folate drug like pemetrexed was active, however, the role of XEL, pro-drug of 5≂J-DFUR, has yet to be defined. Preclinical studies showed a strong synergistic interaction between EGFR-TKI and 5′- DFUR in solid tumors. The current phase II study was designed to investigate the efficacy and tolerability of erlotinib plus XEL as first-line treatment in elderly pts with adenocarcinoma. Methods: This is an open-label, single arm, multicenter trial employing a single- stage design. A total of 62 pts are planned. Eligible pts include those with previously untreated stage IIIB/IV adenocarcinoma, above 65 years old, adequate organ function. Tumor samples availability were mandated. Erlotinib (150 mg p.o. QD. until PD) and XEL (1,000 mg/m2 p.o. BID.D1-14) were given every 21-day cycle (maximum 6 cycles). Primary endpoints were disease control rates (DCR) at 12 and 18 weeks. Second endpoints included objective response, toxicity, progression free survival, overall survival, duration of response and quality of life. Results: Totally 62 patients were included (median age = 71; males/females = 27/35; ECOG PS 0/1/2 = 5/42/15 pts). A total of 287 cycles of XEL (median = 4) and a total of 322 cycles of erlotinib (median = 4) have been administered. Up to Dec 14th 2009, 38 pts discontinued from the treatment mainly because of progression of disease (73.7%). In 58 pts who were assessable for response, the ORR was 29.3% (17/58, 95% CI 0.18∼0.41), the disease control rate was 75.9% (44/58, 95%CI 0.65∼0.87). Grade 3-4 treatment-related adverse events included diarrhea, anemia, hyperbilirubinemia, dyspnea, hand-foot syndrome, hemorrhage of gastrointestinal tract, dental ulcer, and rash, hemorrhage from respiratory tract, cerebral infarction, drowsiness. Conclusions: This is the first clinical study to evaluate erlotinib plus XEL in elderly adenocarcinoma pts. Preliminary results of our study show that the combination is promising and feasible. The survival date and biomarker study (EGFR and K-ras mutation status, mRNA level expression of TS, TP and DDP) result will be available soon. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, GlaxoSmithKline AstraZeneca, Bayer, Novartis, sanofi-aventis
Leveraging the DNA damage and transcriptional-regulatory roles of PARP-1 as a means to improve prostate cancer therapy.
Authors: Matthew Joseph Schiewer, Jamin Steffen, Renee Tholey, Jonathan Robert Brody, John Pascal, Jianqing Lin, Robert Den, Felix Yi-Chung Feng, Leonard G. Gomella, Adam Dicker, William Kevin Kelly, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2014)

179 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of androgen receptor (AR) function in models of prostatic adenocarcinoma (PCa), and is recruited to regulatory sites of select AR target genes. Pharmacological inhibition of PARP-1 enzymatic activity results in diminished AR and PARP-1 residency at AR target gene regulatory loci, reduced AR target gene expression (more than 50%), and reduced AR-driven, PCa-associated phenotypes, including castrate-resistant PCa (CRPC) AR function, tumor cell growth, and transition to CRPC. These data, in part, served as critical rationale for current clinical trials combining PARP inhibition and abiraterone for patients with metastatic CRPC NCT01576172 . Given the clinical importance of targeting AR function in PCa, preclinical studies were performed to assess the impact of leveraging the dual roles of PARP-1 as a means to improve therapy for advanced disease. Methods: In vitro and in vivo model systems were utilized to assess impact on AR and tumor growth. Multiple PARP inhibitors were used for additional studies. The impact of PARP-1 on gene expression was also assessed using unbiased analyses. PARP-1 mutants were also utilized to segregate the DNA damage and transcriptional regulatory roles of PARP-1. Results: Critically, PARP-1 inhibitors cooperated with castration to elicit an enhanced therapeutic response, and PARP-1 inhibitors were effective at suppressing CRPC growth in vivo. Multiple PARP inhibitors diminished AR chromatin occupancy, altered AR transcriptional output and reduction in PCa and CRPC cell growth. Conclusions: These data identify PARP-1 as a feasible therapeutic target for advanced prostate cancer. Multiple PARP inhibitors show pre-clinical efficacy in models of PCa and CRPC and merit consideration for clinical trial, and a concept will be presented.
