tbuckley/cabot-search huggingface dataset:
Phase I trial of concomitant hyperfractionated radiotherapy with docetaxel and cisplatin for locally advanced head and neck carcinomas
Authors: A. S. Allal, D. Zwahlen, M. Becker, P. Dulguerov, N. Mach
Journal: Journal of Clinical Oncology (2005)

5574 Background: To determine the maximum tolerated dose (MTD) of docetaxel when administered concomitantly with radical hyperfractionated radiotherapy (RT) and cisplatin in patients (pts) with locally advanced H&N cancers. Methods: Pts with stages III-IV tumors received radical RT of 74.4 Gy given in 2 daily fractions of 1.2 Gy in 6 weeks. Cisplatin was given once weekly on day 1 at a constant dose of 15 mg/m2. The starting dose of docetaxel was 10 mg/m2 once weekly on day 3, with planned escalation steps of 5 mg/m2. Main end-points of the study were the maximum tolerated dose (MTD) of docetaxel, acute toxicities and the preliminary efficacy results. Results: Twenty-five pts were enrolled. Median follow-up was 15 months (range: 3–40). 2/3 pts presented with dose-limiting toxicities at 15 mg/m2 docetaxel (one pt presented with multiple grade 3–4 toxicities requiring hospitalization for management and another with multiple toxicities including life-threatening broncho-aspiration). Thus, the weekly docetaxel dose of 15 mg/m2 was considered as MTD and the previous dose level (10 mg/m2) as the recommended dose (RD). Nineteen patients were then treated with the RD and no dose-limiting toxicity was observed. RT was completed in all patients except one (median dose 74.4; range 73.2–74.4); 85% of the scheduled cisplatin and docetaxel doses was given in 85% and 88% of patients respectively. Acute toxicities were dominated by grade 3 mucositis (92%) and grade 3–4 dysphagia (68%). The 2-year actuarial local control was 88% and disease-free survival was 75%. At the time of last follow up, 23 pts were alive and 2 deceased from cancer. No distant metastasis was observed. Conclusions: In locally advanced H&N cancers, this study determined the RD of docetaxel to be 10 mg/m2 administered once weekly concurrently with 74.4 Gy hyperfractionated RT and weekly 15 mg/m2 cisplatin. The toxicity profile and the encouraging results suggest that this new combination merits further investigation in a multi-institutional phase II trial. No significant financial relationships to disclose.
A randomized two-arm phase III study to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) versus CAPOX alone in post radical resection of patients with liver metastases of colorectal cancer.
Authors: E. E. Voest, N. Snoeren, S. B. Schouten, A. M. Bergman, E. van Werkhoven, O. J. L. Loosveld, T. M. van Gulik, J. M. Smit, A. Cats, E. Boven, E. Hesselink, A. Rijken, M. Tol, O. Dalesio, H. M. Verheul, R. A. Tollenaar, J. van der Sijp, I. Borel Rinkes, R. van Hillegersberg
Journal: Journal of Clinical Oncology (2011)

3565 Background: This study aimed to improve disease-free survival (DFS) for patients after radical resection of CRC liver metastases by adding bevacizumab to post resection chemotherapy with CAPOX. Methods: Patients with liver only disease who underwent a radical (R0) resection of liver metastases of CRC cancer were randomized between CAPOX (arm A) or the same schedule plus bevacizumab 7.5 mg/kg i.v. day 1 (arm B). CAPOX was given for a total of 8 cycles whereas bevacizumab was given for 12 months. The primary endpoint was disease-free survival (DFS). The study was originally designed to detect a 33% reduction in the hazard ratio of relapse, (HR=0.67) at a predicted median DFS of 17 months. After an amendment allowing more high risk patients, the total number of events that was necessary to provide 80% power to detect such a decrease was 191 requiring 300 patients to be randomized in 3 years. Due to slow accrual the study was closed October 2010. Results: At the time of study closure a total of 79 patients were randomized between October 2006 and October 2010: 39 patients were included in arm A and 40 patients in arm B. Toxicity was evaluated for 74 patients. No significant differences in toxicity between the 2 arms were found. Toxicities differed for hypertension (16% vs 22%), hand foot syndrome (2.6% vs 8.3%), thrombosis/embolism (5.3% vs 11.1%). At the time of analysis (January 2011) 16 events (8% of the total required events) were encountered in arm A and 8 events in arm B. Two year DFS survival rate was 52 % and 70% for arm A and B respectively (p=0.074). Conclusions: Due to changing clinical practice (use of neo-adjuvant chemotherapy, extended indications for surgery, outcome of the C08 study) and reluctancy among patients to be treated for 12 months accrual to the study was slow. The present analysis in 79 patients shows a favorable but not significant improvement in DFS at 2 year for bevacizumab. This may suggest that patients with established metastases differ from patients receiving adjuvant treatment with bevacizumab after resection of the primary tumor.
A phase I study of gemcitabine plus dasatinib (GD) or gemcitabine plus dasatinib plus cetuximab (GDC) in refractory solid tumors
Authors: H. E. Uronis, K. Bullock, G. Blobe, S. Hsu, M. Morse, A. Nixon, S. Haley, M. O’Neill, H. Hurwitz, J. Bendell
Journal: Journal of Clinical Oncology (2009)

