tbuckley/cabot-search huggingface dataset:
Gonadal function in male patients with metastatic renal cell cancer treated with sunitinib: Effects of testosterone replacement on quality of life.
Authors: Alberto Dalla Volta, Francesca Valcamonico, Carlo Cappelli, Andrea Delbarba, Vittorio D. Ferrari, Giuseppina Arcangeli, Giovanni Rangoni, Maurizio Castellano, Alfredo Berruti
Journal: Journal of Clinical Oncology (2016)

525 Background: Sunitinib (S) is a standard first line treatment of metastatic renal cell carcinoma (mRCC). Asthenia and fatigue are the most prevalent toxicities but the relevant causes are not fully elucidated. Since endocrine glands are highly vascularized, the potent antiangiogenic effect of S can potentially impair their function. With the exception of hypothyroidism, the endocrine-related side-effects of S have not been extensively explored. Methods: We performed a cross-sectional study in which pituitary, thyroid, parathyroid, adrenal and gonadal functions were assessed in 25 mRCC patients who received 9 months of S therapy. Since a high prevalence of hypogonadism was observed, we subsequently enrolled 16 mRCC male patients in a prospective cohort study in which serum testosterone (T) serum free T, serum FSH and LH were evaluated at baseline and after 6 weeks (1 cycle) of S therapy. In patients eligible for testosterone replacement after andrologic evaluation, a FACT-G questionnaire for quality of life (QoL) assessment was prospectively administered at baseline and after 3 months. Results: In the cross sectional study 15/22 S treated male patients (68%) had serum T below the normal range and 13 of them (87%) presented with low/normal levels of LH. In the prospective study mean T levels (95% CI) were 5.04 ng/ml (3.4 - 6.7) at baseline and 4.1 ng/ml (3 - 5.3) after 6 weeks (p 0.05). The corresponding free T were 91.4 pg/ml (66 – 116.8) and 80.2 pg/ml (65 – 95.3) (p 0.24), respectively. Hypogonadism was observed in 5 (31%) patients at baseline and 10 (63%) patients after 6 weeks of S therapy. In the 5 patients becoming hypogonadic after S therapy, LH was 11.4 mU/ml (3.2 - 19.5) at baseline and 11.5 mUI/ml (0 – 23.5) after 6 weeks. Four patients were addressed to testosterone replacement. QoL significantly improved in 3 of them, with the strongest advantage in the physical comfort area. Conclusions: S therapy induces hypogonadism in a high proportion of male patients with mRCC. Low or inappropriately normal LH levels are consistent with a pituitary origin of the endocrine disorder. Testosterone replacement may improve the QoL and treatment tolerance.
FOLFIRI followed by radiochemotherapy and surgery in locally advanced gastric cancer: FFCD 0308 phase II trial.
Authors: P. Michel, G. Breysacher, F. Desseigne, L. Dahan, C. Petorin, D. Moussata, J. Grenier, S. Nguyen, F. Viret, N. Carrere, C. Mariette, C. Garnier Tixidre, K. Bouhier Leporrier, M. Galais, F. Fein, I. Iwanicki- Caron, E. Maillard, B. Dousset, F. Mornex, L. Bedenne
Journal: Journal of Clinical Oncology (2011)