Autologous Stem Cell Transplantation Induces a Phenotypical Shift From CMP to GMP Progenitors, Reduces Clonogenic Potential and Enhances in Vitro and In Vivo Cycling Activity Defined by 18f-FLT PET Scan.
Authors: Carolien M. Woolthuis, Ali Agool, Annet Z. Vos, Riemert H.J.A. Slart, Geert A. Huls, W. Martin Smid, Jan Jacob Schuringa, Edo Vellenga
Journal: Blood (2009)
<sup>11</sup>c-choline-PET/CT (C-PET) versus transrectal ultrasound–guided prostate biopsies (TRUS-BP) to diagnose locally recurrent prostate cancer (PCA) following radiation therapy (RT).
Authors: A. Heidenreich, B. Brehmer, R. Epplen, D. J. K. P. Pfister
Journal: Journal of Clinical Oncology (2011)

4669 Background: Radical salvage prostatectomy represents a secondary local treatment option with curative intent for patients with locally recurrent PCA following RT. There are no data available with regard to the sensitivity of C-PET versus TRUS-PB in men with suspected locally recurrent PCA Methods: 45 men with suspected locally recurrent PCA underwent TRUs-BP with 12 cores, C-PET and radical salvage prostatectomy. The findings of C-PET and TRUS-BP were correlated with the pathohistologic findings of the radical prostatectomy specimen with regard to presence of PCA, number and intraprostatic location of PCA foci ≥ 5mm, and presence of extraprostatic extension and lymph node metastases. Results: The mean PSA was 7.8 (2-24) ng/ml; biopsy Gleason Score was 5.6 (4-9). TRUS-BP was positive in 37/45 (82.2%) pts, 8/45 (17.8%) had a negative biopsy despite positive C-PET results. C-PET was positive in 45 (100%) pts revealing 1-3 PCA foci. Pathohistology of the RSP-specimens revealed vital cancer in 44 (97.8%) pts C-PET identified 1, 2, and > 2 intraprostatic cancer foci in 23 (51.1%), 13 (28.9%) and. 9 (20%) pts, resp.. Sensitivity and specificity of C-PET were significantly higher as compared to the TRUS-BP findings. There was a low sensitivity and specificity with regard to the detection of lymph node metastases and EPE. Conclusions: C-PET is an innovative imaging modality to identify locally recurrent PCA, number and .location of cancer foci. C-PET has a better diagnostic accuracy than TRUS-BP and might be used in candidates for radical salvage prostatectomy.
Diagnosis and therapy of illness-related quality of life in breast cancer patients. Results of a randomized clinical trial
Authors: M. Klinkhammer-Schalke, C. Ehret, M. Koller, B. Steinger, B. Ernst, F. Hofstädter, W. Lorenz
Journal: Journal of Clinical Oncology (2008)

9630 Background: Quality of life (QoL) is an accepted endpoint in clinical trials, but not yet systematically utilized as a diagnostic tool in routine patient care. The Tumor Centre Regensburg developed a system for diagnosis and therapy for QoL deficits for patients with breast cancer which was implemented in 5 clinics and 38 doctors’ practices (Langenbecks Arch Surg,393,2008) and evaluated in a randomized clinical trial. Methods: The study was designed as a two-armed, prospective, randomized clinical trial (Zaefq,100,2006). Inclusion criteria comprised diagnosis of primary breast cancer and follow-up at one of the coordinating physicians (CP) of the study. QoL was measured with EORTC-QLQ-C30+BR23 every 3 months up to 12 months after surgery. In the intervention arm, a QoL-profile plus an expert report with QoL specific therapeutic recommendations was sent to the CP. The primary endpoint was the rate of patients with deficits in QoL (<50 points on at least 1 scale, with 0=bad,100=good QoL) 3,6,9 and 12 months after surgery. The hypothesis (H1) to be tested was that lower rates of QoL deficits will be observed in the intervention arm rather than in the control arm; conversely, H0 stated that no such difference will be detected. Power calculation (alpha=5%, beta=90%) suggested a sample size of N = 200. 199 patients were recruited between 11/16/2004 and 07/02/2006 with the last patient visit in 09/19/2007. Results: Intervention (IG) and control (CP) group were equivalent regarding age (median:58y [31–85y] vs. 56.5 [28–85y]), UICC stages 0-IV and baseline global QoL (mean = 76% vs. 69%). Significant differences in the rate of patients with QoL deficits were found at 6 months (56% vs. 71%, p<.05), but not at 3 (73% vs. 73%), 9 (54% vs. 61%) and 12 months (51% vs. 55%). The difference at 6 months was mainly due to emotional functioning (20% vs. 38%, p<.01). Conclusions: QoL of both groups improved during the first year after surgery. However, recovery was faster in the IG which is considered as an important benefit for breast cancer patients. No significant financial relationships to disclose.