e15506 Background: Dasatinib (D) is a small molecule tyrosine kinase inhibitor with activity against both bcr-abl and src. Cetuximab (C) is a monoclonal antibody that blocks EGFR. Preclinical models suggest D reverses resistance to G. In addition, src and EGFR pathways interact; synergism of dual blockade by D + C is possible. We evaluated two combination regimens, GD and GDC, in a Phase I dose escalation study. Methods: Patients (pts) with advanced solid tumors were enrolled in cohorts of 3–6 to either GD or GDC. G was dosed in mg/m 2 weekly for 3 of 4 weeks, D was dosed in mg PO BID, and C was dosed at 250 mg/m 2 weekly after loading dose of C=400; cycle length was 28 days. Dose levels were as follows: 1) G 1000 + D 50 ± C; 2) G 1,000 + D 70 ± C; 3) G 1,000 + D 100 ± C. Standard cycle 1 DLT definitions were used. Eligible pts had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on treatment. Results: 25 pts have been enrolled, including 21 with pancreatic adenocarcinoma, 3 of whom had received prior G. 21 pts were evaluable for toxicity and 18 for efficacy. Four DLT were observed: Gr 3 ANC with infection (GDC1, n=1), Gr 3 ALT (GD2, n=2), and Gr 5 pneumonitis (GDC2, n=1). Possible treatment-related adverse events in later cycles included: Gr3–4 ANC (n=4), Gr4 colitis (n=1), Gr3 bilirubin (n=2), Gr3 Hgb (n=2), Gr3 Plt (n=2), Gr3 edema/fluid retention syndrome (n=1), and Gr3 vomiting (n=2). One previously untreated pt had a partial response. Eight of 18 pts, 3 of whom had received prior G, had stable disease as best response, median duration = 5 months (range 1–7). Biomarker results are pending. Conclusions: The MTD of the GD arm is G1000/D50BID. Stable disease in previous G-refractory pts was noted. Hematologic toxicities were dose-limiting; later toxicities including hematologic, LFT changes, pneumonitis, and fluid retention were seen. To address these toxicities, once daily dosing of D will be explored, followed by an expanded cohort of G + daily D vs G + bid D in pts with treatment-naïve pancreatic cancer. [Table: see text]
Evaluation of toll-like receptor (TLR)-7 agonist imiquimod applied topically to breast cancer chest wall recurrences or skin metastases.
Authors: S. Adams, Z. Dewan, T. Meng, J. D. Goldberg, A. Tiersten, N. Bhardwaj, S. Formenti, S. Demaria
Journal: Journal of Clinical Oncology (2010)

