tbuckley/cabot-search huggingface dataset:
Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy.
Authors: J H Doroshow, P Multhauf, L Leong, K Margolin, T Litchfield, S Akman, B Carr, M Bertrand, D Goldberg, D Blayney
Journal: Journal of Clinical Oncology (1990)

Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.
A phase III randomised trial of sequential high dose chemotherapy (HDC) with peripheral blood stem cell support or standard dose Chemotherapy (SDC) for first-line treatment of ovarian cancer
Authors: J. A. Ledermann, N. Frickhofen, H. Wandt, C. Bengala, K. Champion, A. Hinke, V. Möebus
Journal: Journal of Clinical Oncology (2005)

5006 Background: Retrospective data and pilot studies suggested a possible benefit from high dose intensive therapy in the first-line treatment of ovarian cancer with low tumour burden. A phase III study of multi-cycle HDC in predominately optimally debulked stage IIB to IV epithelial ovarian cancer was conducted as two parallel studies by the EBMT and AGO/AIO between 07/98 and 06/04. Methods: Patients (Pts.) were randomised to a minimum of 6 courses of platinum-paclitaxel based therapy or HDC. For HDC peripheral blood stem cells were collected during induction with two courses of cyclophosphamide (3–4 g/m2) and paclitaxel (200–250 mg/m2). This was followed by three HDC cycles; two of carboplatin (AUC 20) and paclitaxel, and one course of carboplatin, paclitaxel, and melphalan (140 mg/m2). The primary objective was to compare progression free survival (PFS). Secondary objectives were overall survival (OS), toxicity and quality of life. Results: 149 pts (78 HDC, 71 SDC) were randomised. Pts. characteristics were well-balanced in the two arms; median age was 50 yrs and 94% pts. had FIGO III/IV ovarian cancer. 88% had < 2cm residual disease. 87% had 4 cycles and 76% completed all HDC; 95% completed ≥ 6 cycles of SDC. Gastrointestinal toxicity was the major non-haematological side-effect with HDC and 1 pt. (1.3%) died during HDC therapy. With a median follow up of 36 months PFS was 24.5 (HDC) v 21.7 months (SDC) (HR 0.85 (95% CI 0.56–1.29). The survival at 4 yrs. was 57% for both groups (HR 1.04; 95% CI 0.6–1.8). Conclusions: These interim results do not show a short-term benefit for first-line multi-cycle HDC in advanced ovarian cancer. No significant financial relationships to disclose.
Impact of first-line fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with advanced gastroesophageal adenocarcinoma: A retrospective analysis.
Authors: Aline Da Rocha Lino, Raphael Brandao Moreira, Jessica Ribeiro Gomes, Tarcia Tarciane Soares de Sousa, Carina Mina Abrahao, Rodnei Merlrina Martins Junior, Matheus Bongers Alessandretti, Marcus Paulo Fernandes Amarante, Fabio Augusto Barros Schutz, Carolina Kawamura, Rafael Schmerling, Marcelo Rocha Cruz, Fernando C. Maluf, Antonio C. Buzaid, Renata D'Alpino Peixoto
Journal: Journal of Clinical Oncology (2015)

216 Background: Despite a large number of randomized trials, there is no consensus as to the best regimen for advanced gastroesophageal cancer. Combination therapy with docetaxel, cisplatin, and 5-FU has shown increased response rates, progression-free survival (PFS) and overall survival (OS), but at the cost of significant toxicity. Based on a small phase II study, FLOT has been adopted by some groups given its better toxicity profile. We aim at reporting our experience with this regimen Methods: Patients with unresectable advanced gastroesophageal adenocarcinoma who received FLOT (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24h infusion in combination with docetaxel 50 mg/m2 on day 1 every 2 weeks) as first-line therapy at our institution were retrospectively evaluated. PFS and OS were estimated by the Kaplan-Meier method. Results: A total of 23 patients were reviewed, most of them with metastatic disease (60%). Median age was 56 years (range 26–76) and 74% were male. Median PFS and OS were 5,2 (95% CI 4,0-6,3) and 8,5 months (95% CI 4,4-12,6), respectively. Only 13%of the patients experienced prolonged PFS (&gt;12 months). There were no deaths due to the treatment. Conclusions: Before FLOT could be adopted as a first-line regimen for metastatic gastroesophageal cancer, phase III trials are urgently needed comparing FLOT with more traditional regimens.
Small cell carcinoma of the esophagus: Review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience
Authors: G. Y. Ku, D. Kelsen, B. Minsky, V. Rusch, M. Bains, D. H. Ilson
Journal: Journal of Clinical Oncology (2007)