Tri-stimuli-responsive biodegradable theranostics for mild hyperthermia enhanced chemotherapy
Authors: Nan Lu, Peng Huang, Wenpei Fan, Zhantong Wang, Yijing Liu, Sheng Wang, Guofeng Zhang, Junkai Hu, Wenfei Liu, Gang Niu, Richard D. Leapman, Guangming Lu, Xiaoyuan Chen
Journal: Biomaterials (2017)
Novel nomogram combining depth of invasion and size to predict the benefit of regional lymphadenectomy for appendiceal neuroendocrine tumors (A-NET).
Authors: Catalina Mosquera, Haily Vora, Timothy Louis Fitzgerald
Journal: Journal of Clinical Oncology (2016)

389 Background: The need for regional lymphadenectomy for A-NET is predicated on the risk of nodal metastasis. Although depth of invasion is predictive of nodal metastases in other gastrointestinal NET, current guideline recommendations for A-NET are based solely upon size. Methods: Patients with A-NET from 1988-2012 were identified within the SEER registry. Depth of invasion was defined as limited to lamina propria (LP), invading or through muscularis propria (MP), and through serosa (TS). Results: A total of 1,024 patients met inclusion criteria, with majority being female (55.7%), white (86.8%), and node-negative (81.1%). On univariate analysis, risk of nodal metastases was associated with size ( &lt; 1 cm 1.9%, 1-2 cm 19.7%, 2-4 cm 32.5%, and &gt; 4 cm 37.2%), depth of invasion (LP 4.1%, MP 17.4% and TS 44.3%) and extent of surgery (appendectomy 8.7% vs colectomy 31.9%), p &lt; 0.0001. On multivariate analysis, size ( &lt; 1 cm vs 1-2 cm HR 8.80, vs 2-4 cm HR 15.68, and vs &gt; 4 cm HR 15.16), depth of invasion (LP vs TS HR 6.67) and extent of surgery (appendectomy vs colectomy HR 2.98), continued to be associated with nodal involvement, p &lt; 0.0001. When only patients with colectomy were considered results were similar on both univariate and multivariate analyses. On univariate survival analysis, size [ &lt; 1cm 95.6%, 1-2cm 94.9%, 2-4cm 88.4%, and &gt; 4cm 73.7% 5-year disease-specific survival (5-y DSS)], depth of invasion (LP 96.9%, MP 93.2%, and TS 77.1% 5-y DSS), extent of surgery (appendectomy 94.4% and colectomy 87.1%), and N stage (N0 94.7% and N1 77.7%) predicted survival, p &lt; 0.002. In a Cox regression model, extent of surgery and N stage continued to predict survival. A nomogram was created to predict the risk of nodal metastases, AUC = 0.83. Conclusions: This simple nomogram, which incorporates size and tumor extension, accurately predicts the risk for regional nodal metastases in appendiceal NET. In addition to providing valuable information on risk for regional nodal metastases, depth of invasion independently predicts survival.
Phase I study of sunitinib in combination with gemcitabine/capecitabine for the first-line treatment of metastatic or unresectable renal cell carcinoma.