TPS138 Background: Purpose: To assess the clinical and biological activity of imiquimod applied topically to breast cancer metastatic to skin. Breast cancer is the most frequent malignancy and the most common tumor, excluding melanoma to metastasize to the skin in women. Chestwall recurrence is debilitating for patients, substantially affecting quality of life (QOL). Current treatment modalities for nonresectable lesions are rarely curative, indicating the need for more effective and less toxic therapies. Imiquimod (IMQ), a synthetic TLR7 agonist has immunomodulatory activity with profound effects on the tumor environment, leading to clearance of primary skin malignancies. We have shown that IMQ recruits and activates dendritic cells (DC) and primes immune responses to coadministered tumor antigens in cancer patients. We have also demonstrated IMQ's antitumor efficacy in BALB/c mouse–derived TSA mammary adenocarcinoma, a poorly immunogenic tumor that ulcerates through the skin, closely mimicking the clinical scenario of patients with chestwall recurrence. Methods: Eligibility includes patients with biopsy-confirmed breast cancer, measurable skin metastases, ECOG PS 0-2 and adequate organ/marrow function. IMQ 5% cream is applied topically to skin metastases overnight for 5 days/week for 8 weeks followed by a 4-week rest period. Additional cycles are permitted. This phase II study uses a Simon optimal two-stage design: 10 patients in stage I (currently 3 enrolled), if response is observed, an additional 19 patients will enroll in stage II. Primary endpoint is 12 week antitumor response, assessed by clinical exam and computer-aided surface area calculation of skin metastases. Furthermore, effects of IMQ treatment on symptoms and health-related QOL will be determined. Tumor biopsies will be studied for immune signatures. Breast cancer skin metastases are infiltrated by inflammatory cells, including DC with markers of activation as well as tolerogenic function (e.g., IDO), and T cells with markers of effector (e.g., granzyme) as well as regulatory functions (e.g., FoxP3). The effect of IMQ treatment on the balance between these subsets will be determined. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Graceway Pharmaceuticals
Routine screening for mismatch repair proteins: The impact on genetic testing.
Authors: Grainne O'Kane, Delia Flannery, Katrina O'Connor, Carmel Nolan, Michael P. Farrell, Andrew J. Green, Brian Meighan, Paul McCormick, M. John Kennedy, C. Muldoon, David James Gallagher
Journal: Journal of Clinical Oncology (2015)

525 Background: Lynch Syndrome (LS) accounts for approximately 3% of all colorectal cancers (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Increasing literature supports routine screening for LS using immunohistochemistry (IHC) to detect loss of MMR protein expression on tumour samples. We evaluated genetic clinic referrals and consequent LS diagnoses at our institution pre and post the adoption of universal screening. Methods: Reflex immunohistochemistry (rIHC) on all colorectal adenocarcinomas was implemented in November 2008. Prior to this IHC was performed at the pathologist’s discretion or upon request. Tumour specimens reviewed from November 2004 to October 2008 (pre rIHC) and from November 2008 to October 2012 (post rIHC) were evaluated and patients with evidence of MMR deficiency (MMR-D) were identified. The number of genetic referrals and number of patients with confirmed LS were determined. Results: During an 8-year period, 1,131 pathology specimens were reviewed in 1,103 patients (Table). Completion of IHC increased from 19% to 75% post implementation of rIHC. Ninety-two percent of incomplete samples in the post rIHC period (133/145) had insufficient tumour material for analysis. In patients with available IHC, 18/96 (20%) in the pre rIHC era were MMR-D of which 44% were referred to genetics, resulting in the diagnosis of LS in 4 patients. In the post rIHC era 30/429 (7%) of patients had evidence of MMR-D of which 20% were referred for genetic testing resulting in the detection of 3 LS patients. Conclusions: Universal testing for MMR protein expression is difficult to achieve, and does not necessarily result in increased genetic testing or Lynch Syndrome diagnosis. Systematic work-up of test results is essential once mismatch repair evaluation is initiated. [Table: see text]
Abstract 1388A: Assessment of the anti-angiogenic effect of VEGFR2 siRNA in HUVEC using the Lonza 4D-Nucleofecto system
Authors: Srinivasan Kokatam, Kanchan Tiwari, Jenny Schroeder, Andrea Toell, Lubna Hussain, Preeti Kapoor
Journal: Cancer Research (2015)

