tbuckley/cabot-search huggingface dataset:
Phase I/II study of everolimus (E) with irinotecan (Iri) and cetuximab (C) in 2nd line metastatic colorectal cancer (mCRC): Hoosier Cancer Research Network GI05-102.
Authors: E. Gabriela Chiorean, Joel Picus, Timothy Breen, Rafat H. Ansari, Wael A. Harb, Matthew Burns, Aaron John Spittler, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2015)

3618 Background: Preclinically, mTOR and EGFR inhibitors are synergistic. We hypothesized that the mTOR inhibitor E would enhance clinical efficacy when added to C. The Phase I portion determined the safety, and maximum tolerated dose (MTD), and the Phase II evaluated the response and survival rates with this combination. Preliminary results of the Phase I study (ASCO 2011, Shahda et al) determined the MTD as E 5 mg po daily (qd) combined with Iri and C. Here we report overall safety and efficacy results of the Phase I/II study. Methods: Patients (pts) were treated with Iri 125 mg/m2 weekly (qw) x 2 every 3 wks, C 400 mg/m2 loading, then 250 mg/m2 qw, and escalating doses of E: 5 mg qod, 5 mg qd and 10 mg qd in 21-day cycles (Phase I), and 5 mg qd (Phase II). Eligibility allowed KRAS mutated (MUT) mCRC. During phase II, KRAS wild-type (WT) pts were randomized to Iri+C+E vs Iri+C, and all KRAS MUT pts received Iri+C+E. Archival tumors were analyzed for biomarkers of EGFR and mTOR pathways activation. The study was discontinued early due to funding termination by Novartis. Results: 43 pts were enrolled, median age 60 y (25-77), 24 male. 30 pts enrolled in phase I (KRAS WT n = 15, KRAS MUT n = 13, KRAS unknown n = 2), and 13 pts in phase II (KRAS WT: n = 5 Iri+C+E, n = 2 Iri+C; KRAS MUT n = 6 Iri+C+E). The most common gr 3/4 AEs were diarrhea (35%), neutropenia (23%), fatigue (21%), mucositis (21%), and rash (19%). Among KRAS WT pts (n = 22) there were 1 CR, 3 PR (RR 18%), 12 SD (54%), and among KRAS MUT pts (n = 19) there were 1 PR (5%) and 11SD (52%). Median progression-free survival (PFS) and overall survival (OS) rates were 6 and 16 mos, respectively for all KRAS WT pts treated with Iri+C+E (n = 20), and 8.3 and 21.6 mos, respectively for KRAS WT pts treated at MTD (n = 11). Median PFS and OS were 4.3 and 12.3 mos, respectively for KRAS MUT pts. Only 2 KRAS WT pts were randomized to Iri+C before study closure. PD markers will be presented. Conclusions: The combination of Iri+C+E has an expected toxicity profile, and was clinically active as second-line treatment for KRAS WT mCRC pts. Further studies should assess the CRC pts most likely to benefit from mTOR inhibitors in addition to EGFR blockade. (NCT00522665) Clinical trial information: NCT00522665.
Secondary breast cancer (s-BC) after hematopoietic cell transplantation (HCT) for leukemia: Role of total body irradiation (TBI).