Authors: C. Suarez, E. Gallardo, J. Rodon Ahnert, M. Guix, T. Bonfill, F. Pons, M. Beltran, I. Moya, S. Galtes, J. Albanell, J. Carles, J. Bellmunt
Journal: Journal of Clinical Oncology (2011)

e15095 Background: Gemcitabine (G) plus Capecitabine (C) have demonstrated a modest activity in metastatic renal cell cancer (mRCC) patients (pts). The combination of Sunitinib (S) and C resulted in an acceptable safety profile in pts with advanced solid tumors. We hypothesized that the addition of S to G+C in advanced/mRCC would be synergistic and could increase the therapeutic efficacy. Methods: This is an open-label, phase I, dose-escalation study to assess the maximum-tolerated dose (MTD), safety and antitumor activity (in terms of response rate) of S in combination with C and G in naive pts with advanced mRCC. Advanced RCC pts with adequate organ function, performance status (ECOG 0-1), age >18 years, were eligible. Treatment consisted on iv G day 1 and 8, oral C bid days 1–14, and oral S continuous daily dosing (CDD) schedule, for six cycles (21 days per cycle), followed by sunitinib monotherapy, at the investigator’s discretion if clinical benefit was maintained. Dose level 1 G 1000 C 850 S 37.5; dose level 0 G 1000 C 650 S 37.5 (dose level -1 G 850 C 500 S 37.5). Results: 16 pts were enrolled in the study, median age: 67 yrs, histology: 9 clear cell, 4 papillar and 1 sarcomatoid have been treated at the first two dose levels. In DL1, two out of 4 pts had DLT, consisting on G3 diarrhea and mucositis, and G4 thrombocytopenia. Decision was made to reduce down to level 0; only 1/12 pts experienced DLT at this DL (mucositis G3 and thrombocytopenia G3). Other non-DLTs adverse events were asthenia, hand-foot syndrome, mucositis, diarrhea, infection, neutropenia, epistaxis, low gastrointestinal tract bleeding and hypertension. Dose reductions were frequent (58% of pts) and only 7 pts were able to receive the 3 drugs for > 3 cycles. One death was reported as possibly related to study drugs. A partial response was achieved in 3 pts, and stable disease in 6 patients. Conclusions: Although a low rate of DLT were observed at dose level 0, the safety profile of the combination does not seem to be manageable in most patients. In this trial there are no signs of a synergistic activity for the combination therapy of S plus G/C in therapy naïve pts with mRCC.
MRI and Metastatic Bone Survey (MBS) Examinations in Multiple Myeloma (MM): Laboratory Correlates and Prognostic Implications for 611 Patients Receiving Total Therapy 2.
Authors: Ronald Walker, John Shaughnessy, Jeffery Haessler, Joshua Epstein, Jeffery Sawyer, Elias J. Anaissie, Frits Van Rhee, Guido Tricot, Maurizio Zangari, Mauricio Pineda-Roman, Klaus Hollmig, John Crowley, Bart Barlogie
Journal: Blood (2006)
Are the survival benefits associated with primary resection in de novo metastatic colorectal cancer (mCRC) mediated by reversal of systemic inflammation?
Authors: Phillip V. Tran, Mathu Samanthaby, Hui-li Wong, Jayesh Desai, Jeanne Tie, Kathryn M. Field, Suzanne Kosmider, Susie Bae, Peter Gibbs, Ben Tran
Journal: Journal of Clinical Oncology (2014)

464 Background: Despite reported survival benefits for primary tumor resection in de novo mCRC, its use remains controversial, particularly as the biological explanation remains unclear. We explored whether reversal of systemic inflammation, a marker of a tumor-promoting immune response and poor prognosis, is associated with improved survival in pts undergoing primary resection. Methods: We identified pts who underwent primary resection for de novo mCRC from a prospective CRC database, excluding pts who had metastatectomy. Neutrophil-lymphocyte ratio (NLR) was used to represent systemic inflammation. Survival differences associated with reversal of systemic inflammation, as defined by NLR falling from an elevated level (&gt; 5) at diagnosis to ≤ 5 postoperatively, were examined. Associations between falling NLR and primary tumor bulk (maximal length assessed by pathologist) as well as metastatic burden (maximal axial diameter of largest metastasis assessed by radiologist) were explored. Results: Baseline and postoperative NLR were examined in 156 pts with median age 69y and median overall survival (OS) 18.3 mo. Baseline NLR was elevated in 66 (42%) pts; primary resection resulted in falling NLR in 37 of these pts (56%). Compared to pts with persistent NLR &gt;5, a falling NLR was significantly associated with improved OS (HR 0.53, p = 0.012). Falling NLR was also associated with larger primary tumors, although this was not significant (median length 55mm vs. 45mm, p = 0.059). In a preliminary analysis of 26 pts with retrievable radiology, falling NLR was associated with lower metastatic burden compared to an unchanged NLR (median diameter 29mm vs. 41mm, p = 0.046). Conclusions: Our data demonstrates improved OS in pts who have reversal of systemic inflammation following primary resection in de novo mCRC. The possible associations between reversed systemic inflammation with larger primary tumors or a lower metastatic burden suggest an immune mediated response to reduced tumour bulk as an explanation for the reported survival advantage associated with primary resection. If confirmed, this might define a subgroup of pts who might benefit most from primary resection.