4108 Background: In locally advanced gastric cancer, perioperative chemotherapy (CT) is often recommended. The chemoradiotherapy (CTRT) interest is supported by the high risk of regional recurrence. The aim of this trial was to assess the feasibility of complete treatment (CT+CTRT+surgery) with a CT regimen efficient and well tolerated in metastatic phase. Methods: Histologically proven gastric carcinoma, with T3 and or N+, M0 according to CTscan or endoscopic ultrasound, WHO status ≤ 1 and allowing major surgery were eligible in this phase II multicenter study. The treatment consisted of 4 courses of FOLFIRI followed by concomitant CTRT (45 Gy at 1.8 Gy per fraction in 5 weeks, 5FU 200 mg/mg2 days 1 to 5 each week of radiotherapy), followed by surgical resection with partial or total gastrectomy according to the localization of the tumor 30 days after, with D1 or D2 lymphadenectomy. A complete treatment was defined by full CT courses, at least 22.5 fractions of RT (90% fractions) and 75% of the 5FU dose, followed by at least surgical exploration. A feasibility rate of 70% was considered uninteresting, 88% being expected. A Fleming two stages design required more than 34 complete treatments in 42 pts to assert the treatment feasibilty (unilateral alpha 5%, power 83%). Analyses were performed in intent to treat. Results: The 42 pts were included between September 2007 and January 2010 in 16 centers, with a mean age of 60.5 yrs (30-78), serum albumin 38.9 g/l (18-52), 59.5% with performance status 0. All courses of FOLFIRI, 90% RT and 75% of FU during CTRT, and surgery were performed in 39, 34 and 35 pts respectively. Complete treatment was performed in 31/42 pts (73.8%, 95% CI : 60.5-87.1), 28 pts had a R0 resection (80.0%), and 17 pts (40.5%) had at least one severe advserse event (grade 3-4). During FOLFIRI and CTRT, at least one severe adverse event (grade 3-4), was reported in 11 (26.2% , 95% CI: 13.9-42.0) and 8 pts (19.0% 95%CI: 8.6-34.1%) respectively. The post-operative death rate was 5.71%. Conclusions: The feasibility of the therapeutic sequence FOLFIRI–radiotherapy with 5FU-surgery is not significantly higher than 70%. According to the study design, this association would not be recommended.
Correlation of pre-treatment serum levels of Magic Roundabout protein with overall survival in patients with advanced non-small cell lung cancer (NSCLC)
Authors: M. Görn, M. Anige, I. Burkholder, A. Scheffler, L. Edler, I. Boeters, J. Panse, G. Schuch, D. K. Hossfeld, C. Bokemeyer, E. Laack
Journal: Journal of Clinical Oncology (2005)

7199 Background: Magic Roundabout (MR; ROBO 4) is a recently discovered gene which encodes for a protein that possess structural homology with the roundabout family of proteins. Genes of the roundabout family code for neuronal specific cell surface receptors that are involved in axon guidance. MR in contrast showed endothelial specificity in vitro and in vivo using immunohistochemistry and in situ hybridisation. The putative role of MR as an endothelial analogue of Roundabout in angiogenesis makes it a potentially attractive target for antiangiogenic cancer therapy. Patients and Methods: 20 ml venous blood was taken before chemotherapy from 193 non-fasting patients with NSCLC. These patients comprised a non-selected subset of 300 patients who were treated in a randomised phase III trial comparing gemcitabine plus vinorelbine (GV) versus gemcitabine plus vinorelbine plus cisplatin (GVP). Patients with cytologically or histologically confirmed NSCLC stage IIIB disease with malignant pleural effusion or stage IV disease were enrolled. Using specific antibodies against MR peptides we screened the pre-treatment sera of these patients for MR-protein levels. Results: The log rank test showed no statistically significant difference between both chemotherapy treatment arms (JCO, 2004) in overall survival (P = 0.79). Equally, no significant difference in overall survival could be attributed to gender (P = 0.54), stage (P = 0.92), histologic subtype (P = 0.28) or histologic grade (P = 0.87). However, patients with pre-treatment serum levels of MR-protein lower than median (E450nm =0.652) had a median overall survival of 41.0 weeks whereas those with a higher serum level had a considerably shorter median survival of 32.4 weeks. This difference in overall survival was of borderline significance (P = 0.05) in the log rank test. Conclusions: This is the first study to present clinical data that link MR serum levels with outcome in patients with NSCLC. Whether the correlation of pre-treatment serum levels of MR and survival can be attributed to MR dependent angiogenesis remains to be investigated. No significant financial relationships to disclose.
A phase I dose escalation study of Ad GV.EGR.TNF.11D (TNFerade) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer (HNC)
Authors: E. E. Vokes, T. Y. Seiwert, E. Blair, E. E. Cohen, J. Salama, V. M. Villaflor, M. Witt, M. Kovacevic, K. Stenson, D. Haraf
Journal: Journal of Clinical Oncology (2008)

