tbuckley/cabot-search huggingface dataset:
Phase II study of lapatinib in combination with vinorelbine in patients with ErbB2-amplified recurrent or metastatic breast cancer.
Authors: P. Saip, Y. Eralp, M. Ozkan, H. Karaca, M. Benekli, B. Cetin, A. Isikdogan, M. Kucukoner, G. Basaran, F. Sen, O. Un, H. Onur
Journal: Journal of Clinical Oncology (2011)

e13079 Background: There is a need for new treatment options in ErbB2 amplified advanced breast cancer.Limited efficacy and safety data has been reported for a lapatinib (LAP) and vinorelbine (VNL) combination in this setting. This is a multicenter, phase II study of LAP in combination with VNL in women with ErbB2 positive metastatic or recurrent breast cancer who have received prior taxane and/or antracycline. Methods: Patients received 1250mg oral LAP continously once daily and VNL 25 mg/sqm IV in the first 6 pts, and 20 mg/sqm IV on D1 and D8 every 3 week after neutropenia was identified as a DLT. The primary endpoints of the study are response rate and toxicity. Secondary endpoints include progression free survival(PFS) and duration of response. 29 pts were planned and enrolled. RECISTis used for response and NCI-CTCAE is used for adverse events evaluation. We present here the combined results of both VNL doses (6 pts for 25 mg/m2 and 15 pts for 20 mg/m2). Median age of the pts was 60 years (range 33-75). Prior trastuzumab was used in 86% of the pts. Patients with brain metastases without symptoms were included. Results: Median number of prior chemotherapy regimens was 2 (range 1-4). Nineteen pts were evaluable for response. Median follow up was 28,5 weeks(range 7,5-80,5) and 13 patients progressed during this period. Five of 19 patients (26%; 95% CI 9,15-51,2) had partial response and 8 patients (42%; 95% CI 20,25-66,50) had stable disease. The median PFS was 20 weeks (95% CI (12,14-27,86). 21 pts and 120 cycles were evaluated for toxicity. Median number of treatment cycles was 4(range, 2-18 cycles). Grade 3-4 neutropenia without fever in 13 patients(62%), grade 3-4 leukopenia in 4 pts (19%), grade 3 anemia in 1 pt (5%), febrile neutropenia in 1 pt (5%). The most common non-hematologic grade 3 adverse events were adinamia in 3(14%), stomatitis and diarrhea in 2 (10%), insomnia, motor neuropathy, anorexia, abdominal pain, hepatotoxicity, constipation, infection and respiratory distress in1(5%) of the pts. Conclusions: The VNL and LAP combination at 1250mg LAP continously oral once daily and VNL 20 mg/sqm dose is a tolerable alternative for pts with ErbB2 + metastatic breast cancer.
Assessment of current practices among physicians and awareness and concern among patients for bone health in cancer.
Authors: D. Tripathy, J. W. Moul, B. G. Durie, B. D. Mautner
Journal: Journal of Clinical Oncology (2011)

e19617 Background: Little is known about physicians’ (MDs) and cancer patients' (pts) levels of awareness or concern about bone health or how/when MDs discuss bone health with at-risk patients. An online survey was conducted to explore these issues and evaluate knowledge levels and attitudes about bone metastases and cancer treatment-induced bone loss (CTIBL). Methods: MDs from the AMA master list recruited for the survey included urologists (n=113), medical oncologists (med oncs; n=204) and hematologist-oncologists (hem oncs; n=150). Breast (BC, n=212) and prostate (PC, n=186) cancer pts were recruited from Harris' Chronic Illness Panel; myeloma (MM, n=831) pts were recruited from members of the International Myeloma Foundation. Surveys lasted on average 10 minutes; MD, BC pt, and PC pt surveys were weighted to be representative of the populations of interest. Descriptive statistical analyses were used. Results: More nonmetastatic BC than PC pts are familiar with the term “bone metastases” (50% vs 35%) and concerned about CTIBL (39% vs 24%). Of those aware of CTIBL, 79% of BC pts and 55% of PC pts had discussed it with their MD. Both med oncs and urologists consider CTIBL a serious issue for PC pts (98% vs. 90%), but more med oncs believe that pts are concerned about CTIBL (71% vs 37%). For metastatic (M) PC, more med oncs than urologists believe they are responsible for pts' bone health (100% vs 75%), but 68% of MPC pts had not discussed bone mets treatment with their doctor; when discussed, 91% of discussions were initiated by the doctor, usually prior to initiating treatment. In MBC, 66% had not discussed bone mets treatment, and if discussed, initiated by the doctor in 88% of cases, again usually prior to treatment initiation. Most MM pts recognized common symptoms of bone disease, and most had experienced them (85%) and discussed treatment options with their MDs (77%). Among hem oncs, 98% discussed treatment of bone disease with MM pts. Conclusions: Hem oncs and MM pts are knowledgeable and concerned about bone health. Urologists and med oncs are also concerned about bone health but tend not to initiate discussion until an event occurs. Pt and MD awareness/concern and MD discussion are not always concordant in bone health.
Phase II trial of concurrent chemoradiotherapy consisting of two courses with S-1 and cisplatin for locally advanced esophageal cancer.
Authors: H. Iwase, M. Shimada, T. Tsuzuki, N. Ryuge, H. Goto
Journal: Journal of Clinical Oncology (2011)