4631 Background: Esophageal small cell carcinoma (ESC) is rare and accounts for &lt;1% of all esophageal cancers. It is treated like pulmonary SC but the optimal approach of surgery, chemotherapy or radiotherapy is unknown. Prior series (Chest 107:179, Cancer 88:262) indicate a poor median overall survival (OS) of 7–12 months (mos), rare long-term (LT) survival and the need for surgery as part of curative therapy. Methods: We reviewed records of patients (pts) with ESC treated from 1980 to 2005. All pathology was reviewed at MSKCC. Results: 24 pts were identified, with records available for 21. 86% male, 14% female, median age 60, 67% smokers. 81% had pure SC histology, with 85% of tumors in the lower esophagus or gastroesophageal junction. 13/21 (62%) had limited disease (LD) by VALSG criteria. For extensive disease (ED), liver (63%) was most common metastatic site (mets). Treatment for LD was: chemotherapy (chemo) only (3 pts, 23%), surgery only (1 pt, 8%), surgery and adjuvant chemo (3 pts) and chemoradiation (CRT) without surgery (6 pts, 46%). The most common chemo given was cisplatin/carboplatin and etoposide (81%). Pts with ED received chemo alone. Overall median survival was 19.8 mos (range, 1.5 mos to 11.2+ years (yrs)); for LD Pts, 22.3 mos (range, 6 mos to 11.2+ yrs); for ED Pts, 10.9 mos (range, 1.5 mos to 2.2 yrs). At median follow-up of 32 mos, 5 pts are alive (4 without disease (NED) and 1 with disease); 2 pts are alive &gt;5 yrs. 4 originally had LD and 3 of 4 received CRT only without surgery. None received whole brain radiation (WBXRT). 1 LD pt treated with surgery and adjuvant chemo recurred after 4 yrs, was salvaged with CRT and is NED 11.2 yrs after diagnosis. Of 18 pts with progression, 10 (56%) had new mets. Most common site was liver (4 pts) and only 1 pt had brain mets. Of 6 pts with LD who received CRT only, 3 recurred (1 local and 2 distant). Of 4 pts with LD who underwent surgery, all recurred (1 local, 3 distant). Conclusions: Pts with ESC with LD who received CRT without surgery can have LT survival. The role of surgery remains unclear. LT survival for 1 pt who underwent salvage CRT for recurrence after surgery argues for aggressive therapy for recurrence. Unlike pulmonary SC, brain mets are uncommon and WBXRT may not be needed for LT survival. No significant financial relationships to disclose.
Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer
Authors: P. Kiewe, S. Hasmüller, S. Kahlert, M. Heinrigs, B. Rack, A. Marmé, A. Korfel, E. Thiel, H. Sommer, M. Untch
Journal: Journal of Clinical Oncology (2005)

