tbuckley/cabot-search huggingface dataset:
Immediate versus delayed adjuvant chemoradiation for resected pancreatic cancer: An analysis of local control and survival.
Authors: Stephanie Krejcarek Childs, Harvey J. Mamon, Jennifer Yon-Li Wo, Lawrence Scott Blaszkowsky, Carlos Fernandez-del Castillo, Richard Swanson, Brian M. Wolpin, Eunice Lee Kwak, Jill N. Allen, Andrew X. Zhu, Jeffrey W. Clark, Raymond Couric Wadlow, David P. Ryan, Theodore S. Hong
Journal: Journal of Clinical Oncology (2012)

301 Background: Patients with resected pancreatic cancer have a significant risk of both local and distant failures. Because of the importance of chemotherapy (CT) highlighted by recent trials, the ongoing RTOG 0848 delays chemoradiation (CRT) randomization to after 5 cycles of chemotherapy (CT). However, the impact of delaying CRT on LR is unknown. We evaluated the patterns of failure and outcomes for patients treated with immediate vs. delayed CRT. Methods: 174 consecutive patients with resectable pancreas cancer who received post-operative CRT at the Massachusetts General Hospital and Brigham &amp; Women’s Hospital/Dana-Farber Cancer Institute between 1998-2010 were retrospectively reviewed on an IRB approved protocol. CRT was delivered to 50.4 Gy with concurrent 5FU or capecitabine. Patient baseline characteristics, pathologic features, and CA19-9 were obtained. Patients were divided into immediate CRT vs. delayed CRT, defined as receiving any CT prior to CRT. LR was independently re-reviewed and confirmed. LR, PFS, and OS were calculated using the Kaplan-Meier method and groups compared using the log-rank test. Results: Median age was 62 (range, 34-83), 75 were male, and ECOG PS was 0-1 in 95% of patients. Median tumor size was 3 cm, 67% had positive nodes, and 33% had positive margins. Mean pre-operative and post-operative CA 19-9 was 813 U/mL and 19 U/mL, respectively. 123/174 (72%) patients received immediate CRT, of whom 101 received additional chemotherapy (5FU or gemcitabine (GEM)). 51/174 (28%) received delayed CRT, and received a median of 4 cycles of GEM prior to CRT. Median follow-up was 33 months (range, 3.6-67). 6/51 (12%) delayed CRT had LR prior to initiation of CRT. 25/51 in the delayed CRT group had a LR (49%) vs. 35/124 patients (28%) in the immediate CRT group. The 1-year LR rates in the immediate and delayed CRT groups were 18% and 40%, respectively (p=0.0093). There was no difference between immediate or delayed CRT, respectively, in mPFS (12.8 mo vs. 12.2 mo, p=0.6544) or mOS (24.8 mo vs. 26.7 mo, p=0.7163). Conclusions: Delayed radiation is associated with an increased risk of LR, though this did not appear to impact PFS or OS.
