tbuckley/cabot-search huggingface dataset:
A phase II randomized study of custirsen (OGX-011) combination therapy in patients with poor-risk hormone refractory prostate cancer (HRPC) who relapsed on or within six months of 1<sup>st</sup>-line docetaxel therapy
Authors: F. Saad, S. J. Hotte, S. A. North, B. J. Eigl, K. N. Chi, P. Czaykowski, M. Polllak, L. Wood, E. Winquist
Journal: Journal of Clinical Oncology (2008)

5002 Background: There is no standard of care when pts with metastatic HRPC manifest disease progression (PD) after 1st-line docetaxel. Custirsen is an antisense oligonucleotide targeting clusterin which in preclinical studies increased response of taxane-resistant cell lines to chemotherapy. This study evaluated the safety and efficacy of custirsen in combination with either docetaxel or mitoxantrone as 2nd-line therapy (Rx). Methods: Pts were eligible if they had PD while receiving or within 6 mo of discontinuing 1st-line docetaxel. All pts received 640 mg of weekly IV custirsen following 3 loading doses. Pts were randomized to standard doses of docetaxel/prednisone (DPC) or mitoxantrone/prednisone (MPC) on a 21-day cycle for up to 9 cycles. Protocol defined PD was based on RECIST, pain and performance score but not solely on PSA. Results: Analysis as of 03Jan08; median follow-up:13.3 (8.4- 17.1) mo. 42 pts received at least 1 cycle of combined therapy (DPC-20, MPC-22). Prior outcomes with 1st-line docetaxel were similar in both arms. The median time to PD for all pts was 1.8 mo; 16 (38%) pts had PD while receiving 1st line Rx. Following custirsen therapy: median # of cycles delivered: DPC-7.5, MPC-6.0; 40% of pts completed 9 cycles. Best PSA response (≥90, ≥50 ≥30%): DPC-20/40/55%, MPC-0/27/32%. Predetermined pain response: DPC-8/12 (67%), MPC-7 /14 (50%); median duration in both arms: 6 mo. KM estimate of PFS: DPC-4.7, MPC-2.6 mo. At a median follow-up of 13.3 months, 60% of pts are still alive in both arms. Both regimens were well tolerated; there were more Grade 3/4 AEs with MPC (68%) than DPC (50%) + 1 pt died of CHF following 8 cycles of MPC. Conclusions: In pts who progressed during or soon after 1st-line docetaxel, both custirsen combination regimens were well tolerated and associated with impressive PSA + pain responses and better than expected survival. Custirsen/ docetaxel/prednisone appeared superior to custirsen/mitoxantrone/prednisone in both efficacy and safety. A Phase III study is planned utilizing docetaxel/prednisone ± custirsen as 2nd-line Rx in patients progressing after 1st-line docetaxel. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OncoGeneX Technologies
Expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507)
Authors: Y. Gong, E. Yao, M. Arcila, S. Frankel, J. Teruya-Feldstein, M. Zakowski, R. Thomas, M. Ladanyi, W. Pao
Journal: Journal of Clinical Oncology (2009)

8095 Background: The IGF-1R (IGF receptor type 1) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy. We investigated predictive biomarkers of response to an anti-IGF-1R antibody (Ab) in vitro in NSCLC. Methods: We examined the growth inhibitory effects of R1507, a fully-humanized IgG1 anti-IGF-1R monoclonal Ab (Roche), against a panel of 22 NSCLC cell lines using CellTiter Blue assays. Phospho-receptor tyrosine kinase (pRTK) arrays and ELISAs were used to determine the status of IGF-1R and other RTKs. SNP arrays were used to determine IGF-1R copy number. Immunohistochemical (IHC) staining of total IGF-1R was performed with G11 (an anti-total IGF-1R Ab; Ventana) on a tissue microarray (TMA) containing 77 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+ by a pathologist (JF). Results: 5 of 22 NSCLC cell lines were moderately sensitive (25–50% growth inhibition) to R1507 alone. ELISA and pRTK array analysis demonstrated that pIGF-1R levels in the presence or absence of serum did not correlate with drug sensitivity. However, 4 of 5 sensitive lines displayed high levels of total IGF-1R vs 1/17 resistant lines (p=0.003 Fisher's Exact). SNP array analysis showed that sensitive lines also harbor relatively higher copy numbers of IGF-1R. There was no correlation with EGFR/KRAS mutational status. 48% of TMA NSCLC tumors had scores of 2+ or greater, while 5% were scored as 3+. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line, R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway, as pAKT was significantly downregulated by R1507 but not erlotinib. Conclusions: In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy. [Table: see text]
Feasibility report of stereotactic body radiotherapy with tomotherapy for early stage medically inoperable lung cancer using extreme hypofractionation
Authors: C. W. Hodge, D. Khuntia, W. A. Tome, H. Jaradat, M. P. Mehta
Journal: Journal of Clinical Oncology (2006)