2530 Background: Ertumaxomab is an intact bispecific monoclonal antibody targeting HER2 and CD3. The heavy chain is composed of murine IgG2a and rat IgG2b subclasses with strong binding to activatory Fcγ-RI/III-receptors of accessory immune cells. The formation of a tri-cell complex between tumor cell, T-cell and accessory cell results in tumor cell killing by various immunological mechanisms. Methods: Seventeen patients with metastatic breast cancer were enrolled into a multi-center phase I dose-escalating trial. Three ascending doses (10–200μg) were administered intravenously on day 1, 7±1 and 13±1. Patients were followed up for 69 days. Safety and tolerability were primary Objectives: Secondary variables were anti-tumor activity and measurement of different immunological parameters (cytokines, hematological markers). Results: Sixteen out of 17 enrolled patients with a median age of 60,5 years and a HER2-expression score of 1+ (25%), 2+ (12.5%), and 3+ (62,5%) have completed the study up to date. 100μg was identified as maximal tolerable single dose. Most adverse events were mild and transient including fever (75%), chills (50%), nausea (44%), vomiting (25%), pain (38%). Grade 3/4 (CTC) were lymphocytopenia (69%) and elevation of liver enzymes (38%). One patient (200μg dose) developed severe hypotension and respiratory distress syndrome, one patient (150μg dose) developed a systemic inflammatory response syndrome and acute renal failure. All adverse events were fully reversible. Aggravation of congestive heart-failure was seen in a patient (200μg dose) with pre-existing ventricular dysfunction. Antitumor response was seen in 4 out of 15 evaluable patients (1CR, 2 PR, 1 SD) at dose levels of ≥100μg. Measurement of cytokines (IL-6, IL-2, TNF-α, IFN-γ) suggests a strong Th1-associated immune response. Induction of human-anti-mouse/rat-antibodies (HAMA/HARA) was detected in 3 patients (19%) only. Conclusions: Treatment with triple infusions of ertumaxomab yields a strong immunological response. Doses up to 100 μg can be safely infused with close monitoring of patients. Tumor response in some patients is encouraging suggesting anti-tumor efficacy. No significant financial relationships to disclose.
Comparison of rectal and colon cancer outcomes: A population based analysis
Authors: D. J. Renouf, H. F. Kennecke, R. Woods, C. Speers, J. Hay, T. Phang, C. Fitzgerald
Journal: Journal of Clinical Oncology (2008)

4040 Background: Rectal cancer has previously been associated with inferior five year survival in comparison to colon cancer. Total mesorectal excision (TME) and adjuvant therapy have reduced locoregional recurrence and, in some studies, improved rectal cancer survival. Therapy and outcomes of colon and rectal cancer were compared among 3 patient cohorts referred to the British Columbia Cancer Agency (BCCA) between 1990 and 2002. Methods: Patients with resected, pathological stage II or III colorectal cancer referred to BCCA in 1990, 1995/96, and 2001/02 were included. For those patients receiving long-course preoperative radiation, the higher of clinical or pathological stage was used. Kaplan Meier method was used for survival analysis. Results: 1,851 patients were included with a median age range of 64–69 and follow up time of 15.7 [1990], 10.8 [1995/96] and 5.3 [2001/02] years. Between 1990 and 2001/02 the use of adjuvant chemotherapy increased significantly for rectal cancer from 14.7% to 68.5% (p<0.001) and for colon cancer from 32.9% to 54% (p<0.001). The use of preoperative radiation therapy (RT) (p<0.001) and total mesorectal excision (TME) (p<0.001) in rectal cancer also significantly increased. 5 year overall survival (OS) was numerically inferior for rectal compared to colon cancer in 1990 and similar to colon cancer in the later cohorts (Table). The analysis was limited by small sample size and an expanded cohort will be presented. 5 year OS significantly improved for both rectal (p<0.001) and colon cancer (p=0.025) between 1990 and 2001/02. Conclusions: In this population based study, 5 year OS for stage II/III rectal and colon cancer significantly improved between 1990 and 2001/02, with similar outcomes now apparent for both sites. With respect to rectal cancer, improved outcomes are likely related to increased use of TME technique, preoperative RT and adjuvant chemotherapy. Improved outcomes for colon cancer likely reflect increased use of adjuvant chemotherapy. 5 year overall survival for colon and rectal cancer Year N 5 Y Overall Survival (%) Rectal Cancer 5 Y Overall Survival (%) Colon Cancer P-Value 1990 236 43.8 [34.9, 54.9] 53.7 [46.0, 62.7] 0.0969 Stage II 83 55.2 [39.7, 76.6] 63.6 [51.8, 78.2] 0.3954 Stage III 153 38.8 [28.7, 52.4] 47.7 [38.2, 59.5] 0.2088 1995–96 563 59.3 [53.1, 66.3] 61.7 [56.7, 67.2] 0.5607 Stage II 233 68 [58.3, 79.2] 72.3 [65.3, 80] 0.4675 Stage III 330 54.4 [46.6, 63.4] 53.5 [46.8, 61.2] 0.8654 2001–02 1052 63.7 [58.5, 69.4] 66.2 [62.4, 70.1] 0.4543 Stage II 430 70.6 [63.1, 78.9] 77.1 [71.9, 82.7] 0.158 Stage III 622 58.4 [51.4, 66.4] 59.1 [54.2, 64.4] 0.8818 No significant financial relationships to disclose.
Randomized, phase II study comparing interferon combined 5-fluorouracil plus cisplatin hepatic arterial infusion with interferon combined 5-fluorouracil hepatic arterial infusion in patients with advanced hepatocellular carcinoma
Authors: T. Yamashita, K. Arai, H. Sunagozaka, T. Ueda, T. Terashima, E. Mizukoshi, A. Sakai, Y. Nakamoto, M. Honda, S. Kaneko
Journal: Journal of Clinical Oncology (2009)