6067 Background: The prognosis for patients with locoregionally recurrent HNC remains poor. Re-irradiation with concomitant chemotherapy has demonstrated long-term tumor control rates of 20–30%, but a high percentage of pts recur within the irradiated field. Ad GV.EGR.TNF.11D is a second generation replication defective adenoviral vector that carries a human TNF-α gene linked to a chemotherapy and/or radiation inducible promoter [EGR-1]. TNF is a known radiation sensitizer; however, its systemic administration is associated with severe toxicities. Therefore, local administration of Ad GV.EGR.TNF.11D followed by chemoradiation should result in induction of regional TNF-α production and subsequent radiation enhancement without associated systemic side effects. Methods: In a phase I cohort dose escalation trial, eligible pts have locoregionally recurrent, previously radiated HNC and performance status 0–2. The dominant tumor site must be injectable. Patients receive 5 days of daily radiation at 200 cGy/fx with continuous infusion fluorouracil at 600 mg/m2/day x 5 and hydroxyurea at 500mg bid (FHX). Ad GV.EGR.TNF.11D is administered in escalating doses ranging from 4x109 to 4x1011 PU on day 2 of each cycle by direct intramural injection. 3 to 6 pts are entered on each cohort. Treatment cycles are repeated every other week. Results: 10 pts have been entered on three dose levels. Median age is 63 yrs (36–71); PS O: 2 pts; PS I: 6 pts; PS 2: 2 pts, prior surgery: 7 pts. Prior radiation: 60 to 75, Gy; 8 pts had received prior chemotherapy. Dose level 1 was expanded to 6 pts following observation of possibly related dose-limiting toxicity (carotid blow-out) in 1 pt. No subsequent dose- limiting toxicity was observed, and pts are currently entered on dose level 3. Overall, toxicities have consisted of grade III mucositis [8 pts] grade 2 or 3, dermatitis [5 and 4 pts], and are not suggestive of an interaction between Ad GV.EGR.TNF.11D and FHX. Following definition of the maximum tolerated dose level the dose of radiation will be escalated to 150 cGy/dx BID. Conclusions: Ad GV.EGR.TNF.11D can be added to concomitant FHX-based chemoradiotherapy. Updated toxicity and early efficacy data will be presented. No significant financial relationships to disclose.
ALK, MET, and HER2 in esophageal adenocarcinoma with signet ring cell morphology.
Authors: Catherine Elizabeth Moore, Benjamin Darbro, Daniel James Berg, Gerald H. Clamon, Ryan W. Askeland, Taher Abu Hejleh
Journal: Journal of Clinical Oncology (2014)