4034 Background: S-1 is a novel oral fluoropyrimidine anticancer agent designed to enhance clinical efficacy, reduce gastrointestinal toxicity, and enhance the effectiveness of radiotherapy. We conducted a phase II study of concurrent chemoradiotherapy with S-1 and cisplatin in patients with locally advanced esophageal cancer. Methods: Chemoradiotherapy consisted of two courses. The first course consisted of 30 Gy of radiotherapy given over 3 weeks plus daily treatment with oral S-1 (80 mg/m2/day) for 2 weeks and a 24-h infusion of cisplatin (70 mg/m2) on day 8. The second course of chemoradiotherapy was administered after 2 weeks. S-1 was administered in powdered form with water. Responders received at least two 4-week courses of chemotherapy with S-1 and cisplatin. Results: A total of 102 patients were enrolled (median age, 66 years; M/F, 88/14; PS 0/1, 77/25). Twelve patients had stage II disease, 61 had stage III disease, and 29 had stage IVa disease. Ninety-seven patients (95%) completed two courses of chemoradiotherapy. The most prominent toxicity was myelosuppression. Grades 3 and 4 leukopenia occurred in 37 (36%) and 14 (14%) patients, respectively. Nonhematological toxicity was moderate: grade 2 nausea, pain, oral mucositis, and renal dysfunction occurred in 31%, 29%, 20%, and 14% of the patients, respectively. These side effects resolved after one course of chemoradiotherapy in all but 7 patients. In patients with stage II disease, complete response (CR) and response rates (RRs) were 92% and 100%, respectively. In patients with stage III disease, CR and RRs were 64% and 85%. In patients with stage IVa disease, CR and RRs were 24% and 66%. All patients with stage II disease survived.Median survival time in patients with stage III disease was 795 days (95% CI: 589-1,038 days), and in patients with stage IVa disease, it was 369 days (95%CI: 194-523 days). Conclusions: Chemoradiotherapy consisting of two courses of S-1 and cisplatin was very effective with mild toxicity. We believe that this regimen can be one baseline treatment for patients with locally advanced esophageal cancer. Further trials in larger cohorts of patients are expected to strengthen the outcomes of this study.
The prognostic significance of immunohistochemical (IHC) staining of the sentinal lymph node (SNL) in breast cancer patients.
Authors: S. P. Thomas, N. Sood, H. Wang, N. Williams, J. F. Graumlich
Journal: Journal of Clinical Oncology (2010)

e11104 Background: It is debatable whether immunohistochemical staining (IHC) of sentinal lymph nodes (SLN) which are negative by H&E (or touch print cytology) provide additional prognostic value. IHC staining adds additional costs. This study was designed to detect the significance of IHC staining on SLN in a community practice setting with respect to recurrence free survival. Methods: A retrospective observational study was conducted. Patients were identified from a computerized tumor registry database maintained at two large community hospital in Peoria, Illinois. Data was collected and coded by the investigators. Life table method was first used for data reduction and survival function estimation. Survival curve was calculated using Kaplan-Meier method. Log-Rank test was used to detect differences. Results: Records were available for 624 patients who underwent SLN biopsy between January 2000 and December 2003. 458 patients were identified as SLN negative. Of these, 14 patients had IHC staining on the SLN. Median follow-up time for all SLN negative patients was 68.76 months. Median age was 59.19 years. Of the patients who had IHC staining on SLN 12 were reported as negative and 2 as positive. The 6-year probability of being free of breast cancer recurrence was 97.9% for all SLN negative patients, and 100% for patients whose SLN were tested by IHC. There was no significant difference between patients who had IHC performed on the SLN and those who did not (p = 0.2; Log-Rank test).There were two recurrences in the IHC negative group and none in the IHC positive group. Conclusions: There was no significant difference between patients who had IHC performed on their SLN and those that did not, with respect to recurrence free survival. The incidence if IHC positivity is low in SLN that are negative by H&E. We will recommend that IHC testing not be performed in this situation at our center. No significant financial relationships to disclose.
Are regional funding decisions resticting pharmaceutical research and development in metastatic renal cell carcinoma (mRCC)?
Authors: Henry Jacob Conter
Journal: Journal of Clinical Oncology (2014)

