tbuckley/cabot-search huggingface dataset:
Effect of time to initiation of adjuvant chemotherapy on survival in resected pancreatic cancer.
Authors: Katelin Anne Mirkin, Christopher S Hollenbeak, Joyce Wong
Journal: Journal of Clinical Oncology (2016)

368 Background: Pancreatic cancer carries a grim prognosis. Surgical resection followed by adjuvant chemotherapy is standard of care, but little is known about the temporal relationship of chemotherapy initiation and survival. This study analyzed the impact of time to initiation of adjuvant chemotherapy on survival in patients with resected pancreatic cancer. Methods: The National Cancer Data Base (2003-2011) was retrospectively reviewed for patients with clinical stages 1-3 resected pancreatic carcinoma. Time to chemotherapy was stratified at the 12-week post-operative timepoint. Univariate statistics, Kaplan-Meier estimates, and Cox proportional hazard modeling were performed. Results: 5,205 patients who had undergone surgical resection alone, 3,144 patients who had undergone surgical resection and adjuvant chemotherapy initiated at or before 12 weeks, and 906 patients who had undergone surgical resection followed by adjuvant therapy started after 12 weeks were included. Patients who received chemotherapy &gt; 12 weeks tended to be older, have more co-morbidities, receive treatment at academic centers, and undergo whipple procedures. In all pathologic disease stages, adjuvant chemotherapy conferred a significant survival benefit over surgical resection alone (p &lt; 0.0001). However, there was no significant overall survival benefit for patients receiving adjuvant chemotherapy before 12 weeks as compared to after (p = 0.85). When stratified by pathological stage, there was still no significant survival benefit for earlier initiation of chemotherapy (£ vs. &gt; 12 weeks): stage I, p = 0.16, stage II, p = 0.12, stage III, p = 0.38. After controlling for patient, disease, and surgery characteristics, patients who received adjuvant chemotherapy after 12 weeks had a 31% lower odds of mortality at 5 years, while those who initiated it before 12 weeks had a 34% lower odds (p &lt; 0.0001, p &lt; 0.0001 respectively), versus surgery-alone. Conclusions: Earlier initiation of adjuvant chemotherapy does not significantly impact long-term survival in patients with resected pancreatic cancer. However, because adjuvant chemotherapy confers a survival benefit, delayed chemotherapy should be offered when appropriate.
T Cells Expressing a Novel Fully-Human Anti-CD19 Chimeric Antigen Receptor Induce Remissions of Advanced Lymphoma in a First-in-Humans Clinical Trial
Authors: Jennifer N. Brudno, Victoria Shi, David Stroncek, Stefania Pittaluga, Jennifer A. Kanakry, Lauren M. Curtis, Juan C. Gea-Banacloche, Steven Pavletic, Mohammad-Hadi Bagheri, Jeremy J. Rose, Rashmika Patel, Brenna Hansen, Ronald E. Gress, James N. Kochenderfer
Journal: Blood (2016)
Detection of vascular endothelial growth factor receptor 2 (VEGFR2) homodimers, phosphorylation and downstream pathway activation in endothelial cells using eTag Assay System
Authors: S. Moore
Journal: Journal of Clinical Oncology (2005)

9595 Background: It is well established that angiogenesis is a major factor in tumor growth and metastasis. The primary driver of tumorgenic angiogenesis is Vascular Endothelial Growth Factor (VEGF) and its tyrosine kinase receptor VEGFR2. Much effort is being made to block the VEGFR2 pathway and other angiogenic signaling pathways with targeted therapeutics such as Avastin (Bevacizumab). Currently there is not a direct method of detecting the activation and inhibition of angiogenic signaling pathways to prescribe and monitor the effects of antiangiogenic treatments. Methods: In this study, we stimulated Human Umbilical Vein Endothelial Cells (HUVEC) with increasing concentrations of VEGF at different time points. The eTag Assay system was used to detect VEGFR2 homodimer, VEGFR2 phosphorylation, and downstream pathway activation in whole cells lysates. The downstream proteins assayed included Erk, BAD, RSK, and Akt. Results: VEGFR2 homodimers increase with increasing doses of VEGF. Phosphorylation of VEGFR2 is transient- it peaks at 1 minute of VEGF treatment and after 5 minutes phosphorylation is at background level. 1 minute dosing of VEGF shows increasing VEGFR2 phosphorylation with increasing levels of VEGF. Downstream pathway proteins Erk, RSK, and BAD are activated with increasing levels of VEGF. Conclusion: We have demonstrated an assay system that gives a direct measure of the activation of the VEGFR2 pathway. This assay could be used as a diagnostic tool to determine whether a VEGF pathway inhibitor is an appropriate therapy for a patient, and as a direct surrogate marker of an inhibitor’s efficacy. No significant financial relationships to disclose.
Phase II trial of induction mFOLFOX6 plus bevacizumab followed by neoadjuvant S-1-based chemoradiation for MRI-defined poor-risk rectal cancer.
Authors: Tsuyoshi Konishi, Eiji Shinozaki, Keiko Murofushi, Masashi Ueno, Yosuke Fukunaga, Satoshi Nagayama, Yoshiya Fujimoto, Takashi Akiyoshi, Mitsukuni Suenaga, Satoshi Matsusaka, Akiko Chino, Hiroshi Kawachi, Noriko Yamamoto, Yuichi Ishikawa, Masahiro Igarashi, Masahiko Oguchi, Nobuyuki Mizunuma, Takeshi Sano, Toshiharu Yamaguchi
Journal: Journal of Clinical Oncology (2016)

