tbuckley/cabot-search huggingface dataset:
Anticoagulation and bleeding: A pooled analysis of lung cancer trials of the National Cancer Institute of Canada Clinical Trials Group
Authors: A. Le Maître, K. Ding, F. A. Shepherd, N. B. Leighl, A. Arnold, L. Seymour
Journal: Journal of Clinical Oncology (2008)

8065 Background: Clinical trials may mandate LMW heparin (LMWH) rather than coumadin (C) for patients (pts) requiring anticoagulation; lower risks of bleeding and drug-drug interactions are reported. Pts on lung cancer chemotherapy (CT) trials are at risk for venous thromboembolism and frequently are anticoagulated. Using data from three lung cancer trials conducted by NCIC CTG we analyzed bleeding in participating patients using LMWH, C or non-steroidal anti-inflammatories (NSAID). Methods: 3 lung cancer (small cell (SCCL) and non-small-cell (NSCLC)) trials with concomitant medication data were identified: BR18 (774 pts) compared BMS-275291 to placebo in NSCLC pts receiving 1st line platinum based CT, BR20 (107 pts) compared vandetanib to placebo in SCLC pts who had completed primary CT while BR21 (731 pts) compared erlotinib to placebo in 2nd or 3rd line NSCLC. Mantel-Haentzel test stratified by trial was used to analyse the prevalence of bleeding according to LMWH, C or NSAID usage. Analyses were also conducted including bleeding grade 3 or higher, stratified by treatment group. Logistic regression predicting bleeding was used to analyse the use of concomitant drugs adjusted on baseline characteristics (age, sex, performance status, creatinine, platelets). Results: Bleeding was associated with C (p = 0.014) in both the stratified by trial and by treatment received analyses. Bleeding grade 3 or higher (hemoptysis, CNS, gastrointestinal) was higher with C or LMWH and platelet higher than 100 during treatment, although only 37 pts had grade 3 or higher bleeding. C remained the only drug leading to significantly higher risk of bleeding (odds ratio 1.6 [95% Confidence Interval: 1.1 - 2.4], p = 0.02) in the adjusted analysis. Conclusions: C increases bleeding in lung cancer pts enrolled in clinical trials. Clinical trials should consider requiring LMWH usage rather than C if anticoagulation is required. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Roche AstraZeneca
Molecular dissection of the RAS/RAF/MAPK pathway in primary and metastatic melanoma
Authors: J. Rother, J. Bailey, G. Alvarado, V. G. Prieto, A. J. Lazar, D. Jones, W. J. Hwu
Journal: Journal of Clinical Oncology (2006)

8050 Background: Given the reported presence of frequent mutation in NRAS and BRAF in many melanocytic lesions, the association of mutations activating the RAS/RAF/MAPK pathway with tumor progression in melanoma remains unclear. We compared the NRAS and BRAF mutation status with the levels of activated MAPK in paired primary and metastatic melanomas. Methods: 15 patients with material from both primary and metastatic lesions were assessed. Four patients had metastasis at initial diagnosis, the remaining patients developed metastasis from 8.5 to 66 months (mos) following initial diagnosis (median 24.1 mos). Mutations in BRAF (exons 11 and 15) and KRAS and NRAS (exons 1 and 2) were assessed by quantitative pyrosequencing. MAPK levels were assessed by immunohistochemistry on paraffin sections using phosphor-44/42 (Thr202/Tyr204) polyclonal antisera. Results: Activating NRAS point mutations were found in 3 of 15 patients, with 2 detected in the metastatic lesions; both of these had upregulation of activated MAPK compared to the primary lesions. BRAF V599 point mutations were found in 3 of 15 patients and present in both the primary and cognate metastatic lesions. All cases with BRAF or NRAS mutations had moderate to high levels of activated MAPK, as compared to only 2 of 9 patients without such mutations. The correlation of mutational status and clinical course revealed that NRAS/BRAF mutations and/or MAPK activation did not negatively impact overall survival. Conclusions: Molecular alterations in the RAS signaling pathway are associated with activated MAPK in both primary and metastatic melanoma. NRAS mutations and MAPK activation may be preferentially associated with disease progression, as opposed to BRAF mutations. However, neither NRAS/BRAF mutation nor activation of MAPK signaling pathway in primary and/or metastatic melanoma was significantly associated with poor disease outcome. Further molecular dissection using the archived material from two large melanoma neoadjuvant trials conducted in 1988 and 1994 is ongoing to determine the prognostic and predictive power of these biomarkers. No significant financial relationships to disclose.