17097 Background: This is a report on the technical feasibility, dosimetric aspects, and daily image-guidance capability with megavoltage computed tomography (MvCT) imaging of stereotactic body radiotherapy (SBRT) using tomotherapy for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). Methods: Treatment planning was performed using 4D PET-CT in a BodyFix device. A pilot group of 4 patients with &lt;5 cm T1/2, N0 tumors, was treated using IMRT (tomotherapy), utilizing daily image guidance with MvCT. Patients received 60 Gy within 10 days, delivered in five 12Gy fractions. The primary endpoint of this study was evaluation of acute and sub-acute treatment related toxicities. The secondary endpoint was radiographic evaluation for objective tumor response. Results: All 20 fractions were successfully delivered. MvCT provided excellent tumor visualization for daily image guidance. No significant tumor regression was observed in any patient during the 2 weeks of therapy, using volumetric contouring on MvCT images. The relevant dosimetric aspects, measured as median normalized total dose (NTD) were as follows: tumor = 116.5 Gy 10 ; whole lung = 6.8 Gy 3 . Maximum fraction-size equivalent dose (FED) demonstrated median values as follows: esophagus = 4.04 Gy 3 ; spinal cord = 6.53 Gy 3 . All patients are alive at a median follow-up of 6 months, with no grade 2 or higher acute pulmonary toxicities. Early radiographic follow-up demonstrates all 4 patients experienced a partial response. The mean tumor regression is 79% (range 64–85%). Conclusions: 4D PET-CT permits precise target delineation. In this, the first reported clinical experience, IMRT delivery of SBRT using tomotherapy is feasible, safe and free of major acute toxicities. The conformality which is obtained by helical delivery of the therapeutic dose makes it well-suited for dose escalation through extreme hypofractionation, with extremely low mean NTD to normal tissue. The ability to obtain on-treatment megavoltage CT scans to confirm tumor localization is a substantial advantage. Further studies and longer follow-up are warranted to evaluate the efficacy of this treatment modality. [Table: see text]
Medical oncologists’ perceptions of the effect of drug funding decisions for new cancer drugs on their practice: A qualitative study
Authors: S. R. Berry, S. Hubay, H. Soibelman, D. K. Martin
Journal: Journal of Clinical Oncology (2005)

6087 Background: As the costs of new cancer drugs rise, drug funding policies for these drugs may have a greater impact on physician practice. Cancer Care Ontario has established a process to “provide equal access to new effective agents for eligible patients throughout the province” through a “New Drug Funding Program” (NDFP). Purpose: The purpose of this study is to describe oncologists’ perceptions of the impact of NDFP drug funding decisions on their practice. Methods: This was a modified ethnographic study involving semi-structured, in-depth interviews with 46 medical oncologists in Ontario from a variety of practice settings. Oncologists were asked to describe the impact of priority setting decisions for new cancer drugs on the care they provided for their patients and their discussions with patients about treatment options. A modified thematic analysis of interview transcripts commenced with data collection. Results: 5 key themes were identified: 1.) Access to Medications: There was concern about accessing effective cancer drugs because of inflexible funding guidelines and inadequate coverage. 2.) Limits Not Accepted: When the NDFP limited access to effective medications, participants generally overcame those limits but at the expense of significant “hassle”, stress and time. 3.) Impact on Physician-Patient Relationship: Drug funding decisions had a significant impact on the time spent on discussions with patients and moral distress regarding the content of discussions. 4.) Disengagement from the Funding Processes: Oncologists did not feel engaged in the drug funding process because of the “hassle” factor, perceived inflexibility of guidelines and the lack of an appeals mechanism. 5.) Quality of Care: Participants did not perceive the NDFP as affecting overall quality of care. Conclusions: Drug funding decisions have a significant impact on oncologists’ practice including their interaction with patients and how they use their time and energies. Policy makers need to consider the implications of physicians who will go to considerable effort to circumvent their policies in the name of patient advocacy. No significant financial relationships to disclose.
BCCIP: A novel marker for radiotherapy benefit in patients with laryngeal cancer
Authors: A. Rewari, H. Lu, Q. Yang, Z. Shen, B. Haffty
Journal: Journal of Clinical Oncology (2007)