EGFR and K-ras mutations as determinants of gefitinib sensitivity in non-small-cell lung cancer (NSCLC)
Authors: S. W. Han, S. Jeong, I. S. Choi, D. W. Kim, D. H. Chung, S.-A. Im, T. Y. Kim, D. S. Heo, Y. J. Bang, N. K. Kim
Journal: Journal of Clinical Oncology (2005)

7078 Background: EGFR mutation is associated with response and prolonged survival in NSCLC patients treated with gefitinib. We have previously observed negative correlation of p-Erk and efficacy of gefitinib. K-ras mutation may constitutively activate p-Erk. Recently, HER2 mutation was found in NSCLC. We have investigated EGFR, HER2, and K-ras mutations in NSCLC treated with gefitinib. Methods: Advanced NSCLC patients (pt) received gefitinib 250mg/day. EGFR (exons 18, 19, 21, and 23), HER2 (exons 19 and 20), and K-ras (codons 12 and 13) mutations (mt) were identified by direct sequencing of PCR products of DNA extracted from archival paraffin embedded tissue. P-Erk and p-Akt expression was determined by immunohistochemistry (IHC). Baseline characteristics, mutational status, IHC data and efficacy of gefitinib were analyzed in respect to each other. Results: 59 pt were analyzed. 13 pt harbored EGFR mt and 8 pt harbored K-ras mt, whereas HER2 mt was found in none. EGFR mutation was significantly associated with response [response rate (RR) 61.5% in mt(+) vs.13.0% in mt(-), p=0.001], time-to-progression (TTP) [13.7 months (M) in mt(+) vs. 1.3 M in mt(-), p=0.001], and overall survival (OS) [not reached in mt(+) vs. 5.8 M in mt(-), p=0.001]. Among 8 pt with K-ras mt, 2 pt had stable disease (SD), 6 pt had progressive disease (PD), and no pt had response to gefitinib [RR 0% vs. 27.5% in K-ras mt (-), p=0.18]. No association was found between K-ras mt and TTP or OS. 2 pt concomitantly had EGFR and K-ras mt; 1 pt had SD and the other PD. RR in EGFR mt(+)/K-ras mt(-), EGFR mt(-)/K-ras mt(-), and K-ras mt(+) were 72.7%, 15.0%, and 0%, respectively (p<0.001). K-ras mutation was more frequently found in male (p=0.067), squamous cell carcinoma (p=0.095), and smokers (p=0.008). 6/7 pt with K-ras mt exhibited positive p-Erk expression [85.7% vs. 58.8% in K-ras mt (-), p=0.24]. Conclusion: These results support the assumption that K-ras mutation may have role in gefitinib resistance via activation of Ras/Raf/Erk pathway. Together with EGFR mutation, K-ras mutation may aid in patient selection for treatment with gefitinib in NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Phase I study of the pan aurora kinases (AKs) inhibitor PHA-739358 administered as a 24 h infusion without/with G-CSF in a 14-day cycle in patients with advanced solid tumors
Authors: R. B. Cohen, S. F. Jones, M. von Mehren, J. Cheng, D. M. Spiegel, B. Laffranchi, M. Mariani, R. Spinelli, D. Magazzu, H. A. Burris
Journal: Journal of Clinical Oncology (2008)

2520 Background: PHA-739358 is a small molecule that inhibits AKs, a serine/threonine family of proteins regulating mitosis. AKs are overexpressed in many tumor types. Methods: Objectives were to determine the MTD, cycle 1 dose-limiting toxicities (DLTs), safety, PK profiles and antitumor activity. Cohorts of 3–6 pts were allotted to progressively higher dose levels (DL) based on the number of DLTs observed. DLTs were defined as grade 4 neutropenia (G4 ANC) lasting >7 days, febrile neutropenia (FN), neutropenic infection (NI), or any G3/4 nonhematologic drug-related toxicities. Results: Without G-CSF: 40 pts were treated at 7 DLs (45, 90,180, 360, 500, 580, 650 mg/m2). 500 mg/m2 was identified as the recommended dose for phase II (RP2D). DLTs were observed in 6 pts: 1 NI at 360 mg/m2, 1 FN+G4 mucositis at 500 mg/m2, 1 FN and 1 G2 ANC with chills/rigors at 580 mg/m2 and 2 FN at 650 mg/m2. G3/4 ANC and lymphocytopenia were the most frequent treatment-emergent hematologic toxicities (72% and 55% of pts, respectively). G 3/4 anemia and thrombocytopenia were rare. The most frequent PHA-739358-related events were usually of G1/2 severity and included fatigue, anorexia, nausea, vomiting, diarrhea, constipation and pyrexia. 46% of evaluable pts had stable disease as best response. Cmax and AUC increased with dose, with low inter-patient variability. Terminal half-life was 17–29 hr. Inhibition of histone H3 phosphorylation in skin biopsies indicates biomarker modulation at doses ≥ RP2D. With G-CSF: 15 pts were treated at 3 DLs (580, 750, 1,000 mg/m2). Incidence and severity of PHA-739358-induced hematologic toxicities were reduced. The type and incidence of non hematologic toxicities was similar. At 1,000 mg/m2, 1 pt had G4 ANC despite G-CSF and 3 pts had G2 creatinine increase. The 750 mg/m2 DL has been expanded to confirm the MTD. Conclusions: 500 mg/m2 is the RP2D without G-CSF. PK parameters are dose and time independent and characterized by low inter-pt variability. Clinically relevant disease stabilizations are reported as well as biomarker modulation starting at 500 mg/m2. No DLT has been reported in the first 5 pts treated at 750 mg/m2 + G-CSF. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nerviano Medical Sciences Nerviano Medical Sciences Nerviano Medical Sciences
PEAK (study 20070509): A randomized phase II study of mFOLFOX6 with either panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) in patients (pts) with unresectable wild‑type (WT) <i>KRAS</i> metastatic colorectal cancer (mCRC).