506 Background: Targeted therapy has revolutionized the treatment of mRCC. However, cost has lead to variable regional approval and funding. Can such variation in funding of established drugs impede approval of newer agents? Methods: Regulatory agency decisions regarding axitinib, the most recently approved mRCC therapy in the U.S., were reviewed. Reports from the US Food and Drug administration (FDA), the European Medicines Agency (EMA), the pan-Canadian Oncology Drug Review (pCODR), UK's National Institute for Health and Care Excellence (NICE), and the Therapeutic Goods Administration (TGA) of Australia were included. Data abstracted included the date of report publication, basis for determination of clinical efficacy, determination of cost-effectiveness, theme of stakeholder submissions prior to and after the regulatory decision, final decision, and rational for approval/rejection. Results: At the time of analysis, all agency decisions had been finalized. All of the agencies based their assessment of clinical efficacy of primarily on the same phase III clinical trial: the AXIS trial, demonstrating a progression-free survival benefit of axitinib compared to sorafenib (6.7 versus 4.7 months, p&lt;0.001). Cost-effectiveness data was considered by NICE and pCODR, but not the FDA, the EMA, or the TGA. Axitinib was recommended received approval by the FDA, the EMA, and the TGA for use in patients with mRCC who have failed prior treatment with sunitinib or cytokines. pCODR recommended axitinib for funding in the 2 nd line setting only in patients unable to tolerate everolimus. And NICE recommended against the funding of axitinib. Both dissenting organizations cited concerns with the pivotal trial’s control arm, sorafenib, not representing their regional standards of care as primary reasons for restricted access and rejection. Cost considerations were also cited as factors in the rejections. Conclusions: Differing regulatory approvals and funding worldwide are creating regional standards of care that impeding the research, development, and approval of newer agents. Divergent standards of care before and after clinical trials may restrict their external validity and applicability.
Patterns of failure and morbidity associated with palliative intervention in patients with malignant biliary obstruction.
Authors: Matthew Ryan McFarlane, Anil Pillai, Matthew Porembka, Jeffrey John Meyer, Nisa Kubiliun, Michael Ryan Folkert
Journal: Journal of Clinical Oncology (2015)

71 Background: Outcome for patients with malignant biliary obstruction is poor. While endoscopic or percutaneous procedures provide palliative benefit, stents often occlude or migrate, and drains frequently fail requiring repeat procedures in medically fragile patients. As part of a multidisciplinary effort to improve outcomes in this population, we undertook an investigation to determine rates of stent and drain failure and morbidity to identify areas of potential improvement. Methods: After Institutional Review Board approval, retrospective review of all cancer registry patients undergoing percutaneous or endoscopic intervention for biliary obstruction from 1/2004-10/2014 and billing reports from 11/2012-10/2014 identified 230 patients. Cases of biliary obstruction due to malignancy requiring intervention were selected, resulting in 94 evaluable patients. Charts were reviewed to determine dates and cause for stent and/or drain replacement and morbidity. Results: Of 94 analyzable patients, median age was 60 years and 49 were male (52%). Malignant cause of obstruction was gastric/colorectal in 16 (17%), biliary in 37 (39%), hepatocellular in 7 (7%), and pancreatic in 34 (36%). Stenting was part of the initial procedure in 47 (50%), and drain placement in 49 (52%). Ultimately 60 (64%) patients underwent stent procedures and 82 (87%) patients required drains. Of the stented patients, 27 (45%) required repeat stenting, and 13 (22%) required &gt; 1 stent replacement. Of the patients who underwent drainage procedures, 68 (83%) required repeat drainage, and 52 (63%) required &gt; 1 repeat drainage procedure. Cholangitis was observed following stent in 5 (5%) of patients, 60% in patients undergoing &gt; 1 stent procedures. Median survival after initial procedure was 12 months; for patients requiring repeat procedures, median survival was 4.5 months. Conclusions: Malignant biliary obstruction is a morbid disease with high rates of reocclusion requiring repeat procedures, which may negatively impact outcome and increase healthcare cost. Efforts to reduce the rates of repeat procedures are critical to address this clinical need.
Integrating cancer-related employment assessments into oncology care.
Authors: Rebecca Nellis, Joanna Morales, Monica Bryant
Journal: Journal of Clinical Oncology (2016)