Authors: Can-Lan Sun, Jennifer Berano-Teh, Alicia Gonzales, Liezl Atencio, Tongjun Kang, Liton Francisco, Anthony Selwyn Stein, Margaret R. O'Donnell, David Snyder, George Somlo, Ravi Bhatia, Stephen J. Forman, Smita Bhatia
Journal: Journal of Clinical Oncology (2012)

1592 Background: s-BC after conventional chest radiation for histologically distinct cancer is well-recognized, and has resulted in radiologic screening recommendations by American Cancer Society. However, risk of s-BC after TBI is not well-defined. Methods: We determined the risk of s-BC in 648 consecutive females transplanted for leukemia (ALL [19%], AML/MDS [57%], CML [24%]) between 1976 and 2008 with a post-HCT survival of ≥2 years. The study was restricted to leukemia to understand the role of TBI without the influence of pre-HCT chest radiation. Near-complete ascertainment of s-BC was assured by combining institutional follow-up with California Cancer Registry data. Results: Median age at HCT was 38 years (range, 0-71); 14% had received autologous HCT, 64% related and 22% unrelated donor HCT; 70% had received TBI for myeloablative conditioning. After 5,675 person-years of observation, 16 patients developed s-BC (14 after TBI). Median latency from HCT to s-BC was 16y (2-27). Median age at s-BC was 50y (29-66). Cumulative incidence of s-BC was 6% at 20y after HCT, contributed to largely by TBI (s-BC incidence after TBI: 5.7%). Among TBI-exposed, 8.6% were projected to develop s-BC by age 65y (1.6% among non-TBI-exposed, p=0.03). TBI-exposed patients were 2.4 times more likely to develop s-BC compared with general population (p=0.001); non-TBI exposed were not at increased risk (SIR=0.9, p=0.9). Multivariate analysis (adjusted for age at HCT, follow-up and primary diagnosis) revealed a 4.7-fold (p=0.068) increased risk of s-BC among TBI-exposed. Conclusions: Risk of s-BC after TBI as the sole source of radiation to breast is increased. Nearly 9% of those exposed to TBI will develop s-BC by age 65y. Identification of vulnerable sub-populations among the TBI-exposed patients is underway to create targeted screening strategies for early detection of s-BC.
Risk stratification based on screening history: the NELSON lung cancer screening study
Authors: Uraujh Yousaf-Khan, Carlijn van der Aalst, Pim A de Jong, Marjolein Heuvelmans, Ernst Scholten, Joan Walter, Kristiaan Nackaerts, Harry Groen, Rozemarijn Vliegenthart, Kevin ten Haaf, Matthijs Oudkerk, Harry de Koning
Journal: Thorax (2017)

<h3>Background</h3> Debate about the optimal lung cancer screening strategy is ongoing. In this study, previous screening history of the Dutch-Belgian Lung Cancer Screening trial (NELSON) is investigated on if it predicts the screening outcome (test result and lung cancer risk) of the final screening round. <h3>Methods</h3> 15 792 participants were randomised (1:1) of which 7900 randomised into a screening group. CT screening took place at baseline, and after 1, 2 and 2.5 years. Initially, three screening outcomes were possible: negative, indeterminate or positive scan result. Probability for screening outcome in the fourth round was calculated for subgroups of participants. <h3>Results</h3> Based on results of the first three rounds, three subgroups were identified: (1) those with exclusively negative results (n=3856; 73.0%); (2) those with ≥1 indeterminate result, but never a positive result (n=1342; 25.5%); and (3) with ≥1 positive result (n=81; 1.5%). Group 1 had the highest probability for having a negative scan result in round 4 (97.2% vs 94.8% and 90.1%, respectively, p&lt;0.001), and the lowest risk for detecting lung cancer in round 4 (0.6% vs 1.6%, p=0.001). 'Smoked pack-years' and 'screening history' significantly predicted the fourth round test result. The third round results implied that the risk for detecting lung cancer (after an interval of 2.5 years) was 0.6% for those with negative results compared with 3.7% of those with indeterminate results. <h3>Conclusions</h3> Previous CT lung cancer screening results provides an opportunity for further risk stratifications of those who undergo lung cancer screening. <h3>Trial registration number</h3> Results, ISRCTN63545820.
Outcomes associated with sunitinib alternative schedule compared to traditional schedule: a single-center experience.