4588 Background: This randomized phase II trial compared the response rate (RR) of interferon (IFN) combined 5-fluorouracil (5FU) plus cisplatin (CDDP) hepatic arterial infusion (HAI) with IFN combined 5FU HAI in advanced hepatocellular carcinoma. Methods: Patients (pts) with measurable histologically or radiologically confirmed advanced hepatocellular carcinoma (major vascular invasion and/or bilobular multiple ≥5 nodules) were randomized into 2 groups. Arm A (n=57): continuous 5FU HAI (300mg/m2 day1–5, day8–12), CDDP HAI (20mg/m2, day 1, day 8 for 1.5 hours). IFN alpha-2b (3M IU/body) was administrated intramuscularly 3 times per week for 4 weeks. The treatment cycles repeated for 6 weeks. Arm B (n=57): IFN combined 5FU HAI with same dose without CDDP infusion. Treatment was continued until disease progression. The primary endpoint was RR. The secondary endpoints were overall survival (OS), time to progression (TTP) and toxicity. Results: Results for responses are presented for 109 pts and toxicity for 114 pts. The best overall response rate (RR) was 46% for group A and 25% for group B. This included 1 (2% of group A) vs. 3 (6% of group B) complete responses, and 25 (44% of group A) vs. 11 (19% of group B) partial responses. Fifteen pts in group A (26%) vs. 19 pts (33%) in group B had stable disease and 13 pts (23%) vs. 22 (39%) in respectively group A and B progressed while on treatment. RR was significantly higher in group A (p=0.02). The median TTP was 6.5 ± 2.0 months (mo) for group A vs. 3.3 ± 2.0 mo for group B (p=0.005). The median OS was 17.6 ± 3.2 mo for group A vs. 10.5 ±2.3 mo for group B (p=0.38). The median OS was 13.7 ± 4.9 mo for both groups. Grade 3/4 toxicity occurred in 65.8% of pts. Hematological toxicity was common and occurred in 53.5%. The thrombocytopenia and infusion port-related toxicity occurred more frequently in group A. Conclusions: IFN combined 5FU plus CDDP HAI shows higher antitumor activity and longer TTP than IFN combined 5FU HAI. Although OS is also longer without significant difference, these results show the clinical efficacy of additional CDDP to IFN combined 5FU HAI. No significant financial relationships to disclose.
Abstract #5605: Silencing glucose-regulated protein 78 sensitizes malignant glioma towards radiation therapy
Authors: Shin-ei Noda, Kamalakannan Palanichamy, Arnab Chakravarti
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Purpose/Objective(s):The purpose of this study was to investigate whether Glucose-regulated protein 78 (GRP78), a major endoplasmic reticulum chaperone with prosurvival properties, plays a direct role in mediating radiation resistance in Glioblastoma multiforme (GBM) cell lines and the underlying mechanisms. Materials/Methods: Stable knockdown cell lines of GRP78 using lentiviral based short hairpin RNA transduction were generated in GBM cell lines U87 and LN18. A co-immunoprecipitation was done to confirm that Phosphoinositide 3-kinase p85 formed complex with GRP78. The radiosensitivities of GRP78-knockdown U87 and LN18 cell lines were evaluated using clonogenic assay. Cells were given gamma-radiation and were allowed to form colonies for 14 days. Additionally, the GBM cell lines were exposed gamma-ray and subsequently evaluated for extent of double-strand DNA damage using the neutral comet assay at various time points in the ranging from 30 minutes to 96 hours after radiation exposure. An apoptosis was evaluated by Annexin V assay using a flowcytometer at various time points in the ranging from 10 minutes to 120 hours after 6Gy gamma-ray exposure. In vivo determinations of the respective radiosensitivities of GRP78-knockdown cells are ongoing and will be presented at the AACR annual meeting. Results: Co-immunoprecipitation verified interaction of p85 with GRP78. A dose enhancement factor at a surviving fraction of 0.1 of LN18 and U87 was 1.34 and 1.31, respectively. The maximum length of comet tails of GRP78-knockdown cell line of LN18 and U87 after 6Gy irradiation was 4.4 times and 3.0 times longer than that of Non-Target knockdown cell line. The maximum apoptotic index of wild type, Non-Target knockdown, GRP78-knockdown cell line in LN18 and U87 cell line was 26%, 20%, & 51% and 13%, 16%, & 38% respectively, indicating greater enhanced sensitivity to radiation in the GRP78-knockdown cell lines. GRP78 knockdown releases cells from G1 phase and accumulates cells in the chemo-/radio- sensitive G2/M phase as evidenced from the cell cycle analysis. Conclusions: Our findings suggest that GRP78 plays a critical role in mediating radiation resistance in GBM cells and show that GRP78-inhibition strategies might represent a novel approach to enhance the therapeutic gain of radiotherapy in the management of GBMs.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5605.
Treatment with bevacizumab (BEV) upregulates expression of the transcription factor Sp1 and its downstream target genes in human carcinoid cells: Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A (MIT)
Authors: J. Zhang, Z. Jia, L. Wang, Q. Li, L. Xiangdong, K. Xie, J. C. Yao
Journal: Journal of Clinical Oncology (2007)