700 Background: Induction chemotherapy has been explored as a novel treatment option to improve oncological outcomes in poor-risk locally advanced rectal cancer (LARC). Although previous studies have suggested high pCR rate with a favorable toxicity profile in S-1-based neoadjuvant chemoradiation, no study has evaluated induction chemotherapy added with this regimen. The present study is designed to evaluate the safety and efficacy of induction chemotherapy with bevacizumab followed by neoadjuvant S-1 based chemoradiation in MRI-defined poor-risk LARC. Methods: This was a single-center phase II trial at a high-volume cancer center. Eligible patients had low rectal adenocarcinoma with MRI-defined poor-risk features. Patients received 12-week (6 course) mFOLFOX plus bevacizumab (5 mg/kg every 2 weeks) followed by concomitant oral S-1 (80mg/m2/day on days 1-5, 8-12, 22-27, and 29-33) plus radiotherapy (50.4Gy). Surgery was scheduled for 6-10 weeks after chemoradiation. Pathological complete response (pCR) was the primary endpoint. Results: A total of 43 eligible patients were enrolled. Forty-two patients (98%) completed induction chemotherapy. Forty-two patients (98%) completed planned radiation dose. One patient with cCR after completion of preoperative treatment declined surgery, but all the other 42 patients (98%) underwent R0 resection thorough a laparoscopic approach. A pCR was achieved in 16 patients (37%; 95% confidence interval 24.4%-52.1%). CTCAE grade 3 adverse events (AEs) occurred in 4 patients (9.3%) during induction chemotherapy and 5 patients (12%) during chemoradiation. There were no grade 4 AEs. Clavien-Dindo Classification grade III-IV surgical complications occurred in 6 patients (14%), including 1 grade IVa delirium, 1 grade IIIb anastomotic leakage, 1 grade IIIb bleeding, 2 grade IIIa pelvic abscess and 1 grade IIIa urethral fistula. There was no mortality. Conclusions: Induction FOLFOX plus bevacizumab followed by S-1-based chemoradiation achieved a high pCR rate with favorable toxicity and tolerable surgical complications in poor-risk LARC. Phase III trial is needed for further evaluation. Clinical trial information: UMIN000011457.
Lapatinib versus lapatinib plus capecitabine as second-line treatment in HER-2-overexpressing metastatic gastro-esophageal cancer (GC): A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: Sylvie Lorenzen, Jorge Riera-Knorrenschild, Georg Martin Haag, Michael Pohl, Peter C. Thuss-Patience, Florian Bassermann, Ulrike Helbig, Florian Weissinger, Elisabeth Schnoy, Klaus Becker, Gertraud Stocker, Josef Ruschoff, Andreas Eisenmenger, Irini Karapanagiotou-Schenkel, Florian Lordick
Journal: Journal of Clinical Oncology (2015)

112 Background: HER2 amplification is present in a subgroup of gastroesophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-EGFR and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. Methods: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1-21 plus capecitabine (CAP) 2000mg/m² on days 1-14 of a 21-day cycle or LAP 1500 mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary endpoint was the objective response rate (ORR) as assessed by the investigator using RECIST 1.1 criteria. We aimed to include 38 pts per arm to show a response rate of &gt;20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines, however, the treatment was intended to be tested as a second-line treatment. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP+CAP group. Other secondary efficacy endpoints (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhea were higher with LAP+CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] vs. 17 [90%]). Conclusions: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. Clinical trial information: NCT01145404.
Phase I study of clofarabine and liposomal daunorubicin in childhood acute myeloid leukemia.
Authors: P. Kearns, N. J. Graham, M. Cummins, B. Gibson, J. D. Grainger, R. Keenan, D. Lancaster, G. Shenton, J. Vormoor, D. Webb, I. Hawley, P. J. Johnson
Journal: Journal of Clinical Oncology (2011)