224 Background: This presentation will provide oncology healthcare professionals with information and tools to help navigate their patients through the employment-related legal and practical issues that arise after a cancer diagnosis. These issues include working though treatment and/or taking time off work for treatment and recovery, deciding whether or not to disclose their diagnosis, returning to the workplace, managing side effects on-the-job and maintaining income. The Institute of Medicine (IOM) has called on healthcare teams to address the whole patient and warned that failing to address employment and financial concerns may threaten a patient's health. Methods: Attendees will be given information about state and federal laws that may apply to patients in the workplace, including protections against discrimination and access to reasonable accommodations. Attendees will also learn about the different needs of individuals along the continuum of care. Results: Healthcare professionals can play a meaningful role in helping patients navigate these decisions around work. Cancer and Careers surveyed oncology professionals about their patients’ work-related issues and 77.56% said their patients are asking for guidance on working through treatment (2009-2015). Seventy-seven percent of oncology healthcare professionals surveyed by Triage Cancer said it was important to include employment issues in distress screening tools, but only 25% felt comfortable or very comfortable in answering patients’ questions about the Americans with Disabilities Act (ADA), a primary tool in assisting patients navigate work and cancer. Healthcare professionals surveyed after attending a similar event responded that (a) 99.5% would recommend a similar event to others; (b) 98% said the information received can be applied to their daily patient interactions; and (c) 97.1% rated the overall usefulness of information as good or excellent. Similar responses can be expected from attendees of this presentation. Conclusions: It is critical for oncology healthcare professionals to receive education in this area, because they are uniquely positioned to help patients navigate balancing cancer and work, provided they receive appropriate training and resources.
Phase II trial of sorafenib (S) and erlotinib (E) in unresectable pancreas cancer (UPC): Final results and correlative findings.
Authors: Dana Backlund Cardin, Laura Williams Goff, Emily Chan, Melanie Holloway, Pamela McClanahan, Yu Shyr, Chung-I Li, Krista Meyer, Julia Grigorieva, Jordan Berlin
Journal: Journal of Clinical Oncology (2013)

191 Background: The MAP kinase pathway plays a central role in PC pathogenesis. Blockade of this pathway at multiple levels using S and E is attractive mechanistically. S also targets VEGF receptors. Evidence suggests that dual blockade of both EGFR and VEGF pathways has potential for additive, if not synergistic, effects. This phase II trial was designed to evaluate the efficacy of the combination of S and E in patients (pts) with UPC. An exploratory correlative study analyzing pre-treatment serum samples using a proteomic mass-spectrometry test (VeriStrat), previously shown to correlate with outcomes in lung cancer pts treated with E or the combination of E and S, was performed to evaluate the possible clinical utility of the test in pts with UPC. Methods: Pts with UPC received S 400mg daily along with E 150mg daily as primarily second-line therapy (first-line was allowed). Primary endpoint was 8-week progression free survival (PFS) rate. Pre-treatment serum sample analysis by proteomic test was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups was assessed using log-rank p values; hazard ratios (HR) were obtained from Cox proportional hazards models. Results: Thirty-seven pts received study drugs and were included in the survival analysis. Eight-week PFS rate 0.47 (95% CI 0.32-0.67) did not meet the primary endpoint of a rate of ≥ 0.70. Thirty two pts were included in the correlative analysis. VeriStrat “Good” pts had superior PFS and OS compared to VeriStrat “Poor” pts (Table). Conclusions: This study did not meet the primary endpoint and this drug combination will not be further pursued. In this small retrospective analysis the proteomic classification was significantly associated with clinical outcomes (PFS and OS), meriting further evaluation. This will include a companion study to an ongoing phase I study evaluating gemcitabine, erlotinib and dasatinib in UPC (NCT01660971). Clinical trial information: NCT00837876. [Table: see text]
The effect of PARP inhibition on BAX/BAK independent synthetic lethality of BRCA1-deficient non-small cell lung cancer.
Authors: I. Paul, K. Savage, E. Lamers, K. Gately, K. J. O'Byrne, J. K. Blayney, K. M. Kerr, M. Sheaff, D. J. Richard, P. W. Hamilton, J. James, J. E. Quinn, D. A. Fennell
Journal: Journal of Clinical Oncology (2011)