138 Background: Signet cell morphology (SCM) is seen in various cancers. In Non-Small Cell Lung Cancer (NSCLC), SCM is associated with ALK gene rearrangements and MET amplification. Crizotinib is an ALK/MET inhibitor that showed dramatic responses in ALK rearranged NSCLC. In this study, we explored ALK rearrangements as well as MET and HER-2 amplification in esophageal carcinoma with SCM. Methods: We reviewed the medical records for 9 patients (pts) seen at the University of Iowa with a diagnosis of esophageal adenocarcinoma and SCM. Clinical characteristics were abstracted. The tumors were tested for ALK rearrangement by fluorescence in situ hybridization (FISH) using the ALK break-apart probe set (Abbott Vysis) and for MET amplification utilizing a MET/CEP7 FISH-probe combination. Both rearrangements and copy number of ALK were assessed as was amplification of MET relative to the centromere signal of chromosome 7. HER-2 was tested by immunohistochemistry (IHC) utilizing the FDA approved DAKO Hercept Test per the ToGA trial methods. Results: Average age at diagnosis was 60 years (43-82). Five pts were males. Neoadjuvant treatment was delivered in 5 of 9 pts. Esophagectomy was done in 7 of 9 pts. Median survival time was 5.8 months (range, 2.4 to 24 months). Histology was consistent with adenocarcinoma in all specimens. No ALK rearrangements were detected. One case had 4-15 extra copies of ALK in 58% of the nuclei. In that same case, there was a relative gain of MET compared to CEP7 (ratio MET/CEP7 = 1.88). Regarding HER-2, 7 of 9 pts were negative (&lt;2+), 1 was equivocal (2+), and one was not done due to lack of tissue. The patient with high copy gain of ALK and a relative copy number increase of MET was treated with Crizotinib on compassionate use basis for 3 weeks after which the treatment was discontinued due to significant progression clinically and radiographically. Conclusions: SCM in esophageal adenocarcinoma was not associated with ALK rearrangements, or increased frequency of MET or HER-2 amplification. Overall, the results were most consistent with copy number variable status of ALK and MET as a result of chromosomal aneuploidy as opposed to locus specific rearrangement or amplification and did not result in significant response to Crizotinib.
Improving quality of early breast cancer care with a predictive test for taxane response.
Authors: Carolyn Bodnar, Ruth Brown, Kevin B. Knopf
Journal: Journal of Clinical Oncology (2012)

146 Background: Patients (pts) with high-risk early breast cancer (BC) frequently have adjuvant taxane (TAX) treatment, but only 22% experience benefits in disease-free survival and many experience toxicities which impact quality of life (QoL) and increase costs. Research is underway to develop biomarkers which predict TAX response and hence identify pts who will benefit from the regimen and pts who will not, avoiding futile treatment and associated toxicities. Methods: A predictive economic model estimated the potential avoided toxicities and related costs of testing 100 BC pts with a biomarker to guide therapy selection compared to no pretesting. The no biomarker test group all received AC-T (AC-T) (doxorubicin 60mg/m 2 , cyclophosphamide 600mg/m 2 , followed by weekly paclitaxel 80mg/m 2 ) for 12 weeks ($572). The model included rates and costs of 3 associated side effects (average $2024/patient): neutropenia (14%), thrombocytopenia (1%), and peripheral neuropathy (1%). In comparison, all pts were biomarker tested ($950) pre-treatment initiation and only those with biomarker overexpression were treated with AC-T versus AC, accruing the appropriate related costs plus the biomarker test cost. The model assumed the biomarker test was 70% to 90% predictive of expression. Results: The model found the biomarker group identified 55 to 70 non-expressing pts who would likely not have an increased benefit from the addition of TAX. For this group, 55% to 70% of the 3 AE toxicities and the associated impacts on QoL would be avoided producing $110,505 to $142,078 cost offsets. Between $25,792 and $60,304 of treatment expenditures could be avoided and better used. Budget neutrality occurred when neutropenia rates were reduced to 7%. The biomarker group identified 30–45 expressing pts who likely would benefit from AC-T. Conclusions: Applying a biomarker test to identify BC pts likely to respond to TAX may improve quality of care, particularly for non-expressers who could avoid QoL decrements of futile therapy and instead be managed with a less toxic and more beneficial therapy. Further development of such a biomarker should assess all pt impacts and healthcare system costs for both biomarker-identified expressers and non-expressers.
Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data.
Authors: Scott T. Tagawa, Gurkamal S. Chatta, Reza Mazhari, Ely Benaim
Journal: Journal of Clinical Oncology (2016)