Abstract Angiogenesis is a hallmark of most cancers, and is thus an attractive target for the treatment of cancer. One of the easiest screening and target validation strategies for anti-angiogenic target identification involves knocking down targets in Human Umbilical Vein Endothelial Cells (HUVEC) and assessing subsequent effects on tube formation in Corning's Matrigel product. The usage of small interfering RNA (siRNA) is one of the strategies to knock-down RNA, and thereby protein expression within cells. siRNA can be delivered within cells using either chemical transfection or electroporation-based strategies such as the one offered by the Lonza Nucleofector™ Technology. In the current study we used the Lonza 4D-Nucleofector™ X-Unit to transfect single-donor Clonetics™ HUVEC cultured in EGM™-2 Endothelial Cell Growth Media. Cells were transfected with siRNA directed against Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). Transfection conditions were fine-tuned using pmaxGFP™ vector, and it was shown that the Nucleofection™ process had no deleterious effect on the tube formation potential of HUVEC on Corning's Matrigel product. Efficient knock-down of VEGFR2 protein levels was demonstrated after the transfection of VEGFR2-siRNA. Best knock-down efficiency was observed 24 hours after transfection. VEGFR2-siRNA transfected cells demonstrated significant inhibition of tube formation on Corning's Growth Factor Reduced Matrigel product in comparison to control samples. Since the efficient knock-down of the VEGFR2 protein in Clonetics™ HUVEC using the Nucleofector™ Technology can be demonstrated at time points as early as 24 hours after transfection, this is an efficient approach for target identification, validation and screening of siRNA based anti-angiogenesis therapeutics for cancer treatment. Citation Format: Srinivasan Kokatam, Kanchan Tiwari, Jenny Schroeder, Andrea Toell, Lubna Hussain, Preeti Kapoor. Assessment of the anti-angiogenic effect of VEGFR2 siRNA in HUVEC using the Lonza 4D-Nucleofecto system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1388A. doi:10.1158/1538-7445.AM2015-1388A
What is the best drug in combination with a platinum-derivative in the treatment of advanced non-small cell lung cancer (NSCLC)? A gemcitabine (G)/vinorelbine (V) retrospective study
Authors: P. Barradas, A. Costa, M. Cristóvão, A. P. Alves, A. S. Oliveira, I. Faria, M. J. Melo
Journal: Journal of Clinical Oncology (2004)

7295 Background: Although combinations of platinum-derivatives with G or V were largely used in the treatment of NSCLC, very few studies directly comparing these associations were available. Methods: We retrospectively compared results in all patients (pts) with advanced NSCLC and performance status (PS) ≤2 treated in our unit during 7 years with the regimens of G (1000 mg/m2/w) and V (30 mg/m2/w) plus a platinum derivative. 249 pts were from randomized trials (not comparing these associations) and 263 on a clinical-practice basis. Results: From 1/97–10/03, 512 pts used regimens of G (342) or V (170) plus a platinum derivative. The groups were well balanced in age, sex, histology, PS, stage, and Cyfra 21–1 baseline median levels. Cisplatin (P) and carboplatin (C) combinations were used for about 60% (308) and 40% (204) of pts, respectively. Mean dose-intensities of P (G 24.6; V 24.8 mg/m2/wk) and C (G AUC 5.2; V AUC 5.3) were similar for both groups. Mean dose intensities for G and V were 641 mg/m2/wk and 19.2 mg/m2/wk, respectively. Hematologic toxicity was similar between groups except grade 3–4 thrombocytopenia was more frequent in G-based regimens (G 24% vs V 4%; p<.001). Median follow-up (40 mo) was similar for both groups. ORR was significantly higher for G (38.3%; 95 CI 33.1–43.5%) than for V (29.4%; 95 CI 22.5–36.3%; p=.049). G-based regimens had significantly higher median survival (G 11.6 mo vs V 9.0 mo; p=.005), time to progression (G 6.2 mo vs V 4.4 mo; p=.019) and 1, 2 and 3-year survival rates (G 49, 19 and 10% vs V 34, 10 and 6%, respectively; p=.016, .025, .044). These differences are significant for stage III and IV (p=.034 and .012) and for P or C associations (p=.032 and .044). Kaplan-Meier curves also favored G-based combinations (log-rank p=.0056), which are still more pronounced after adjustment (using Cox's model) for main survival prognostic factors (log-rank p=.0031). Conclusions: In advanced NSCLC pts, G with a platinum derivative is more efficacious when compared with V plus a platinum-derivative. The results must be confirmed in a large randomized trial or meta-analysis. No significant financial relationships to disclose.
A new strategy is needed
Authors: B. Stenson
Journal: BMJ (1995)

EDITOR,—Fiona Godlee is right: the World Health Organisation is in crisis.1 In the past it came to occupy a position of leadership in major global undertakings such as the eradication of smallpox, the work resulting in the code on breast milk substitutes, the programme on essential drugs, and the primary health care movement. It grasped the importance of these issues, brought its own resources to bear, and harnessed resources from the outside. It became the instrument by which the global community could agree on common goals and achieve collective action.