Authors: Lee Steven Schwartzberg, Fernando Rivera, Meinolf Karthaus, Gianpiero Fasola, Jean-Luc Canon, Hua Yu, William Y. Go
Journal: Journal of Clinical Oncology (2013)

446 Background: Pmab has demonstrated significant improvement in progression-free survival (PFS) in pts with WT KRAS mCRC as 1st-line tx in a phase III trial comparing pmab + FOLFOX4 vs FOLFOX4 alone. Here, we describe the results of PEAK, a multicenter, randomized phase II study evaluating pmab + mFOLFOX6 and bev + mFOLFOX6 in pts with previously untreated WT KRASmCRC. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg + mFOLFOX6 Q2W or bev 5.0 mg/kg + mFOLFOX6 Q2W. Pt eligibility criteria included: WT KRASmCRC, ECOG performance status ≤ 1, and no prior chemotherapy, anti-VEGF tx, or anti-EGFR tx for mCRC. The primary endpoint was PFS; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. No formal hypothesis was tested. Results: 285 pts with WT KRASmCRC were randomized and 278 pts received tx. Demographics were balanced between arms. Intent-to-treat efficacy results are shown (Table). Worst grade 3/4 adverse events (AE) occurred in 86% of pts in the pmab + mFOLFOX6 arm vs 76% of pts in the bev + mFOLFOX6 arm. Grade 5 AEs occurred in 5% of pts in the pmab + mFOLFOX6 arm and 6% of pts in the bev + mFOLFOX6 arm. Tx discontinuation due to any AE was 24% in the pmab + mFOLFOX6 arm and 27% in the bev + mFOLFOX6 arm. Conclusions: In this estimation study of pts with WT KRASmCRC without any prior therapy for mCRC, PFS and ORR were similar between arms. The median OS was not reached in the pmab + mFOLFOX6 arm. The safety profile for both arms was consistent with previously reported studies of either combination. Tx discontinuation rates due to AEs were similar between arms. Clinical trial information: NCT00819780. [Table: see text]
Multidisciplinary breast clinic: Impact on patient satisfaction, timeliness, and guideline concordant care.