Bevacizumab in combination with 5-FU/leucovorin improves survival in patients with metastatic colorectal cancer: A combined analysis
Authors: R. D. Mass, G. Fyfe, J. Hambleton, F. Kabbinavar, H. Hurwitz, W. Novotny, S. Sarkar
Journal: Journal of Clinical Oncology (2004)

3616 Background: Bevacizumab [Avastin (BV)], a recombinant, humanized monoclonal antibody against VEGF, improves survival in combination with chemotherapy for first line treatment of metastatic colorectal cancer (CRC). In a randomized, placebo-controlled phase III study, the addition of BV to irinotecan/5-FU/Leucovorin (IFL) resulted in significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.6 months to 20.3 months). BV has been combined with 5-FU/leucovorin (LV) alone in 3 randomized studies (see table). In the phase III study, a third treatment arm of BV/5-FU/LV was included until the safety of IFL/BV was demonstrated in a pre-specified analysis. BV/5-FU/LV has been studied in 2 randomized phase II studies. In the larger phase II study, patient characteristics were similar to those in the phase III study with the exception that median age was 71 compared with 60 years, and ECOG performance status ≥ 1 was 72% versus 41% of patients. Combining the patient data from these 3 studies allows a more robust evaluation of efficacy and safety of BV/5-FU/LV in comparison with a combined control of 5-FU/LV and IFL. Methods: The combined control group included patients with metastatic CRC randomized to 5-FU/LV or to IFL. The comparator arm included patients randomized in these same studies to BV/5-FU/LV. BV dosing was 5mg/kg every 2 weeks in all patients evaluated. Results: The efficacy results are shown below. There was a 26% reduction in daily risk of death with BV/5-FU/LV compared with 5-FU/LV or IFL alone (hazard ratio 0.742; 95% CI: 0.59, 0.93). Adverse events were consistent with those previously reported. Conclusion: This large combined analysis confirms that the combination of Bevacizumab with 5 FU/LV improves survival and progression-free survival compared with 5-FU/LV or IFL alone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
Efficacy of FOLFOX4 as adjuvant therapy in stage II colon cancer (CC): A new analysis of the MOSAIC trial according to risk factors.