9521 Background: This phase I study evaluated the tolerability of clofarabine with liposomal daunorubicin in childhood refractory/relapsed AML. Clofarabine is a purine nucleoside analogue, approved by EMA and FDA in relapsed/refractory childhood ALL but its application in childhood AML is unproven. AML17, the UK front line study for AML is investigating the efficacy of daunorubicin with clofarabine vs a standard chemotherapy block for a high-risk subgroup. Patients under 16 yrs are excluded, as safety data and a recommended dose for a clofarabine/anthracycline combination are not available. The primary objective is to establish the MTD of clofarabine combined with liposomal daunorubicin. Liposomal daunorubicin is used to minimize potential cardiotoxicity in eligible patients with previous exposure to significant doses of anthracyclines. The study characterizes the safety and tolerability of the combination and the overall response rate and the number of patients that subsequently undergo stem cell transplant (SCT). Eligibility criteria include; AML relapse within 12 mths of initial diagnosis,AML refractory to induction therapy or 2nd/subsequent relapse, Age; 6 mths to <18 yrs. previous daunorubicin/ equivalent exposure < 450mg/m2. Patients with extramedullary leukemia and CNS involvement were excluded. Methods: Using a standard 3+3 dose escalation design, patients recieved iv clofarabine days 1-5, and iv liposomal daunorubicin 60mg/m2 days 1,3 and 5. The starting dose of clofarabine was 30mg/m2 escalating to 40mg/m2. The primary endpoint was the appearance of dose limiting (DLTs) and defining the MTD. Results: 9 patients were recruited. The most common SAE was neutropenic fever. No DLTs were observed. 3/9 patients had a complete response and proceeded to SCT. The 40mg/m2 cohort is being extended to accrue more efficacy data. Conclusions: The combination of clofarabine with liposomal daunorubicin was well tolerated in heavily pre-treated pediatric AML patients. The MTD was not reached but promising responses were observed at both dose levels of clofarabine
First-line treatment of metastatic NSCLC (mNSCLC) patients without actionable mutations in U.S. community oncology clinical practice.
Authors: Caroline McKay, Ashwini Arunachalam, Thomas A. Burke, Xiting Cao, Amy P Abernethy, David Paul Carbone
Journal: Journal of Clinical Oncology (2016)

307 Background: Benchmarking high quality care requires defining optimally effective practice patterns. As first step, contemporary real-world practice must be detailed. The purpose of this study is to describe patient flow from diagnosis of mNSCLC to initiation of anti-cancer drug therapy in patients without known EGFR/ALK genomic tumor aberrations; the characteristics and first-line (1L) anti-cancer treatment of these patients, including induction and maintenance therapy. Methods: Retrospective database cohort study using data from an oncology EHR system, representing 17% of incident cancer cases from US community setting. Study population includes patients diagnosed with stage IV mNSCLC treated between 11/ 1/12 and 1/31/15 with follow-up to 7/31/15. Treatment patterns include regimen, number of doses, and time to regimen discontinuation. Data are analyzed descriptively, for overall cohort and by histology, with time to treatment discontinuation analyses using the Kaplan Meier method. Results: Of 4441 patients with mNSCLC, 88% had EGFR/ALK negative or unknown status. Of 79% who initiated 1L therapy, 69.5% (n = 2014) of patients (78.4% non-squamous, 21.7% squamous) were included. 55.1% were men; 89.8% were age 65+. 83.4% received induction therapy only; 16.6% received induction and maintenance therapy. 85% received a platinum combination as induction therapy; the majority either received a carboplatin doublet (53.5%) or carboplatin doublet in combination with targeted therapy (23.3%). 14.4% received a non-platinum based regimen. During induction therapy only, mean duration for the most common regimen category (platinum based combination) was 96.9 (IQR 43-129) for squamous and 79.45 (IQR 36-108) days for non-squamous patients. Of non-squamous patients who received induction followed by maintenance, mean duration of therapy was 103.9 (IQR 66-134) and 140.7 (IQR 45-208) days for induction and maintenance, respectively. Conclusions: Results describe treatment patterns in the US community 1L setting, prior to introduction of anti-PD1/PD-L1 inhibitors and new angiogenesis inhibitors. These form a starting point for benchmarking high quality care in mNSCLC.
A phase I/II trial of MM-121 in combination with erlotinib in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: L. V. Sequist, W. A. Harb, M. Modiano, D. M. Jackman, K. Wong, J. A. Engelman, R. Nering, M. Onsum, V. M. Moyo
Journal: Journal of Clinical Oncology (2011)