6006 Background: It has been well established that the functionality of the p53 pathway is related to radiosensitivity in various human cancers. The status of proteins regulating p53 activity may also be valuable markers for radiosensitivity. Recent studies have shown that BCCIP (BRCA2 &amp; CDKN1A interacting protein) is essential for maintaining the transactivation activity of wild type p53. We hypothesize that functional BCCIP may contribute to effective radiotherapy in the clinical setting. To test this hypothesis, we analyzed the expression of BCCIP and p53 in a cohort of laryngeal cancer treated with radiotherapy and assessed whether BCCIP and p53, alone or in combination, would correlate with local control and overall survival. Methods: One hundred thirty-five patients treated between 1975 and 2000 for early stage (stage I &amp; II) squamous cell carcinoma of the larynx were included in the study. Treatment consisted of definitive radiation therapy (RT) with standard fields and fractionation to a median dose of 6,590 cGY. Tissue was collected from pre-RT biopsies and constructed in a tissue microarray, with duplicate cores created for each case. BCCIP and p53 expression was analyzed by immunohistochemistry and qualitatively scored with greater than 10% nuclear reactivity the cutoff for positive staining. Results: Expression of BCCIP and wild type p53 in combination was associated with significant improvements in 5-year local control (68.75% vs. 46.27%, p = .04) and 5-year overall survival (67.68% vs. 34.62%, p = .006) compared to patients who did not express BCCIP. Expression of BCCIP or p53 alone was not found to be independently associated with benefits in local control or overall survival. Conclusions: This study provides clinical evidence that BCCIP contributes to effective local control and overall survival in patients with laryngeal cancer treated with radiation. This benefit may be a result of increased radiosensitivity in patients who have functional BCCIP and p53. Using immunohistochemical methods, BCCIP and p53 co-expression can act as markers to identify sub-groups of laryngeal cancer patients who are more likely to be cured with radiotherapy. No significant financial relationships to disclose.
Comparison of different methods for detecting epidermal growth factor receptor mutations in peripheral blood as a predictor of response to gefitinib.
Authors: J. Wu, H. Bai, G. Zhu, J. Xu, W. Jiang, L. Lin, C. Xue, L. Zhang
Journal: Journal of Clinical Oncology (2010)