Authors: L. Teixeira, T. Hickish, C. Tournigand, J. Bachet, A. Bonetti, F. Rivera, C. Boni, J. Tabernero, T. Andre, A. De Gramont
Journal: Journal of Clinical Oncology (2010)

3524 Background: Although oxaliplatin/5FU-based chemotherapy after surgery is standard for patients with stage III, its role in stage II remains controversial where T4 and/or number of examined lymph nodes (LN) <12 are the most powerful high-risk (HR) prognostic factors. No benefit in OS was observed while a trend in DFS was observed in HR stage II (André, JCO 2009). Methods: A new subgroup analysis was performed in patients with HR (T4 and/or LN <12) and low risk (LR) stage II, reviewing clinical characteristics, co-morbidities according to Adult-Co-morbidity Evaluation-27, SAEs, relapses, treatment at relapse and cause of death. Results: 503 HR stage II and 396 LR stage II pts were randomized between FOLFOX4 (253 and 198 pts, respectively) and LV5FU2 (250 and 198 pts, respectively). Median follow up was 6 years. In HR stage II, DFS hazard-ratio was 0.72; 95% confidence interval [CI] 0.49-1.06 and OS hazard-ratio was 0.81 [CI] 0.52-1.26. In LR stage II, DFS hazard-ratio was 1.39 and OS hazard-ratio was 1.02. No imbalance was observed in reference to the initial characteristics except for gender in LR population. Table shows data in HR stage II. Conclusions: FOLFOX4 remains an option in HR stage II but can not be recommended in LR stage II. Excess in SAEs, death of other cancers, less aggressive therapy at relapse can explain the discrepancy between OS and DFS. Reduction in duration of chemotherapy and improvement of relapse management may increase the therapeutic ratio of FOLFOX4. Update until 10-year follow-up and block collection for translational research are ongoing to better define the population who can benefit of FOLFOX4. HR II HR II FOLFOX HR II LV5FU2 p N 503 253 250 >70 year 80 38 42 Comorbidities (1/2) 211 116 95 Cardiovascular (1/2) 154 (131/23) 85 (73/12) 69 (58/11) SAE 53 33 20 0.08 Treatment/Cvasc/other (23/5/25) (16/3/14) (7/2/11) Relapse or death at 5 yrs* 105 46 59 Living with relapse 31 11 20 0.10 Treatment at relapse 64 26 38 Irinotecan/oxaliplatin/(both) 32 15 : 13/2 27 : 14/15/(2) Surgery metastases 28 7 21 0.03 Death colon cancer at 6 yrs 59 24 35 Death other at 6 yrs (second cancer) 25 (6) 13 (5) 12 (1) OS from relapse (months) 105 17.3 23.6 * Including death of any cause. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Baxter International, Roche, sanofi-aventis Baxter International, Pfizer, Roche, sanofi-aventis sanofi-aventis sanofi-aventis
Toxicity and safety of weekly high-dose 5-FU as 24-h infusion and folinic acid (AIO regimen) in adjuvant therapy of UICC stage III colon cancer. InTACT: A multicenter phase III trial
Authors: A. Wein, T. Lehnert, T. Liersch, D. Braumann, A. Schaible, M. Eckart, R. Thiemann, W. Teichmann, W. Hohenberger, E. G. Hahn
Journal: Journal of Clinical Oncology (2004)

3586 Background: The AIO regimen is common for palliative treatment of colorectal cancer. We report for the first time on the toxicity and safety of the AIO regimen in an adjuvant phase III trial for UICC stage III colon cancer (CC). Methods: A prospective phase III trial based on quality controlled surgery and pathology (QSCP) in UICC stage III CC (R0). Group A: QSCP vs. group B: QSCP+AIO regimen for 6 months. End of trial: 9/01 after interim analysis (Wein et al, Ann Oncol 2002). Trial monitoring: by IMEREM, Nuremberg. In group B chemotherapy was terminated in all 79 patients (pt.). The AIO regimen was administered in the form of a 500 mg / m2 application (appl.) of folinic acid (FA) as 1–2 h i.v., followed by 2000 mg/m2 5-FU as a 24-h i.v. (AIO regimen) via port-a-cath on d 1, 8, 15, 22, 29, 36, qd 57; 3 cycles (6 months). Median follow up: 45.3 months. Results: AIO regimen: n = 79 pt.; m/f: 62%/38%; age: 61 years (28–75). ECOG: 0/1: 71%/29%; Frequent concomitant diseases: arterial hypertension: n=27 (34%); DM: n=12 (15%); glaucoma: n=3 (3,8%); elevated CEA prior to surgery: yes/no/"missing": 27%/66%/7%. Median start of treatment after surgery: d 29. Total number of 5-FU applications: 1295. The mean 5-FU appl./pt. was 16 (1–18); 18 appl: 77%; > 12 appl. 89% and the mean 5-FU total dose per pt. 32.5 g/m2 (90% of the maximum dosage). As higher grade toxicity grade 3+4 presented: diarrhea: n=7/n=1 (9% / 1.3%); nausea/vomiting: n=3/n=1 (3.8%/1.3%); stomatitis + cheilitis: n=3 /n=1 (3.8% / 1.3%); cardiac toxicity: n=1/n=1 (1.3%/1.3%); no deaths. Thrombosis due to port-a-cath complications: n=3 (3.8%). A dose reduction to 75% was carried out in 2.0% of the appl. and to 50% in 2.9% of the appl., respectively. Conclusions: The AIO regimen is well tolerated in adjuvant chemotherapy treatment of CC. It may be comfortably applied on an outpatient basis and presents a high mean 5-FU dose of 32.5 g/m2 per pt. Compared with 5-FU/FA bolus regimens the AIO regimen appears to offer a more favorable toxicity profile and a higher mean 5-FU dose. For definite conclusions the results of the EORTC (40963) phase III trial remain to be seen. No significant financial relationships to disclose.