Capecitabine dosing using skeletal muscle index (SMI) compared to body surface area (BSA).
Authors: Julia Sun, Alastair Ilich, Christina Kim, Grace Wong, Sunita Ghosh, Melanie Danilak, Karen E. Mulder, Jennifer L. Spratlin, Carole Chambers, Michael B. Sawyer
Journal: Journal of Clinical Oncology (2016)

722 Background: Capecitabine dose used to treat colorectal (CRC) and breast cancer (BC) is calculated using BSA. Capecitabine dose is 1250 mg/m 2 in CRC and 1000 mg/m 2 in BC. Using BSA to calculate dose does not consider body composition. We hypothesize that differences in capecitabine dose between CRC and BC patients (pts) is due to body composition differences between men and women, not cancer type. We hypothesize females starting treatment at 1250 mg/m 2 have a higher capecitabine dose/SMI than males, and dose reductions for dose-limiting toxicity (DLT) would lead to male and female CRC pts receiving the same capecitabine dose/SMI. Methods: This is a retrospective study of early stage CRC pts treated with adjuvant capecitabine from 2008-2012. Collected demographic data included age, stage, gender, height, weight, and performance status. Capecitabine doses at cycles 1 and 3 were documented. SMI was calculated using pre-treatment CT scans. Results: 183 pts (101 males, 82 females) were identified. Females received a higher starting capecitabine dose compared to males based on SMI. Mean capecitabine/SMI dose was 5107.4 mg/cm 2 /m 2 (SD 1113.8) for females compared to 4711.9 mg/cm 2 /m 2 (SD 870.6) for males (p = 0.009). At cycle 3, females still had a higher dose of 3875.1 mg/cm 2 /m 2 (SD 1663.5), although it was not statistically significant from their male counterparts at 3691.6 mg/cm 2 /m 2 (SD 1629.5) (p = 0.4580). Conclusions: Females received higher capecitabine doses/SMI than males at the CRC 1250 mg/m 2 dose. This is in keeping with our previous study that showed female CRC pts on adjuvant capecitabine experience more DLTs compared to males. After adjusting capecitabine doses for DLTs, male and female CRC pts received the same cape dose/SMI. This suggests SMI may be more useful than BSA when adjusting capecitabine doses.
Clinical pathways: An emerging tool for quality improvement.
Authors: Hillary Kleiner, Francesca Pirog
Journal: Journal of Clinical Oncology (2016)

222 Background: Clinical pathways have emerged as a tool for payers to encourage provider adherence to evidence-based care. Avalere sought to understand how oncology pathways are incorporated into broader organizational quality improvement initiatives and what impact they have on care quality. Methods: Avalere conducted white and grey literature searches to assess pathways used in quality improvement initiatives. The research was augmented by interviews with leading pathways organizations. Results: Research suggests that pathways can play the following roles in quality improvement: Ensure Adherence to Guidelines. Pathways are typically built on guidelines. Guideline adherence thresholds improve care quality by incentivizing appropriate care. While pathway adherence thresholds are typically set at 80%, little research has been conducted on whether adherence thresholds have improved guideline adherence. Ensure Adherence to Quality Measures. Quality metrics can be tied to pathway adherence, which in turn can also incentivize appropriate care. Quality measures tied to pathways can be used as a risk-mitigation and management tool for providers that assume more risk. Improve Patient Outcomes by Reducing Treatment Variability. Some clinical pathways programs have been shown to improve outcomes. Between 2010-2012, after implementing breast, colon and lung cancer pathways, US Oncology and Aetna experienced 1.2 inpatient days for patients vs. 2.1 prior to launch, as well as a 10% ER visits in the pathways group vs. 14% in the control group. Enable Comparative Outcomes Assessment. CPs could allow for benchmarking of outcomes over time. Treatment choices could be tracked through pathways and the outcomes could potentially be matched to those choices. Conclusions: While pathways have been shown to play a role in quality improvement, initial results have been short-term and isolated. To ensure that pathways can be a viable part of organizational quality improvement, additional research must be conducted on the impact of pathways on outcomes. Additionally, given the lack of pathway transparency and consistency there is a need for increased oversight to ensure that pathways are appropriately incentivizing adherence to guidelines and quality measures.