10557 Background: Several studies have reported the detection of active EGFR mutation DNA in peripheral blood can also predict the response to EGFR-TKI in NSCLC. But heterogeneity in methodologies makes it difficult to use in daily practice. Goal of this study is to compare different methods for detecting EGFR mutation DNA in peripheral blood. Methods: From July 2007 to April 2009, fifty-one advanced NSCLC patients with pairs of tumour and serum samples treated with gefitinib were included. Response was evaluated by RECIST criteria. EGFR mutations in tumor tissues were detected by Scorpions-Amplification Refractory Mutation System (Scorpions-ARMS). Three methods were used to detect the mutations DNA in peripheral blood: denaturing high performance liquid chromatography (DHPLC), Mutant-Enriched-Liquidchip (ME-Liquidchip) and Scorpions-ARMS. Results: The Objective response rates (ORR) in whole group patients are 33.3% (17/51). EGFR Mutation rate were identified 15.7% (8/51), 27.5% (14/51), 29.4% (15/51) by DHPLC, ME-Liquidchip, Scorpions-ARMS in peripheral blood respectively. Only 34 cases were available for paired tumor sample EGFR mutation detection. In these 34 patients, EGFR mutation rate in tumor tissue was 41.2% (14/34). The corresponding rates of EGFR mutation status in peripheral blood with tumor tissues are 58.8% (by DHPLC), 58.8% (by ME-Liquidchip) and 70.6% (by Scorpions-ARMS). The ORRs by different method of EGFR mutation detection were 71.4% (Tumor sample), 62.5% (Blood DHPLC), 50.0% (Blood, ME-Liquidchip) and 66.7% (Blood, Scorpions-ARMS). EGFR Mutation detected by Scorpions-ARMS in tumor tissues and peripheral blood have a better prediction of ORR of EGFR-TKI (p=0.002 and p=0.003) compare DHPLC and ME-Liquidchip method. Conclusions: Tumor tissue is the better source of samples to detect EGFR mutation of NSCLC patients than peripheral blood. Scorpions-ARMS method is superior to DHPLC and ME-Liquidchip in serum EGFR mutation DNA detection. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Innovation Centre China, R&D AstraZeneca, Surexam, Inc AstraZeneca, GlaxoSmithKline AstraZeneca, Bayer, Novartis, sanofi-aventis
Resectability of liver metastases (LM) in patients with advanced colorectal cancer (ACRA) after treatment with the combination of oxaliplatin (OXA), irinotecan (IRI) and 5FU. Final results of a phase II study
Authors: A. Abad, A. Antón, B. Massuti, F. Rivera, E. Marcuello, M. Navarro, J. Tabernero, E. Aranda, A. Carrato, E. Díaz-Rubio
Journal: Journal of Clinical Oncology (2005)

3618 Background: OXA, IRI and 5FU have shown its efficacy in ACRC. The synergism of these three drugs has been shown in vitro and in vivo models. The purpose of this trial was to determine the response rate of the triple combination of OXA+IRI+5FU and to assess prospectively its impact on secondary resectability of previously non-resectable LM. Methods: 47 patients were included in the trial after signature of IRB-approved informed consent. All patients received OXA (85 mg/sqm) + IRI (150 mg/sqm) + 5FU (2250 mg/sqm in 48 h CI - TTD scheme) on D1 every 15 days, according to the recommended dose obtained from the phase I part of the trial (Anti-Cancer Drugs 2004, 15;469–471). Results: Male/female: 28/19, Median age 61.6 years (31–75), ECOG 0/1/2: 26/20/1. Efficacy and safety have been analyzed from a total of 489 cycles, being the median number of cycles per patient 11 (1–18). Grade 3–4 toxicities per patient were: neutropenia (40%), febrile neutropenia (4%), diarrhea (18%), nausea/vomiting (11%/15%), fatigue (11%), anemia and alopecia (9% each). Neurosensory symptoms observed were grade 0: 34 (72%), grade 1: 11 (23%) and grade 3: 2 (4%). No grade 2 neurotoxicity was observed. Efficacy: Tumor response has been assessed in the 42 patients for whom at least one measure was available: CR 1 (2%), PR 28 (67%), SD 13 (31%) and PD 0. TTP was 10.9 months and OS was 19.9 months. Secondary liver surgery was possible in 12 patients with previously non-resectable LM, with a rescue rate of 26%, being as high as 40% in patients with liver-only metastases. In this cohort, median OS has not been reached at 22 months median follow-up, with only 2/12 patients having died. Conclusions: The results of this prospective study show that first-line combination of OXA+IRI+5FU is highly active with an ORR of 69%, and has allowed the resectability of previously non-resectable LM up to 40% of patients with liver-only metastases, offering them the possibility of long-term survival without significant impact over safety profile. No significant financial relationships to disclose.
Randomized open label phase II study of pegilated liposomal doxorubicine (PLD) four or six-week scheduled in metastatic breast cancer (MBC) patients (p)
Authors: M. Ruiz, J. L. Bayo, J. A. Moreno Nogueira, J. Dorta, A. M. Casas, M. Morales
Journal: Journal of Clinical Oncology (2006)