Authors: Bradley J. Atkinson, Sarathi Kalra, Xuemei Wang, Tharakeswara Bathala, John Perpich, Paul Gettys Corn, Nizar M. Tannir, Eric Jonasch
Journal: Journal of Clinical Oncology (2013)

e15611 Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 28 days (d) on/14 d off (traditional schedule; TS). Sunitinib is associated with several adverse events (AEs). An ideal treatment modification algorithm is not known. We sought to identify 1) common AEs, 2) alternative schedules (AS) that maintained dose intensity while decreasing AEs, and 3) the impact of AS on outcomes. Methods: Single-center retrospective review of mRCC pts performed from 1/26/06 to 3/1/11. Pts &gt; 18 years of age with mRCC who received first-line antiangiogenic therapy with sunitinib were eligible. A subset of pts were switched at first intolerable AE from TS to a 14 d/7 d, or further adjusted to 7 d /3 d, or other AS. Control group underwent standard dose reduction. Pt characteristics including demographics, disease status, laboratory data, AEs, AS, and treatment outcomes were analyzed. Results: 186 eligible pts were identified. At baseline, 87% received sunitinib 50 mg and 88% were on TS. 99 pts (53%) continued TS and 87 pts (47%) were switched to AS. Baseline characteristics were similar. Median age was 61 yrs; by MSKCC criteria 5% were good, 50% intermediate, and 45% poor prognosis. Pts had median 2 visceral mets and 42% had primary tumor in place. AEs included fatigue (47%), diarrhea (24%), and hand-foot syndrome (26%). Median time to AS was 126 d with 14 d/7 d the most common (82%). Median time on treatment was 14.9 months (mo) (95% CI:10.2 – 17.0 mo) in AS pts vs 4.2 mo (95% CI: 3.6 – 5.7 mo), respectively (p &lt; 0.0001). Median OS was 32.9 mo (95% CI:28.3-54.1 mo) vs 18.5 mo (95% CI: 10.3-21.5 mo), respectively (p = 0.0001). ECOG PS &gt; 2 (HR 3.9), elevated LDH (HR 2.04), and &gt; 2 mets (HR 1.79) were associated with decreased OS. MSKCC intermediate vs poor (HR 0.57) and AS (HR 0.54) were associated with improved OS by multivariate regression analysis (p &lt; 0.05). Conclusions: In our cohort study, AS sunitinib significantly prolonged time on treatment and was predictive of OS. Prospective investigations of alternate dosing schemas are warranted.
Health-related quality of life (HRQoL), treatment satisfaction, and work productivity for patients (Pts) with advanced renal cell carcinoma (aRCC) in a chart review across six countries.
Authors: Robert Hawkins, Justin Doan, Chinmay Deshpande, Caitlyn Solem, Shuo Yang, Shan Jiang, Cynthia Macahilig
Journal: Journal of Clinical Oncology (2017)

487 Background: The humanistic burden of aRCC is not well understood. We describe HRQoL, functional status, treatment satisfaction, and work productivity reported by pts treated with ≥2 lines of treatment (LOT) for aRCC in 6 countries. Methods: Retrospective, observational medical chart review of adults with stage IIIB/IV aRCC who completed the EuroQoL-5D-3L (EQ-5D), Functional Assessment of Cancer Therapy – General (FACT-G)/FACT-Kidney Symptom Index (FKSI-19), Cancer Therapy Satisfaction Questionnaire (CTSQ), and Work Productivity and Activity Impairment (WPAI) questionnaires. FACT-G scores were examined with regression analysis. Results: All measures were impacted by aRCC (Table). Dimensions affected: EQ-5D, pain/discomfort; FACT-G and FKSI-19, functional/emotional; CTSQ, feelings about side effects; WPAI, activity impairment. EQ-5D, FACT-G, FKSI-19 scores were higher (by minimal important difference) in France and Canada vs. other countries. FACT-G scores differed by region, and were higher in Canada and France vs. the USA. Female sex and 2 nd LOT were predictors of lower FACT-G score. Conclusions: This study showed a high humanistic burden on aRCC pts across countries. New treatments with reduced side effects and improved effectiveness can help yield improvements in HRQoL, treatment satisfaction, and work productivity. [Table: see text]
Population pharmacokinetics (popPK) to evaluate the effect of intrinsic and extrinsic factors on regorafenib (REG) exposure in REG studies including patients with hepatocellular carcinoma (HCC).
