tbuckley/cabot-search huggingface dataset:
Co-morbidity is a better predictor of 5-fluorouracil pharmacokinetic than chronological age in older adults
Authors: M. Gusella, L. Stievano, R. Padrini, E. Ferrazzi, A. Bononi
Journal: Journal of Clinical Oncology (2007)

9038 Background: Fifty percent of all cancers occur in elderly people and the total cancer burden is expected to rise. Data are needed to ensure the safe administration of chemotherapy in the older patient population. Aging can affect the pharmacokinetics in a number of ways and the selection of chemotherapy in the elderly is frequently and empirically determined by degree of comorbidity and the patients’ functional status. The aim of our study was to determine whether high level of comorbidity, measured using a standardized instrument, can predict 5-fluorouracil (5FU) disposition in older adults. Methods: Geriatric outpatients affected by stage 2 or 3 colorectal cancer and treated with adjuvant MAYO Clinic regimen were the study population. The evaluation was conducted on men aged 70 years old or more, with varying levels of chronic illness. All of them had a good performance status (ECOG score= 0–1). Non neoplastic disease burden was measured using the Cumulative Illness Rating Scale (CIRS) and drug disposition using area under the curve (AUC) of the drug plasma levels during 30 min immediately after 2 minute bolus administration of 5FU 375–425 mg/mq. Results: Forty men were studied, aged between 70 and 80 years old (median = 72); their CIRS scores ranged between 0 and 12 (median=3). Pharmacokinetic analysis confirmed an elevated interpatient variability: 5FU plasma AUC after bolus administration ranged between 241 and 1,140 mg × min/L. There was no correlation between age and comorbidity burden or age and 5FU AUC in that population. On the contrary with increasing comorbidity (increase in CIRS score) there was a proportional increase in 5FU AUC: patients with CIRS score from 0 to 3 (n=22), between 4 and 7 (n=11) and greater than 7 (n=7) had mean AUC of 523.5± 139.6, 637.0±124.0 and 877.4±195.0 mg × min/L respectively (p&lt;0.0001). Conclusions: This study shows that chronological age did nor correlate with CIRS score or 5FU disposition. In older adults with varying degrees of chronic illness, administrated with the same chemotherapy doses, the comorbidity level influenced the magnitude of 5FU exposition, suggesting that the CIRS score could be used to tailor treatment doses. Funded by AIRC-Veneto No significant financial relationships to disclose.
Docetaxel (T) followed by capecitabine (X) as first-line chemotherapy in patients (pts) with metastatic breast cancer (MBC): Preliminary findings from a phase II study
Authors: J. L. Bayo, M. Lomas, J. Salvador, M. Ruiz, A. Moreno
Journal: Journal of Clinical Oncology (2006)