TPS215 Background: Although EGFR tyrosine kinase inhibitors (TKIs) are very effective at treating EGFR-addicted cancers, resistance almost invariably occurs. It has been suggested that tumor cells may become resistant to EGFR TKIs by upregulating survival signaling via ErbB3 dependent activation of the PI3K/AKT pathway. In NSCLC tumors that harbor wildtype EGFR, simultaneous inhibition of EGFR and ErbB3 produces an additive effect on tumor growth inhibition preclinically. MM-121 is a monoclonal antibody (MAb) to ErbB3 that has pre-clinical activity in NSCLC, particularly in cancers with ligand-dependent activation of ErbB3. The current study will evaluate three distinct groups of NSCLC pts when treated with MM-121 and erlotinib. Methods: The following 3 pt groups will be studied:(Group A) EGFR wild type, EGFR-TKI naïve pts, who have received at least 1 line of prior chemotherapy to assess whether MM-121 enhances intrinsic sensitivity of tumors to erlotinib; (Group B) EGFR mutated and EGFR TKI naïve to assess whether MM-121 delays or prevents acquired resistance or enhances intrinsic sensitivity to erlotinib; (Group C) EGFR mutated pts previously responding to single agent EGFR TKI but subsequently developing acquired resistance, to assess whether MM-121 can reverse acquired resistance. This is a phase I/II study, in which the phase I portion is evaluating safety at escalating doses of the combination, as well as varying dosing schedules of the combination. The primary endpoint in phase II is PFS in each group. Secondary endpoints include overall survival and objective response rates of the MM-121 + erlotinib combination. In addition, adverse event, pharmacokinetic and immunogenicity and biomarker profiles will be evaluated in all pts. The phase I portion is ongoing.
Factors affecting resection rate in patients undergoing neoadjuvant therapy for pancreatic cancer.
Authors: M. Khawandanah, R. Chimpiri, C. Kurkjian, T. S. Herman, O. M. Qubaiah, R. Postier, B. Ghabach, D. Thompson, S. Pant
Journal: Journal of Clinical Oncology (2011)

e14531 Background: Patients who derive benefit from neoadjuvant therapy in pancreatic cancer is unclear. A subset, borderline resectable (BR) has been defined in whom therapy may be of benefit. We evaluated factors affecting resection, in particular those patients deemed borderline resectable. Methods: This is a retrospective chart review of patients who received neoadjuvant therapy at the University of Oklahoma over a 5 year period. Pre-therapy scans were reviewed and classified as locally advanced (LA) or BR per the AHPRA/SSO/SSAT Consensus Conference. Unless otherwise speicified, p-values are exact calculations from Chi-square tests on the equality of two independent proportions. Results: Among 18 patients studied, 9 underwent surgery. Pathology was available for 8 patients. All underwent R0 (62%) or R1 (38%) resections. Amongst those with LA, 5/6 (83%) underwent surgery, compared with 4/12 (33%) with BR disease (p value Pearson chi-square=0.1312). Kaplan-Meier analysis estimated median survival at 24 months in those with LA and 19 months with BR disease (p from log rank test=0.3475). Seven of 12 (58%) of patients who received only chemotherapy underwent surgery, compared with 2 of 6 (33%) patients who received chemoradiation (exact p=0.6199). High baseline level of Ca19-9 (>100) was not predictive of resectability (exact p=1.0) in the 12 patients whose Ca19-9 expression was unaccompanied by high levels of total bilirubin (>1.4). Among these patients, mean Ca19-9 expression was nonsignificantly higher (exact p from Wilcoxon test=0.5417) among those with BR disease. Two of 7 (29%) patients ≥ 65 y/o underwent surgery, compared with 7 of 11 (64%) younger patients (exact p=0.3348). Outcome did not differ between patients who underwent surgery more than 90 days from start of therapy (8/14 or 57%) vs less than 90 days (1/4 or 25%; exact p=0.5765). Conclusions: A higher percentage of LA patients underwent resection than those with BR. This preliminary data underscores the importance of disease biology in this patient group and the need, in future multivariable analysis on more patients to adjust for factors like age, CA 19-9 levels and pathologic grade that may independently affect surgical candidacy and survival.
Pattern of CA19-9 response to neoadjuvant chemotherapy in locally advanced, borderline resectable pancreatic cancer to predict progression.
Authors: J Bart Rose, Alicia M Edwards, Adnan Alseidi, Thomas R Biehl, Bruce S. Lin, Vincent J. Picozzi, Flavio G. Rocha, Scott Helton
Journal: Journal of Clinical Oncology (2016)