Authors: Caitlin Laurel Gomez, Nicole Ann Dawson, Robyn Lynn Dvorak, Nova Foster, Anne Hoyt, Sara A. Hurvitz, Amy Kusske, Charles Y. Tseng, Susan Ann McCloskey
Journal: Journal of Clinical Oncology (2014)

124 Background: After recent implementation of a multidisciplinary breast clinic (MDC) for newly diagnosed women at our institution, we sought to examine the impact of MDC on patient satisfaction, timeliness and guideline concordant care. Methods: Women with newly diagnosed breast cancer at our institution are referred to MDC where they are seen by a team of breast specialists for initial consultation. The MDC model is further facilitated by a patient navigator/coordinator who serves as a single point of contact across disciplines and through the continuum of care. We deployed patient satisfaction surveys querying helpfulness of the care coordinator and satisfaction with seeing breast cancer specialty physicians together in one visit. We further retrospectively analyzed timeliness of care and guideline concordant care since MDC implementation. Results: Patient satisfaction survey response rate was 42% (n=133).On a scale of 1 (very poor) – 5 (excellent), 93% of respondents rated helpfulness of care coordinator as excellent and seeing specialty physicians together in one visit as excellent. 99% of respondents rated these factors as either excellent (5) or good (4). Regarding timeliness, among 202 women with newly diagnosed, non-metastatic breast cancer seen in MDC between June 2012 and April 2014, mean time from neoadjuvant chemotherapy to surgery was 43.1 days (range 26-78 days), from surgery to adjuvant radiation was 39.2 days (range 22-79 days), from surgery to adjuvant chemotherapy was 40.6 days (range 19-89 days), and from adjuvant chemotherapy to radiation was 34.9 days (range 13-67 days). All timeliness metrics well exceeded established national standards of 60-90 days. Regarding guideline concordant care, 94% and 90% respectively received indicated radiation therapy and chemotherapy in accordance with National Comprehensive Cancer Network (NCCN) Guidelines. Those not receiving guideline concordant care either declined, were of advanced age, or had prohibitive co-morbidities. Conclusions: The MDC model, which emphasizes care coordination via a team approach and patient navigation, is associated with excellent patient satisfaction and timely, guideline concordant breast cancer care.
Improving safety in first-line metastatic colorectal cancer (MCRC) therapy with bevacizumab: Modified FOLFOX7 versus XELOX2—Results of the induction phase of the GERCOR DREAM randomized phase III study.
Authors: Christophe Tournigand, Benoist Chibaudel, Benoit Samson, Werner Scheithauer, Gérard Lledo, Pascal Artru, Frédéric Viret, Jean-Francois RAMEE, Nicole Tubiana-Mathieu, Jérôme Dauba, Olivier Dupuis, Yves Rinaldi, May Mabro, Nathalie Aucoin, Franck Bonnetain, Christophe Louvet, Annette K. Larsen, Thierry André, Aimery De Gramont
Journal: Journal of Clinical Oncology (2015)

670 Background: FOLFOX7 is an oxaliplatin FOLFOX regimen without 5FU bolus, first used in the OPTIMOX1 MCRC study (Tournigand, JCO 2006). Modified (m) FOLFOX7 has a reduced dose of oxaliplatin (100 mg/m²) and has been used in the OPTIMOX2 trial (Chibaudel, JCO 2009). XELOX2 derived from the bi-weekly XELOX regimen with oxaliplatin 85 mg/m² (Scheithauer, JCO 2003). Methods: First-line induction therapy (IT) allocation was randomized in unresectable MCRC patients with performance status (PS) 0-1 between 6 cycles of mFOLFOX7 with bevacizumab (B) or 6 cycles of XELOX2 with B. Stratification criteria were: center, age, ECOG PS, number of metastatic sites and LDH level. After 3-month IT, a second randomization for maintenance therapy allocation was done in non-progressive patients between B or B-erlotinib. mFOLFOX7-B consisted in B 5 mg/kg followed by folinic acid (FA) 400 mg/m² and oxaliplatin 100 mg/m² followed by 5-flurouracil (5FU) 2,400 mg/m² 46h-infusion. XELOX2-B consisted in B 5 mg/kg followed by oxaliplatin 100 mg/m² followed by capecitabine 1,250 mg/m² twice daily for seven days. Cycles were repeated every two weeks. The objective was to compare the safety and efficacy of XELOX2-B to mFOLFOX7-B (secondary objective of the study). Results: 156 patients were randomized to mFOLFOX7-B and 154 to XELOX2-B. Medians (mFOLFOX7/XELOX2) were: PFS 7.9/8.7 months (HR 0.98, CI 0.74-1.31; p=0.918), OS 26.6/23.4 months (HR 1.24, CI 0.98-1.59; p=0.075). RR (mFOLFOX7/XELOX2) was 50.0%/49.3%. Main grade 3/4 toxicities (mFOLFOX7/XELOX2) were neutropenia 9.2%/2.6% (p=0.018), diarrhea 5.2%/18.3% (p&lt;0.001), asthenia 2.6%/11.8% (p=0.003), all 27.5%/37.6% (p=0.068). Conclusions: Both regimens have the same activity as the parent regimens with a reduced toxicity, especially mFOLFOX7-B. These regimens could be good backbones for future combinations with other agents and are well suited for frail and elderly patients. Clinical trial information: NCT00265824.