10692 Background: X and T are highly active single agents in MBC. The XT combination leads to superior overall survival (OS), time to progression (TTP) and response rate (RR) vs. T alone in anthracycline-pretreated MBC [O’Shaughnessy et al. J Clin Oncol 2002]. The aim of this trial was to evaluate the efficacy and safety of sequentially administered T then X as first-line treatment in MBC. Methods: Pts ≥ 18 years with previously untreated, HER2neu-negative MBC, ECOG PS ≤ 2, were included in this prospective, multicenter, non-randomized, phase II study. Pts received 3 cycles of T (100mg/m 2 d1) followed by 3 cycles of X (1250mg/m 2 bid d1–14), every 3 weeks. Results: To date, 38 pts are evaluable for safety and 33 pts for efficacy. Baseline characteristics: median age 54.4 years (range 33–76); PS ≥ 1 50%; 36 (95%) pts had previous (neo)adjuvant anthracyclines, 8 (21%) concomitant with paclitaxel. The most frequent metastatic sites were: bone 47%, nodes 39% and liver 36%. 69% of pts had ≥ 2 metastatic sites. To date, 38 pts have received 3 cycles of T and 33 have also received 3 cycles of X. A total of 195 cycles have been administered: T 108 cycles (median 3, range 1–3); X 87 cycles (median 3, range 1–3). Dose reductions and interruptions for T vs. X were 32 vs. 21% and 21 vs. 21%, respectively. Median relative dose intensity: T 0.97 (range 0.62–1.00), X 0.93 (range 0.26–1.00). T grade 3/4 toxicities (37 evaluable pts): asthenia 19%, mucositis 16%, nausea 13%, febrile neutropenia 11%, rash 5%, diarrhea 5%, infection 3%. X grade 3/4 toxicities (33 evaluable pts): hand-foot syndrome 9%, diarrhea 9%, vomiting 9%, asthenia 6%, nausea 3%, anorexia 3%. In the 33 pts evaluable for efficacy, the RR was 61%, including 4 CRs and 16 PRs. At a median follow-up of 6.1 months, median TTP has not yet been reached. Conclusions: These preliminary results show that the sequential regimen of T followed by X is feasible, effective and well tolerated in first-line MBC, although giving X before T should also be investigated. Findings from a recent trial of XT vs. T followed by X [Beslija et al. ECCO 2005] suggest that XT should be standard in fit poor-prognosis pts with aggressive disease. No significant financial relationships to disclose.
Clinical benefit with compassionate use gefitinib in a subset of non-small-cell lung cancer (NSCLC) patients with the bronchoalveolar (BAC) subtype treated during an expanded access program (EAP)
Authors: R. B. Reiling, J. L. Wade, R. Govindan, A. J. Wozniak, T. A. Hensing, S. Koshy, C. D. Thienelt, R. B. Natale, C. P. Belani
Journal: Journal of Clinical Oncology (2004)

7087 Background: Little clinical data are available in BAC, a slow growing but relentlessly progressive clinico-pathologically defined adenocarcinoma patient subset in NSCLC. A 14% partial response (PR) rate and median survival of 12 months were reported in 58 BAC patients who received paclitaxel. A recent analysis of 138 good performance BAC patients treated with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, showed a PR rate of 21% in previously untreated patients and 10% in previously treated patients. Retrospective data are being collected on 1639 consecutive patients who were treated with gefitinib before January 2003 in an EAP; data collection is complete on 533 patients. This interim retrospective report includes data from a subset of 54 patients with histologically confirmed BAC. Methods: Patients with BAC had failed standard treatment or were unsuitable for systemic chemotherapy. Patients received oral gefitinib 250 mg daily for as long as clinical benefit was present in the absence of significant toxicity. Results: Of 54 patients, there were 23 men and 31 women. The median age was 69.5 years (range, 25.7–88.5 years). Forty-six patients (85.2%) had stage IV disease and 11/35 (31.4%) had a performance status ≥ 2. Most patients were treated previously with chemotherapy (75.9%) and 38.9% received prior radiation. In 41 patients with imaging studies, 1 patient had an investigator-assessed PR (2.4%); the stable disease rate was 48.8% (95% CI, 33.5–64.1%). The median duration of treatment was 3.0 months (0–29+ mo). The Kaplan-Meier 1-year survival rate was 37.3% (95% CI, 22.6–52.0%). Adverse events consisted primarily of mild to moderate skin rash (33.3%) and diarrhea (37%). Conclusions: Gefitinib appeared to provide clinical benefit and was well tolerated in a population that had a large proportion of poor performance status and BAC patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Lilly AstraZeneca AstraZeneca; Bristol-Myers Squibb; Lilly AstraZeneca
Do gender and race influence survival in patients with non-small cell lung cancer brain metastases? An outcomes study utilizing the RTOG RPA class stratification
Authors: G. M. Videtic, C. A. Reddy, S. T. Chao, T. W. Rice, D. J. Adelstein, G. H. Barnett, T. M. Mekhail, M. A. Vogelbaum, J. H. Suh
Journal: Journal of Clinical Oncology (2006)