321 Background: As neoadjuvant therapy of locally advanced, borderline resectable pancreatic cancer (BRPC) is becoming more widely utilized; better indicators of progression are needed to help guide therapeutic decisions. The aim of this study is to determine if CA19-9 response during treatment predicts disease progression. Methods: A retrospective review was performed on all patients with BRPC (by AHPBA/SSO consensus criteria) between 2008-2015 who received 24 weeks of neoadjuvant gemcitabine and docetaxel. Patients with medical comorbidities limiting treatment completion were excluded. Serum CA19-9 levels were checked at baseline and every 3 weeks while on therapy. A normal CA19-9 level was defined as &lt; 37.5 units/mL and levels with concomitant biliary obstruction were censored. CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. Results: Eighty patients were included with a mean of 11 CA19-9 levels checked per patient during treatment. Thirty-two (40%) progressed on treatment (18 local and 14 distant) and 48 (60%) were resected (79% R0). CA19-9 responses were categorized into 5 groups: 1) Always normal [n = 13]; 2) Increasing [n = 3]; 3) Slow decline [n = 7]; 4) Rapid decline with plateau [n = 41]: and 5)Rapid decline with late rise [n = 16]. Univariate logistic regression analysis found that a final CA19-9 decline &gt; 50% of baseline (OR 0.06, p = &lt;.0001), a normal final CA19-9 (OR 0.08, p = &lt;.0001), pattern group 1 (OR 0.16, p =.0001), and group 4 (OR 0.10, p =.0001) were predictive of non-progression. Baseline or maximum CA19-9 levels were not predictive of progression. All patients in group 2 progressed; none were resected. Patients in pattern group 5 that underwent resection had an increased risk of recurrence (HR 12.5, p =.0005). Median overall survival for groups 1-5 were 20.4, 9.3, 20.8, 31.4, and 16.4 months respectively. Conclusions: Patients with measurable CA19-9 levels who do not have rapid decline with sustained low or normal levels should be considered high risk for progression or recurrence and alternative treatment strategies should be entertained prior to curative resection.
Gemcitabine (G) and epirubicin (E) combination, in platinum-resistant or refractory advanced ovarian cancer (PROC) patients: Results of a multicentric phase II trial
Authors: V. Murgia, O. Caffo, R. Sorio, C. Griso, S. Scalone, A. Ferro, A. Caldara, E. Arisi, G. Lo Re, E. Galligioni
Journal: Journal of Clinical Oncology (2008)

5566 Background: Among several drugs presently used in the management of PROC pts, single agents G and E have shown a response rate ranging from 15 to 20%. The efficacy and toxicity of GE combination in PROC pts, has been evaluated in our group in a phase II study and is presented in this report. Methods: PROC pts (including peritoneal and tubaric cancers), resistant to a platinum- based regimen (in progression during treatment or recurred within 12 months after treatment), and no pretreated with anthracycline, with measurable disease, ECOG PS ≤ 2, age ≥18 and ≤ 75, were included in this study. Treatment consisted of G 1000 mg/sqm2 (days 1, 8) and E 60 mg/sqm (day 1) every 3 weeks for 3 courses, or for 6 if no progressive disease was documented. Responses and toxicities were assessed according to RECIST and NCIC criteria. Results: Between June 2002 and October 2007, a consecutive series of 50 pts, median age 60 yrs (38–74), median PS 0 (0–2), FIGO stage I-II: 4, III: 31, IV: 15 and with serous histology: 31, endometrioid: 2, unclassified: 10, other: 7, entered this study. All pts were pretreated wit 1–4 regimens ( median 1,5). The median platinum-free interval was 5 months (range 0–12). Among 48 evaluable pts (1 lost after the first course and 1 too early), 1 CR and 20 PR were observed, with an overall response rate of 43.75%. Moreover, 16 pts (33.3%) presented stable disease. The median PFS was 7 mos and the 1-year OS was 67.6%. Beside alopecia in all pts, major grade 3–4 toxicities consisted of: anemia 4%, neutropenia 56%, thrombocytopenia 6%, vomiting 4%, diarrhoea 2%, liver 8%, mucositis 6% alopecia. No life threatening events occurred. Conclusions: It appears from our experience, that the GE combination is active in these pretraeted pts, with a manageable toxicity profile No significant financial relationships to disclose.