Electronic operative reports to support quality improvement and patient-centered care.
Authors: Shaheena Mukhi, Elaine Maloney, Mary Agent-Katwala, Geoff Porter
Journal: Journal of Clinical Oncology (2016)

95 Background: Operative reports (OP) for cancer surgery are usually narrated, although they provide inconsistent and incomplete information for patient care. National standards for cancer OP were unavailable until 2007. Over 10 years, surgeons in four Canadian provinces have transitioned from narrative to electronic synoptic reporting (ESP) for specific cancers. The electronic OP are now considered a patient medical record and integral to subsequent patient care. Surgeons are using electronic reports for quality assurance, billing, medical-legal conflict resolution and research. Methods: Disease-site expert panels were formed to bring together surgeons to discuss, identify, develop and form consensus on a core set of elements for breast, colorectal, ovary, endometrial, lung, prostate, and thyroid cancer surgeries and 64 quality indicators to set practice standards to consistently and comprehensively record pre-operative, operative procedures, intra-operative observations and pathology, clinical stage findings, complications and outcomes. These standards were implemented using ESP in four provinces and a mixed methods evaluation was carried out. Results: 245 surgeons in academic and community hospitals piloted and implemented pan-Canadian standards and generated 2000 synoptic reports and 729 discharge summaries over six months. In comparison to narrative reports, surgeons reported that the electronic synoptic reports: Capture complete and essential content (89% - 96%), 50% more; Contain 25 – 50 items vs. 2000 narrated words; Faster completion and turnaround time (5- 15 minutes) vs. 5 days; Rapid transmission to patient charts (91% in 1 hour and 97% within 24 hours) vs. 30 – 90 days; Result in cost savings $90/case; Enable performance measurement of surgical care to assess quality and outcome of surgery (e.g., residual disease and survival in patients) and length of aggressive vs. non-aggressive surgery and hospital stay (5.49 hours and 8.39 days vs. 3.06 hours and 6.83 days). Conclusions: Surgeons are building partnerships with key players to strategize best approaches to enable a system-wide adoption and implementation of synoptic operative reporting and quality of care measurement across Canada.
Association between DNA-repair gene and glutathione S-transferase gene polymorphisms and clinical outcome in patients (pt) with localized non-small cell lung cancer (NSCLC) treated with sequential radiochemotherapy.
Authors: J. Stoehlmacher-Williams, B. Krassler, M. Kramer, G. Ehninger, G. Hoeffken, E. Goekkurt
Journal: Journal of Clinical Oncology (2011)

7008 Background: To evaluate the impact of DNA-repair and glutathione S-transferase gene polymorphisms on clinical outcome measured by progression-free (PFS) and overall survival (OS) in patients with localized non-small-cell lung cancer (NSCLC). Methods: DNA for genotyping was extracted from archived paraffin embedded formalin-fixed tumor tissues. Genotyping was performed using PCR-based methods. Genomic polymorphisms of ERCC1, XRCC1, XRCC2, XPA, GSTP1, GSTT1 and GSTM1 were analyzed using PCR-based methods. Results: 116 pt with NSCLC Ib-IIIb 85% received cisplatin-based chemotherapy (cx) prior to radiation. Pt demographics: median age 63 years; ECOG 0/1 and 2: 90%, 10%; 87% male/13% female; 90% of pt got local treatment (radiation and/or resection) following cx. Responses: 72 pt (62%) complete or partial remission, 32 pt (27%) stable disease and 14 pt (11%) progressive disease (PD). Median follow up time was 23.1 months (mo). Relapse