Authors: Bart Ploeger, Adriaan Cleton, Anne Keunecke, Jordi Bruix, Gerold Meinhardt
Journal: Journal of Clinical Oncology (2017)

320 Background: REG is approved for refractory metastatic colorectal cancer (CRC) and gastrointestinal stromal tumors (GIST). In the phase 3 RESORCE trial (N = 573), REG (160 mg QD, 3 weeks on/1 week off) significantly (P &lt; 0.001) improved overall survival (OS) vs placebo in HCC patients who progressed on sorafenib (HR 0.63; 95% CI 0.50‒0.79). We evaluated REG PK in RESORCE using a popPK model and the influence of intrinsic and extrinsic factors (covariates) on REG PK. Methods: The average concentrations of REG and its pharmacologically active metabolites (M-2, M-5) were estimated based on sparse PK sampling in cycles 1–2. A covariate analysis was conducted using exposure and covariate data in 16 clinical REG trials in CRC, GIST, and HCC (1337 subjects) using a graphical and generalized additive modeling (GAM) approach. Results: eGFR, total plasma protein, hematocrit, total bilirubin, AST, ALP, and Asians vs non-Asians did not significantly (p &gt; 0.05) influence exposure, whereas covariates significantly (p &lt; 0.05) influencing exposure in 16 studies including RESORCE were: being a healthy volunteer vs a patient, sex, age, hemoglobin at baseline, plasma albumin at baseline, BMI, and body weight. The identified covariate effects were considered small compared with observed overall variability in exposure. Visual comparison of the exposure estimates in RESORCE showed these were comparable to those in phase 3 studies in CRC and GIST. Exposure in Asians was comparable to that in the rest of the world (ROW) and there was no apparent difference in exposure between Japanese, Chinese, and ROW and between patients with mild/moderate hepatic impairment vs normal hepatic function. Only small numerical differences in exposure across different age categories were observed, with a tendency towards higher exposure in patients ≥ 65 years of age. Conclusions: The RESORCE data confirm previous observations that the identified covariates that significantly (P &lt; 0.05) correlated with exposure only describe a small fraction ( &lt; 10%) of the overall variability in exposure and, thus, are not expected to have a clinically relevant impact on REG exposure. Clinical trial information: NCT01774344.
Development of a PD-L1 immunohistochemistry (IHC) assay for use as a companion diagnostic for pembrolizumab (MK-3475) in non-small cell lung cancer (NSCLC).
Authors: Marisa Dolled-Filhart, Charlotte M. Roach, Grant Toland, Jeanette Musser, Gregory M. Lubiniecki, Gary Ponto, Kenneth Emancipator
Journal: Journal of Clinical Oncology (2015)

11065 Background: Tumors express PD-L1 to contribute to escape from immunosurveillance. We developed a PD-L1 IHC assay to investigate whether it could predict response to pembro in NSCLC patients (pts) and be used as a companion diagnostic. Methods: The assay uses the 22C3 anti–PD-L1 murine monoclonal antibody on the Dako platform. One pathologist scored each tumor sample by 4 methods: percentage of cells staining at any intensity (PS1), percentage of cells staining at moderate/strong intensity (PS2), percentage of cells staining at strong intensity (PS3), and H-score (HS = PS1 + PS2 + PS3). Only cells with at least partial membrane staining were counted. Receiver operating characteristic analysis was used to compare scoring methods and determine a cutoff using data from 146 NSCLC pts treated with pembro in KEYNOTE-001 who had tumor evaluable for PD-L1 expression by IHC and data for response (immune-related response criteria, investigator review). Samples from the first 31 pts were also tested with a prototype assay by a different pathologist who scored the presence or absence of a regional, primarily inflammatory cell or “interface” pattern in addition to the above. PFS and OS were assessed in the 146 pts with measurable disease (RECIST 1.1, central review). Results: The various scoring methods are summarized in the table. Incorporating the interface pattern did not improve scoring. Using PS1, 19 (43%) of 44 pts with ≥ 50% tumor cell staining responded, versus only 8 (8%) of 102 pts with < 50% tumor cell staining (odds ratio = 8.93). Median PFS and OS were 4.0 mo and not yet reached, respectively, for pts with ≥ 50% staining and 2.1 and 6.1 mo, respectively, for pts with < 50% cell staining. Conclusions: The PD-L1 IHC assay is potentially useful to enrich trial populations and as a companion diagnostic in NSCLC. While all 4 scoring methods assessed performed similarly, the percentage of cells staining at any intensity with a cutoff of 50% is the simplest and easiest method to implement in practice. Clinical trial information: NCT01295827. Area Under Curve Youden Index Cutoff False Positive Rate, % True Positive Rate, % PS1 0.743 0.494 50 21.0 70.4 PS2 0.758 0.462 11 16.8 63.0 PS3 0.736 0.445 1 18.5 63.0 HS 0.758 0.502 63 20.2 70.4
Clinical impact of disseminated tumor cells in patients with non-metastatic prostate cancer treated by definitive radiotherapy
Authors: A. Berg, A. Berner, W. Lilleby, Ø. S. Bruland, S. D. Fosså, J. Nesland, G. Kvalheim
Journal: Journal of Clinical Oncology (2006)

4575 Background: Detection of disseminated tumor cells (DTCs) in bone marrow (BM) has been proven to be an independent prognostic factor in breast cancer. To our knowledge, we here present the first larger study of radically treated prostate cancer (PC) with sufficiently long-term follow-up where the association between DTCs at diagnosis and clinical outcome has been studied. Methods: We screened 272 cT 1–4 pN 0 M 0 PC patients for DTCs in BM-aspirates between 1994 and 2004. Monoclonal antibodies against cytokeratins (AE1/AE3) and standardized immunocytochemical methods were applied for detection. BM-status was compared with clinical and histopathological factors at diagnosis in all patients and with long-term clinical outcome in 131 patients. They all started treatment including definitive radiotherapy (RT) before June, 2000 and had a relatively poor prognosis defined as cT 3–4 or Gleason score (GS) ≥ 7B (4 + 3) or PSA ≥ 10 μg/l. Kaplan-Meier plots were generated by BM-status with the following end-points: Overall death, cause-specific death, distant metastases (DM) as first clinical relapse, local failure as first clinical relapse and biochemical failure. Results: DTCs were detected in 18% of the patients and were significantly associated with increasing percentage Gleason grade 4/5 (p = .035, Mann-Whitney) but not with dichotomized GS, tumor-stage or PSA. In the follow-up cohort (median observation time 6.9 years), the 7-year cumulative risk of DM was 21% in BM-positive patients vs. 6% in BM-negative patients (p = .069, log rank). No association was found between DTCs and other end-points. A sub-group analysis of 73 patients with GS ≥ 7B yielded a 34% 7-year cumulative risk of DM in BM-positive patients vs. 10% in BM-negative patients (p = .039, log rank). DTCs did not predict DM in 55 patients with GS ≤ 7A (3 + 4). In a multivariate analysis, dichotomized GS (RR = 7.8 [95% confidence interval (CI) = 1.0–60.7], p = .049) and BM-status (RR = 3.0 [95% CI = .9–9.4], p = .066) had independent impact on DM. Conclusions: The presence of DTCs in BM at diagnosis of non-metastatic PC is associated with the histological differentiation of the primary tumor and seems to predict development of DM after definitive RT. No significant financial relationships to disclose.
A salvage treatment with combination of docetaxel and epirubicin in patients with recurrent or metastatic gastric cancer after fluoropyrimidine failure.