10751 Background: PLD has the advantage of delivering the active anthracycline directly to the tumour site, provide comparable efficacy to conventional doxorubicin with a more favourable toxicity profile and significantly less cardiotoxicity. The most frequent dosing schedule is 50 mg/m 2 every 4 weeks. Recent studies have shown that PLD 60 mg/m 2 every 6 weeks is an active and well tolerated treatment, and could be more convenient for the p. The primary objective was to evaluate response rate in six- and four-week schedule (arms A and B). Secondary objective was toxicity profile. Methods: P histologically confirmed of MBC, age 18–75 years old, ECOG PS ≤ 2, at least one measurable lesion and adequate bone marrow, renal, hepatic and cardiac function, were eligible. Prior chemotherapy with anthracyclines for MBC or adjuvant anthracycline-based regimen in the previous 12 months was not allowed. P were randomly assigned to receive PLD 60 mg/m 2 i.v. in 1 hour every 6 weeks (arm A) or PLD 50 mg/m 2 i.v. in 1 hour every 4 weeks (arm B). Results: Ten p have been included in the interim analysis over 11 enrolled, with median age of 50 years, ECOG PS 0–1 70% and stage IV 50%. Median time from diagnosis of metastatic disease was 9.2 months. Histology: 80% of p had ductal carcinoma, 10% lobular and 10% undifferentiated. Main tumour locations were lung (60%), liver (60%) and bone (40%). Two p had positive hormonal receptor status in arm A and 4 in arm B. Previous treatment included chemotherapy (80%), hormonotherapy (80%) and radiotherapy (40%). Up to date, a total of 15/17 cycles (median 3/3, range 1–6/1–5) were administered. Absolute dose intensity was 2.2 mg/day in arm A and 3.0 mg/day in arm B. Two p were not evaluated and over 8 evaluable p for efficacy (4 A and 4 B), 2 achieved partial response in arm A and 1 in arm B. Median time to progression was 168 days in arm A and 104 in arm B. The only grade III/IV toxicity was mucositis and stomatitis in 4 p. The most common grade I/II toxicities were palmar-plantar erythrodysesthesia (5p), anorexia (4p) and alopecia (4p). Conclusions: PLD at 50 mg/m 2 every 4 weeks and 60 mg/m 2 every 6 weeks are effective and well tolerated regimens in MBC p. The most relevant adverse events were mucositis and palmar-plantar erythrodysesthesia. No significant financial relationships to disclose.
Abstract 1982: TCEB3C (Elongin A3) on chromosome 18 presents a putative tumor suppressor gene of small intestine neuroendocrine tumors.
Authors: Katarina Edfeldt, Tanvver Ahmad, Göran Åkerström, Eva Tiensuu Janson, Per Hellman, Peter Stålberg, Peyman Björklund, Gunnar Westin
Journal: Cancer Research (2013)

Abstract Small intestine neuroendocrine tumors (SI-NETs) arise from the enterochromaffin cells and produce hormones which can cause the carcinoid syndrome. The incidence is increasing and the five-year survival rate is 60-80 %. Loss of one copy of chromosome 18 is a very frequent event in these tumors, supporting the presence of a crucial tumor suppressor gene. This study investigated whether TCEB3C, encoding Elongin A3, presents a putative tumor suppressor gene in SI-NETs. This gene is currently the only known imprinted gene on chromosome 18, requiring only one gene copy inactivation event to fulfill the Knudson hypothesis. Elongin A3 expression in SI-NETs (n=47) was heterogeneous and negative in most cells. 5-Aza-2’-deoxycytidine induced expression of Elongin A3 in a carcinoid tumor cell line and in tumor derived primary cell cultures, but not in a control cell line. Also the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in the carcinoid tumor cell line, but not in control cells suggesting further that the TCEB3C gene was epigenetically suppressed in neuroendocrine tumor cells. The TCEB3C gene encompasses an CpG island and quantitative cytosine CpG methylation analysis will be presented. Furthermore, overexpression of Elongin A3 led to a decrease in clonogenic survival of carcinoid tumor cells, but not of control cells strongly supporting a growth-regulatory role. These results support a putative tumor suppressor role of TCEB3C in neuroendocrine cells of the small intestine. Citation Format: Katarina Edfeldt, Tanvver Ahmad, Göran Åkerström, Eva Tiensuu Janson, Per Hellman, Peter Stålberg, Peyman Björklund, Gunnar Westin. TCEB3C (Elongin A3) on chromosome 18 presents a putative tumor suppressor gene of small intestine neuroendocrine tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1982. doi:10.1158/1538-7445.AM2013-1982