Image-guided intensity modulated radiation therapy (IG-IMRT) affords increased survival for biliary tract tumors: Results from preliminary analysis
Authors: G. Starling, C. D. Fuller, C. R. Thomas, M. Fuss
Journal: Journal of Clinical Oncology (2006)

4131 Background: The purpose of this study is to determine the effect of image-guided radiotherapy on survival in adenocarcinoma of the biliary tract. Methods: Between 1995 and 2005, 43 pts with primary biliary tract (gallbladder or bile duct) neoplasms were treated with radiotherapy. 26 of the pts were female and 17 were male. Their average age at registration was 64, and ranged from 25 to 86. Twenty-five pts (58%) were Hispanic, while 18 (42%) were white. 31 pts (72%) underwent surgical treatment, most having cholecystecomy (50%). 29 pts (67%) had chemotherapy: 21 (72%) were given fluorouracil-based drugs, 2 (7%) received gemcitabine, and 6 (21%) received other agents. 23 pts (53%) received conventional radiation treatment using AP/PA, AP/PA with opposing lateral, or AP with opposing lateral fields. 20 pts (47%) received IG-IMRT using Nomos Peacock and daily ultrasound image guidance (BAT, Nomos, Cranberry, PA). For daily ultrasound-based image-guidance, sagittal and axial ultrasound images were acquired, and used to align pt anatomy through superimposition of CT derived organ and vascular guidance structures. Pts were treated using a boost technique to a reduced volume at gross disease after an initial dose to gross tumor and clinically evident microscopic disease. Results: Median dose to target was 54 Gy, with median conventional and IG-IMRT total doses of 48.6 and 60 Gy respectively (p=0.05). Treatment was well tolerated, with only two patients reporting RTOG grade 3 toxicity. All other patients exhibited Grade ≤2, with 23/43 reporting Grade ≤1 The median survival time from the date of registration for all patients was 8.7 months; conventional RT pts had a median survival of 6.1 months, while the IG-IMRT cohort had a median survival of 11.4 months (p = .02). Conclusions: Ultrasound-based image-guided IMRT is a feasible mechanism of delivering moderate dose escalation in conjunction with tighter safety margins, resulting in acceptable acute toxicities. Early survival data with this novel technique are encouraging and demonstrate a notable survival differential using image guided radiotherapy as component of multi-modaility regimens. No significant financial relationships to disclose.
The influence of ER on small HER2-positive invasive breast cancers.