Authors: Jun Ho Yi, Su Jin Heo, Choong-kun Lee, Minkyu Jung, Hyo Song Kim, Hyun Cheol Chung, Sun Young Rha
Journal: Journal of Clinical Oncology (2014)

e15081 Background: For patients with recurrent or metastatic gastric cancer (GC), second-line chemotherapy is considered as standard in practice with various regimens. While docetaxel and epirubicin are one of the most commonly used agents in GC, the feasibility of the combination has not been evaluated. Methods: In this phase II trial, patients with recurrent or metastatic GC who had failed to fluoropyrimidine-based chemotherapy were recruited. Docetaxel (50 mg/m2) and epirubicin (50 mg/m2) were administered every 3 weeks. The primary end-point was disease control rate (DCR) and the secondary end-points were OS, PFS and toxicities. As there is a notion that anthracycline is effective in HER2-positive breast cancer, we also analyzed the efficacy according to HER2 status in GC patients. Results: From Sep 2012 to Oct 2013, a total of 22 patients were enrolled. The median age was 51 (range 33-70) and M:F ratio was 15:7. Five patients were HER2 positive and they all had progressed after anti-HER2 treatment. Out of 22 patients, 16 patients were evaluable for efficacy at 14 weeks after the treatment because of early drop-out from hematologic toxicity (N=5) and poor performance status (N=1). There were no PRs while 3 patients showed SD and 5 patients showed Non-PR/non-PD, resulted in DCR of 50.0%. The median PFS was 16.0 weeks (95% CI 5.6-26.4) and median OS was 29.7 weeks (95% CI 24.0-35.4). Although HER2-positive patients demonstrated prolonged PFS, 16.0 weeks vs11.3 weeks, none of the clinical variables showed statistically significant improvement, probably due to small number of patients. Grade 3-4 toxicities including neutropenia (72.7%), febrile neutropenia (13.6%), anemia (4.5%), and fatigue (4.5%) resulted in that 16 patients (72.7%) had experienced either dose reduction or delay of cycles. Conclusions: Although the combination of docetaxel and epirubicin as second-line treatment in advanced GC showed modest clinical efficacy, the hematologic toxicities caused patients’ intolerance, so that proper patient selection and close monitoring will be important. Whether HER2 positivity may affect the response to anthracycline in GC needs further investigation.
Use of intravaginal 17-β estradiol to improve sexual function and menopausal symptoms in postmenopausal women with breast cancer on aromatase inhibitors.
Authors: Shari Beth Goldfarb, Maura N. Dickler, Ann M. Dnistrian, Sujata Patil, Lara Dunn, Kaity Chang, Alyssa Peri Berkowitz, Noah Tucker, Jeanne Carter, Richard R. Barakat, Clifford Hudis, Mercedes Castiel
Journal: Journal of Clinical Oncology (2013)

9610 Background: The majority of women with early stage breast cancer (BC) will become long-term survivors, living with the sequelae of treatment. Attention to symptoms and quality of life (QoL) are therefore of increasing importance both during treatment and survivorship. Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone-receptor positive (HR+) BC and can lead to profound urogenital atrophy. Atrophic vaginitis in BC survivors is prevalent, its management is complex and it negatively impacts QoL. Methods: A prospective longitudinal IRB-approved study was performed at MSKCC in26 postmenopausal women with stage I-III HR+ BC on adjuvant letrozole or anastrozole for at least 3 months and had urogenital atrophy. All women were initiated on 10µg intravaginal 17-β estradiol. Patients completed the Female Sexual Function Index (FSFI) and Menopausal Symptom Checklist (MSCL) at baseline and wks 12 &amp; 24. Increase in FSFI score means better sexual function and a decrease in MSCL score means improved symptoms. We used the Wilcoxon Signed Rank Sum test to compare QoL measures at baseline to wks 12 and 24. The primary endpoint was change in systemic estradiol level from baseline to wk 12. Serial estradiol/FSH levels were measured at baseline and wks 2, 7, 12, 18 &amp; 24; we used a highly sensitive estradiol radioimmunoassay, ESTR-US-CT, from Cisbio US, Inc. Herein we report the results from the QoL secondary endpoints. Results: During treatment with intravaginal 17-β estradiol 10mcg, improvement in sexual function as measured by the FSFI was seen from a median of 12.4 at baseline to 21.2 at wk 12 (p=.0091) and 21.8 at wk 24 (p=.0271). Improvement was seen from baseline to wk 12 in lubrication (p=.0091), desire (p=.0303), satisfaction (p=.0331) and pain (p=.0005) and from baseline to wk 24 in lubrication (p=.0210), desire (p=.0309) and orgasm (p=.0369). A reduction in menopausal symptoms was also seen from 30.0 at baseline to 23.6 at wk 12 (p=.01) and 22.5 at wk 24 (p=.003). Conclusions: Intravaginal 10μg 17-β estradiol provided relief from menopausal symptoms and improvement in sexual dysfunction in the domains of lubrication, desire, satisfaction, orgasm, and pain.