or PD was observed in 80% of cases. Median OS of all pt was 23.4 mo and median PFS was 9.8 mo. GSTP1-105Val/Val genotype was associated with superior PFS and OS. In this group the median was not reached whereas median OS for heterozygots or homozygous wildtypes was 23.4 mo (p=0.056). Median PFS for GSTP1-105Val/Val was 24.4 mo compared to 9.8 mo (p=0.048). Moreover, all GSTP1-105Val/Val patients (n=8) were responders (R) to cx compared to only 59% R in pt with at least one Ile allele (p=0.023). Pt with a GSTT1 deletion showed shorter OS with 10.7 mo compared 23.8 mo in pt without a GSTT1 deletion (p=0.12). Median OS in the XPD-312N/N genotype group was 69.7 months compared to 23.4 mo in pt with at least one D allele (p=0.08). All XPD-312N/N pt were R (n=6) compared to 63% R in XPD-312D/D or D/N pt (p=0.08). Multivariate cox regression analyses revealed performance status (p=0.006), XPD-312N/N (p=0.038), GSTT1 (p=0.03) and surgical resection (p=0.001) as independent predictors of OS. Conclusions: DNA-repair and GST polymorphisms may be associated with clinical outcome in NSCLC patients with localized disease and multimodal chemoradiation.
Association of intratumoral FOXP3-positive regulatory T cells (Tregs) with adverse prognosis in radically resected (R0), stage II- III gastric cancer (GC)
Authors: F. Graziano, P. A. Ruffini, G. Perrone, V. Catalano, C. Spino, C. Spoto, D. Santini, P. Muretto, C. Zingaretti, G. Tonini, C. Rabitti
Journal: Journal of Clinical Oncology (2008)

4527 Background: To assess the clinical significance of tumor-infiltrating FOXP3-positive Tregs in patients with R0, stage II-III, GC. Methods: From a single-institution database, tumors of 110 consecutive GC patients who underwent R0 resection for stage II- III disease were studied for FOXP3-positive Tregs by immunohistochemistry. A minimum 3-year follow-up time and the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria were used for planning the study. The recurrences of GC had to be confirmed by cytology biopsy or surgery. None of the patients received chemotherapy or radiation therapy before or after surgery as a part of an adjuvant program. The study was conducted in a blinded fashion so that patients’ outcomes were unknown to investigators performing immunohistochemistry. The observed median number of FOXP3-positive Tregs was used as cut-point in analyses (<6 vs. >6 count). To explore the association between overall survival (OS) and relapse-free survival (RFS) with FOXP3 count stratified log-rank tests were used. To further define these relationships, Cox proportional hazards models for multivariate analyses with Hazard Ratio (HR) and 95% confidence interval (95%CI) were employed. Results: Tregs numbers were significantly higher in GC than in normal tissue (p=0.0001) and Tregs count >6 was significantly associated with vascular/lymphatic/perineural invasion (VELIPI) in the tumor (p=.03). Forty-eight patients (44%) relapsed and died after receiving cisplatin/fluorouracil-based palliative chemotherapy. In multivariate analysis, adverse RFS was associated with grading 3 (HR=2.15; 95%CI 1.19–3.89, p=0.01), stage III (HR=2.34; 95%CI 1.20–4.57, p=0.01), VELIPI (HR=1.96; 95%CI 1.08–3.55, p=0.02) and Tregs count >6 (HR=2.00; 95%CI 1.10–3.65, p=0.02), while adverse OS was associated with grading 3 (HR=2.21; 95%CI 1.22–3.98, p=0.008), stage III (HR=2.40; 95%CI 1.23–4.67, p=0.01) and Tregs count >6 (HR=2.34; 95%CI 1.27–4.28, p=0.006). Conclusions: Quantification of FOXP3-positive Tregs may be a novel marker for identifying high-risk GC patients. Present findings deserve additional investigation as Tregs may also represent an innovative therapeutic target. No significant financial relationships to disclose.