Authors: V. Caggiano, C. Parise, K. Bauer
Journal: Journal of Clinical Oncology (2010)

1586 Background: There is controversy regarding the risk of recurrence of the node-negative, HER2-positive pT1a-b tumors. We have shown considerable variation in survival of HER2-positive tumors of all sizes. We now examine the HER2-positive breast cancers with regard to ER status, node-status, and tumor size. Methods: Using the California Cancer Registry 2000-2007, we studied 16,958 cases of stages 1-3, HER2-positive primary invasive breast cancer. Kaplan-Meier cause-specific 5-year overall survival (OS) was computed and the log-rank test was used to compare survival between node-positive and node-negative tumors within the T1a, T1b, T1c, and T2 categories. Cox-proportional hazards analysis was used to determine the effect of ER/PR/HER2 subtype within each tumor size category for the node-positive tumors after adjusting for age, race/ethnicity, stage, grade, and socioeconomic status. Anti-HER2 treatment information was not available. Hazard ratios (HR) and 95% confidence intervals were computed. Results: For all tumor sizes, survival was statistically significantly better for negative node-tumors than for node-positive tumors (p < 0.001). Node-negative T1a, T1b, and T1c tumors had 5-year survival of 99%, 98%, and 97% respectively. There were 7,430 node-positive cases and survival was 93% for T1a, 94% for T1b, and 90% for T1c. No variables were associated with risk of death for the T1a and T1b tumors. Compared with the ER-/PR-/HER2+ subtype (the molecularly defined HER2-positive subtype), the ER+/PR+/HER2+ (HR = 0.33; 95% CI = 0.22-0.49) and ER+/PR-/HER2+ (HR = 0.49; 95% CI = 0.30-0.81) subtypes were associated with a reduced risk of death for T1c and T2 tumors. Conclusions: It is not surprising that node-negative breast cancers have better survival than node-positive cases. We found that for HER2-positive, node-negative, T1a, T1b, and T1c tumors, 5-year OS is excellent and for node-positive cases, it is only slightly lower but still 90% or greater. For tumors less than 10mm, ER/PR/HER2 subtype does not appear to influence survival. For larger tumors, ER-positivity reduces the risk of death when compared with the molecularly defined HER2-positive subtype, suggesting that ER rather than HER2 has greater influence on OS. No significant financial relationships to disclose.
A phase I/II trial of induction chemotherapy followed by concomitant docetaxel with concomitant boost radiotherapy (CBR) and amifostine for advanced head and neck cancer (HNC)
Authors: C. Saurel, R. Meredith, J. A. Bonner, G. Peters, W. Carroll, S. A. Spencer, L. Nabell
Journal: Journal of Clinical Oncology (2006)

15525 Background: Concomitant chemo-radiation for head and neck cancer has emerged as the optimal method of treating advanced head and neck cancers, although the acute and late toxicities can be formidable. The addition of induction chemotherapy to concomitant chemo-radiation for head and neck cancer is designed to impact the incidence of distant metastasis while delivering aggressive local treatment. This trial evaluates the tolerability and effectiveness of induction chemotherapy followed by CBR with concurrent docetaxel and subcutaneous (SC) amifostine in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods: Patients with stage III/IV nonmetastatic SCCHN received 3 cycles of primary chemotherapy with docetaxel and cisplatin, each at 75 mg/m 2 . Patients then received 4 weekly doses of docetaxel at 20 mg/m 2 with concurrent CBR. SC amifostine was given at a dose of 500 mg in divided doses during each day of XRT. Results: The phase I component defined the MTD of concurrent docetaxel as 20 mg/m 2 for 4 cycles during CBR. 18 patients are evaluated for response. No patient developed progressive disease during primary chemotherapy. Grade 3–4 mucositis was common, but all patients completed the planned concomitant docetaxel. At 6 months after treatment, 7/18 patients still used a feeding tube, though most have had them subsequently removed. Amifostine given by SC was well tolerated; 7 patients developed transient hypotension not requiring any intervention, with grade1 dermatitis and nausea reported. 2 patients discontinued amifostine due to rash or persistent hypotension. Conclusions: Response to induction chemotherapy was greater then 75% by radiological assessment, with no patient developing distant metastasis thus far. Local control has been excellent but side effects from docetaxel and CBR have necessitated prolonged use of feeding tubes for up to 6 months. SC amifostine has been well tolerated without significant side effects. This aggressive therapy is effective treatment for locally advanced SCCHN. No significant financial relationships to disclose.