550 Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m 2 /day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m 2 /day (n = 3) or 200 mg/m 2 /day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.
Efficacy and safety of irinotecan monotherapy as third line treatment for advanced gastric cancer.
Authors: Takeshi Kawakami, Nozomu Machida, Masahiro Kawahira, Sadayuki Kawai, Yosuke Kito, Yukio Yoshida, Satoshi Hamauchi, Takahiro Tsushima, Akiko Todaka, Kentaro Yamazaki, Tomoya Yokota, Akira Fukutomi, Yusuke Onozawa, Hirofumi Yasui
Journal: Journal of Clinical Oncology (2016)

113 Background: Several randomized trials demonstrated the survival benefit in advanced gastric cancer patients (AGC pts) receiving irinotecan or taxanes as second-line chemotherapy (SLC). Taxanes are used for SLC in daily clinical practice in Japan because of its less toxicity, especially in AGC pts with peritoneal dissemination, compared with irinotecan. Although irinotecan is often administered after refractory or intolerant to taxanes as SLC, the efficacy and safety of irinotecan as third-line chemotherapy (TLC) is still unclear. Methods: We retrospectively investigated the data of AGC pts administered irinotecan 150mg/m 2 as TLC every two weeks until disease progression, unacceptable toxicity, or pts’ refusal between December 2002 and June 2015. Inclusion criteria were (1) age 75 years or less (2) refractory or intolerant to fluoropyrimidine with or without platinum as first-line chemotherapy (3) refractory or intolerant to taxanes as SLC. Results: A total of 52 pts were analyzed. Pts’ characteristics were as follows: median age, 66 (range, 33-75) years; male/female, 35/17 pts; ECOG PS 0-1/2, 42/10 pts; peritoneal dissemination +/-, 32/20 pts; ascites +/-, 22/30 pts, number of metastatic sites 1-2/3-4, 44/8 pts. Median follow-up period was 548 (141-1931) days. Median progression-free survival was 70 days (95%CI 49-137) and median overall survival was 144 days (95%CI 120-231) from the initiation of irinotecan administration. Response rate and disease control rate was 10.8% and 50.4%, respectively. Relative dose intensity was 74.7% (56 mg/m 2 /week); 14 pts needed dose reduction in the first course, and 22 pts after the second course. Grade 3 or 4 neutropenia, anemia, diarrhea, nausea, and febrile neutropenia were observed in 13 (25%), 21 (40.4%), 5 (9.6%), 3 (5.8%) and 3 (5.8%) pts, respectively. No treatment-related death was observed. Conclusions: This study suggests that irinotecan monotherapy as TLC has acceptable anti-tumor effect and has manageable toxicity in appropriately selected AGC pts.
Role of polymorphic fc gamma receptor II/III in the efficacy of cetuximab in KRAS-NRAS-BRAF-PI3K mutated.
Authors: Jesus Garcia-Foncillas, Javier Rodriguez, Valentina Boni, Iosu Sola, Beatriz Honorato, Ruth Zarate, Eva Bandres
Journal: Journal of Clinical Oncology (2012)

477 Background: The immunoglobulin G1 (IgG 1 ) monoclonal antibody (MoAb) cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumors. IgG1 may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by FcγR polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus cetuximab. Methods: Tumor tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester. UK). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays. Results: DCR was significantly higher in KRAS wild-type tumors (61% vs 39%, p=0.049). In EGFR downstream-mutated mCRC patients, those harbouring a FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% vs 33%, p=0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p=0.008). Conclusions: FcγR polymorphisms may play a role in the clinical efficacy of cetuximab in EGFR downstream mutated mCRC patients. Further research into cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.
Y90 Plus High Dose BEAM with Autologous Stem Cell Transplantation for Chemorefractory Non Hodgkin Lymphoma.
Authors: Amrita Krishnan, Andrew Raubitschek, Joycelynne Palmer, Auayporn P. Nademanee, N. Kogut, Dave Yamauchi, Leslie Popplewell, Laura Federico, Jennifer Simpson, Ni-Chun Tsai, Stephen J Forman
Journal: Blood (2009)