e13519 Background: Evasion of apoptosis contributes to both tumorigenesis and drug resistance. The proapoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. In contrast, prosurvival BCL-2 family proteins eg. MCL-1 and BCLX are among the most frequently amplified in human cancers, consistent with negative regulation of this pathway. New strategies for targeting cancer in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. Mutation of BRCA1 confers a defect in homologous recombination mediated DNA repair that can be exploited by synthetic lethality through inhibition of PARP. It is not known whether BAX and BAK play an essential role in mediating synthetic lethality. Methods: The effect of BRCA1 loss on response to PARP inhibitor therapy in non small cell lung cancer was studied in vitro using clonigenic assays in a panel of NSCLC cells, cells where both BAX and BAK expression was silenced (rendering them mitochondrial apoptosis defective), and cisplatin resistant NSCLC cells. BRCA1 immunohistochemistry was performed on a total of 302 primary NSCLC tumours from two independent cohorts to determine the frequency of BRCA1 immunonegativity in the patient population. Results: We show that BRCA1 silencing enhances sensitivity to PARP inhibitor therapy in a panel of NSCLC cell lines and in cells defective for mitochondrial apoptosis. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance but can still sensitize to PARP inhibition in the platinum resistant setting. BRCA1 immunohistochemistry showed an immunodeficiency (<10% cells stained positive) rate of 11% and 19% in two independent cohorts. Conclusions: In summary, targeting BRCA1 negative NSCLC by PARP inhibitors results in bypass of mitochondrial apoptosis block and can override platinum resistance. The existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic.
Oral vinorelbine (NVBo) at 3-weekly flat-dose intakes (FDI) as single agent or with cisplatin (CDDP) concomitantly with thoracic radiotherapy (RT) in stage III NSCLC: Escalation-dose phase I trial results.
Authors: D. M. Kowalski, M. J. Krzakowski, K. Zajda, C. Lucas
Journal: Journal of Clinical Oncology (2011)

7045 Background: In vitro, vinorelbine (NVB) has shown to be a powerful radiosensitizer. Based on the bioavailability of NVBo, a dose-determination study was implemented in patients (pts) with untreated locally advanced or inoperable stage III NSCLC assessing continuous exposure to NVBo through 3 times a week (w) FDI during the RT period, either alone (1st part of the trial) or in combination with CDDP (2nd part). Methods: 3 pts with stage IIIAN2/IIIB NSCLC were expected at each dose-level (L) with 3 additional pts in case of a dose-limiting toxicity (DLT): age 18-70 years, adequate bone marrow, hepatic and renal function, KPS ≥80%. NVBo was given concomitantly with 60 Gy RT (2 Gy/day; 5 days/w) from 60 mg up to 180 mg total-dose/w splited on days (D) 1, 3 and 5 during 6 w. Based on the maximal tolerated dose (MTD) defined as 2 DLT in a L and the recommended dose (RD) of NVBo alone, the trial assessed its RD in combination with CDDP 80 mg/m2 D1 every 3 w (q3w) in a 2nd cohort. Results: In the 1st cohort, 21 men and 5 women were enrolled from 06/02 to 10/07: stages IIIA N2 (6 pts) or IIIB (20 pts), median age 60.6 years, median KPS 100%; no DLT occurred in the first 5 L. MTD was reached at L7 (160 mg/w) with 3 Grade (G) 3 oesophagitis and 1 G3 pneumonia as DLT out of 5 pts. In the RD level (L6, 150mg/w: 50mg D1, 3, 5), only 1/6 pts experienced a DLT: a febrile neutropenia (FN) with G4 thrombopenia and G3 fatigue. In the 2nd cohort (11/08-04/10), 11 additional pts received NVBo weekly total FDI from 130 mg to 150mg in combination with CDDP (3L). The NVBo doses of 130 and 140 mg/w were administered without reaching the MTD. Only 2 pts received 150 mg/w and the trial closed before MTD could be determined: 1 DLT as FN in 1 pt but no DLT in the later. The confirmed response rate (RR) was 42% and 55% in the 1st and 2nd cohort (all L), respectively. Conclusions: NVBo with this original schedule of 3 times a w intake concomitantly with RT for 6 w is well tolerated. The RD as single agent is 50 mg D1,3 and 5 (total dose of 150mg/w); combined with CDDP 80 mg/m2 q3w, the weekly NVBo RD should be 140-150 mg adapted on hematology. The RR is promising, warranting further development of this fractionated scheme.