But today's challenges are not …
Association of body mass index and outcome in advanced breast cancer.
Authors: Claudia Andreetta, Pamela Driol, Marta Bonotto, Lorenzo Gerratana, Francesca Valent, Stefania Russo, Alessandro Minisini, Gaetano Pascoletti, Stefano Moroso, Roberta Sottile, Mauro Mansutti, Gianpiero Fasola, Fabio Puglisi
Journal: Journal of Clinical Oncology (2012)

1044 Background: Obesity represents a well-known risk factor for the development of breast cancer and an adverse prognostic factor in early disease. Overweight is associated with reduced efficacy of aromatase inhibitors in adjuvant setting. Few data have been reported about the potential relationship of overweight and outcome in advanced breast cancer (ABC). Methods: We retrospectively evaluated body mass index (BMI) in a consecutive series of 400 ABC patients treated at our institution. BMI was calculated at baseline of diagnosis of ABC. We evaluated association of BMI and other prognostic and predictive markers with Progression Free Survival (PFS) and Overall Survival (OS). We evaluated PFS at first and subsequent lines of chemotherapy (CT) and endocrine therapy (ET). Overweight patients were defined as having BMI &gt; 25. Results: Overweight patients were 52%. Median age of the population was 58 years. Median OS was 33.7 months. Overall, 76% of patients presented with ER+ and 17.7% with HER2+ ABC.Overweight was associated with increased age at diagnosis, menopausal status and luminal B or triple negative immunophenotype. At multivariate analysis, BMI &gt; 25 was associated with better PFS at first-line ET (HR= 0.68, 95% CI 0.46-0.99). BMI was not associated with OS. Conclusions: BMI at baseline does not seem to be an adverse prognostic factor for ABC patients. Overweight may be associated with better PFS in endocrine responsive ABC treated with ET, especially in first-line setting. The role of BMI in ABC deserves to be further investigated.
Evaluation of outcomes after discontinuing androgen suppression therapy in a series of elderly patients with advanced prostate cancer and in prolonged clinical and biochemical response
Authors: B. Castagneto, V. Ferraris, I. Stevani, M. Perachino
Journal: Journal of Clinical Oncology (2008)

20504 Background: To describe and discuss the outcomes following the suspension of androgen suppression therapy (AST) in a series of elderly patients in advanced stage of prostate cancer and in established clinical and biochemical response after an extended period of treatment. Methods: A retrospective review of 371 consecutive patients with stage T3–4 NX- 1M0–1 prostate cancer and treated with single or combined androgen suppression therapy revealed 44 older patients who, after at least 36 months of treatment, showed the following findings of stable response (SR): absence of noteworthy dysuria, normal prostate findings on digital rectal examination (DRE), and prostate specific antigen (PSA) value lower than 0.50 ng/ml. Treatment was suspended in these patients, but was to be re-scheduled in one of the following cases: onset of important dysuria, evidence of palpable lesion on DRE, rise in PSA above 10 ng/ml or above pre-treatment values if these were below 10. Progression disease was defined as follows: PSA level increase at two subsequent measurements, and/or appearance of new lesions, and/or evidence of progression disease on DRE. Results: After a median follow-up of 93.9 months from the start of AST and 57.5 months from its suspension, 27 (61.4%) patients resumed therapy. Median age of patients at the moment of therapy suspension was 78.5 years (95% CI, 76 - 81). Fourteen (31.8%) showed progression disease, but only seven (15.9%) of these died. In seven (15.9%) patients serum testosterone level did not exceed 0.5 ng/ml, indicating an absence of gonadal activity. The median time to progression was 138.2 (95% CI, 14.3% - 66.1%) months, and the median cumulative survival from the start and from the suspension of AST was 105.5 (95% CI, 30.6% - 64.5%) months and 64.1 (95% CI, 31.4% - 65.1%) months, respectively. The savings in drug costs amounted to 772,267 euros. Conclusions: We can conclude that, taking in consideration these outcomes of survival and of savings in drug costs, in these selected elderly patients, this option of treatment could be of interest. No significant financial relationships to disclose.
Extended adjuvant letrozole following five years of tamoxifen is cost-effective from a Belgian health care payer's perspective
Authors: Pascal Lecomte, Martine Berlière, Fabrice Branle, Frederic Buxant, Herman Depypere, Luc Dirix, Guy Jerusalem, Fabienne Liebens, Patrick Neven, Robert Paridaens
Journal: Annals of Oncology (2006)