Sorafenib for advanced hepatocellular carcinoma (HCC): Impact of rationing in the United Kingdom.
Authors: D. H. Palmer, S. A. Hussain, A. J. Smith, D. Hull, P. J. Johnson
Journal: Journal of Clinical Oncology (2010)

e14516 Background: HCC is the third commonest cause of cancer death worldwide. Prognosis depends on performance status (PS), underlying liver disease, tumour stage and available therapies. Sorafenib improves survival for carefully selected patients with advanced HCC and has become standard of care in this context. However, in the current health economic climate, the potential financial burden of novel anti-cancer drugs is of increasing relevance. In the UK, availability of new drugs within the government-funded healthcare system is determined by the National Institute for Health and Clinical Excellence (NICE) based on an assessment of clinical- and cost-effectiveness. Pending NICE assessment, access to sorafenib was at the discretion of patients' local health funding bodies (Primary Care Trust, PCT), a process that may delay or deny access to the drug. Methods: In a large supra-regional hepatobiliary oncology unit, applications were made to PCTs for patients with advanced HCC where sorafenib was considered appropriate. The primary outcome measure was overall survival from the date of application. Results: 62 applications were made: 26 (42%) were approved and 36 (58%) declined. Demographics and prognostic factors were balanced between the two groups. Notably, this cohort had a number of adverse prognostic features: patients were predominantly PS 1-2; one-third had Child-Pugh B cirrhosis; the majority had multi-focal disease with largest lesion > 5 cm; and macroscopic vascular invasion and metastases were each present in one-third of cases. Median survival was 3.4 months in the absence of sorafenib, and 7.1 months in those receiving sorafenib (HR 0.489; 95% CI 0.254-0.9027; p = 0.0228). Conclusions: These data provide a comparison of sorafenib with no treatment and demonstrate the potential detrimental impact on patient outcomes of rationing healthcare resources on the basis of cost. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Schering Pharma Bayer Schering Pharma Bayer Schering Pharma
Nutritional assessment with body mass index in elderly cancer patients: Influence of chemotherapy exposure.
Authors: N. Magné, P. Chaïbi, C. Hochart, J. Duron, L. Hannoun, C. Tresallet, J. Lefranc, F. Cajfinger, A. Bellanger, J. Spano
Journal: Journal of Clinical Oncology (2010)

e19614 Background: Nutritional aspects remain an important problem in elderly cancer patients care and cure. However, the real impact of chemotherapies regimens in elderly patients is not clearly established. The aims of the present study were to evaluate the nutritional status in a series of elderly cancer patients treated by common chemotherapies regimens. Methods: From May 2005 to October 2009, 375 patients aged over 70 years with solid malignancies were systematically treated by common chemotherapies regimens and registered in a prospective databank at the salpetriere hospital, in Paris. Body Mass Index (BMI) measurements were assessed at baseline and before each chemotherapy. According to Body Mass Index patients were classified as underweight (< 18.5), normal weight (between 18.5–24.9), overweight (25–29.9) and obesity (over 30). Results: One hundred sixty five male and 210 female with a mean age of 76.3 years (range 70-101.3) were evaluated. Each patient received between 1 to 16 lines of chemotherapy (median of 2) for a total of 1135 lines. More than 75 % of patients had a colorectal, breast, lung, ovary and prostate cancer. At baseline, 16 out of 375 elderly patients (4.2 %) presented a BMI under 18.5 and were considered as under weighted. At the end of the treatment 17 out of 375 patients (4.5 %) with a BMI under 18.5 and were considered as under weighted, 8 out 16 patients had an improvement in the initial BMI score and were at the end of evaluation well nourished and at the contrary 9 out 17 patients had a decrease of their initial BMI status Conclusions: Chemotherapeutic drugs and regimens did not influence the nutritional status as measured by BMI in this representative elderly patients treated by common chemotherapeutic regimens. No significant financial relationships to disclose.