15031 Background: Our previous studies show that human carcinoid cells overexpress pro-angiogenic factors, vascular endothelial growth factor A (VEGF), and transcription factor Sp1 plays a critical role in VEGF inducible and constitutive expression. However, the impact of antiangiogenic therapy on the Sp1/VEGF pathway remains unclear. Method: Groups of 10 athymic BALB/c nude mice were implanted with 1.5 million human H727 carcinoid cells. Treatment with VEGF neutralizing monoclonal antibody, BEV, MIT, or BEV + MIT was initiated once implanted tumor reached 4 mm in size. Result: Treatment with BEV, suppressed human carcinoid growth in nude mice (tumor size at week 5 1280 mm 3 vs 480 mm 3 ; p &lt; 0.001). Gene expression analyses revealed that this treatment substantially upregulated the expression of Sp1 (7 folds) and its downstream target genes, including VEGF (5 folds) and epidermal growth factor receptor (4 folds), in tumor tissues, whereas it did not have this effect on carcinoid cells in culture. Treatment with mithramycin A, an Sp1 inhibitor, suppressed the expression of Sp1 and its downstream target genes in both cell culture and tumors growing in nude mice. Median survival of mice treated with PBS, BEV, MIT, and BEV + MIT groups were 88, 112, 121, and &gt;160 days respectively (p &lt; 0.001). Combined treatment with bevacizumab and mithramycin A produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Conclusion: Treatment with bevacizumab may block VEGF function but activate the pathway of its expression via positive feedback. Given the fact that Sp1 is an important regulator of the expression of multiple angiogenic factors, bevacizumab-initiated upregulation of Sp1 and subsequent overexpression of its downstream target genes may affect the potential angiogenic phenotype and effectiveness of antiangiogenic strategies for human carcinoid. No significant financial relationships to disclose.
Abstract 16892: Tetrahydrobiopterin Increases Myocardial Tolerance to Ischemia/reperfusion Injury in Diabetes Mellitus and Hyperglycemia by Preventing eNOS Uncoupling
Authors: Zhi-Dong Ge, Thorsten M Leucker, Jesse Procknow, Yanan Liu, Jianhai Du, Mark Paterson, Yang Shi, David C Warltier, Judy R Kersten
Journal: Circulation (2012)

Tetrahydrobiopterin (BH4), an essential factor for endothelial nitric oxide synthase (eNOS), is significantly decreased in diabetes and hyperglycemia (HG). We hypothesized that modulation of cardia...