7153 Background: To explore gender, race and their interactions in the setting of NSCLC brain metastases only, a single-institution brain database was analyzed, using the RTOG recursive partitioning analysis (RPA) brain metastases classification. Methods: From 1/82 to 9/04, 831 NSCLC pts with brain metastases were registered. RPA criteria for analysis were: class I- Karnofsky performance status (KPS) ≥ 70, age&lt;65 years, primary tumor controlled, no extracranial metastases; class III- KPS&lt;70; class II- all others. Results: Median follow-up was 5.4 months (m) (range 0–122.9). Median age was 62.4 (range 25–90). Median KPS was 80 (range 20–100). There were 485 males [M] (58.4%) and 346 females [F] (41.6%). 824 pts (99%) were either African-American (AA; n = 142[17%]) or White (W; n = 682[83%]). Pts characteristics were balanced when stratified by RPA class and by treatments. Median survival (MS) in months from time of brain metastasis diagnosis for all pts was 5.8. MS in months by gender [F vs. M] and race [W vs. AA] was: 6.3 vs. 5.5, p = 0.013; 6.0 vs. 5.2, p = 0.08, respectively. By RPA class for gender, MS trends (in months) favored F over M in classes I and II but not III: 17.1 vs. 9.5 (p = 0.11); 6.8 vs. 6.0 (p = 0.09), 2.7 vs. 2.5 (p = 0.42), respectively. By RPA class for gender and race, MS trends (in months) favored AAF over AAM in classes I and II but not III: 30.0 vs. 12.4, p = 0.50; 11.2 vs. 4.6, p = 0.021; 3.2 vs. 3.2, p = 0.64, respectively; and WF over WM in classes I but not II or III: 14.4 vs. 9.5, p = 0.11; 6.6 vs. 6.3, p = 0.38; 2.4 vs. 2.3, p = 0.49, respectively. On multivariable analysis, significant variables were gender (p = 0.041; RR 0.83); RPA class (p &lt; 0.0001; RR 0.28, for I vs. III; p &lt; 0.0001; RR 0.51, for II vs. III). Conclusions: Gender significantly influences NSCLC brain metastasis survival while race trends to significance. MS trends by RTOG RPA class suggest race may interact with genderprimarily in class I but pt numbers limited significance. Further characterization of these factors is warranted. No significant financial relationships to disclose.
The association of cancer and allergic symptoms among female adult participants aged ≥40 years in NHANES III
Authors: Y. Chae, J. Kim, W. Tester
Journal: Journal of Clinical Oncology (2009)

e22060 Background: The contribution of inflammation to carcinogenesis has been reported. Allergic diseases are now recognized as a systemic inflammatory process. We investigated whether common allergic symptoms are associated with cancer risk. Methods: The Third National Health and Nutrition Examination Survey (NHANES III) is a stratified probability sample of the U.S. population collected during 1988–1994. The prevalence of cancer excluding skin cancer was obtained by personal medical interview. Allergic symptoms were categorized into three categories: no symptoms (NO), rhinitis/conjunctivitis without wheezing (RC), and wheezing (WZ). Other risk factors for cancer were defined by NHANES III questionnaire and results of physical examination. Multivariate logistic regression was used to obtain odds ratios of cancer according to the existence of allergic symptoms adjusted for other possible confounding variables considering complicated sampling methods and weights. Results: 4,558 female adults were selected out of 5076 female adults aged ≥40 years who participated in both interview and physical examination. Cancer was present in 7.41% (n=301). 36.3% (n=1,893) of subjects did not have any allergic symptoms (NO), 47.6% (n=1,979) showed RC, and 16.2% (n=726), WZ. The prevalence of cancer was 5.43% in NO, 7.63% in RC, and 11.23 in WZ (p=0.006). Unadjusted odds ratios of cancer were 1.44 (95% CI: 0.99–2.08, p=0.053) in RC and 2.20 (1.27–3.80, p=0.006) in WZ compared with NO. Odds ratios are 1.49 (1.00–2.22, p=0.048) in RC and 2.08 (1.11–3.89) in WZ adjusting for age, race, education, income, asthma, COPD, C-reactive protein, obesity, smoking, alcohol drinking, physical inactivity, and menopausal status. In subgroup analysis, adjusted odds ratios of breast cancer were 1.89 (1.04–3.42, p=0.037) in RC and 2.08 (0.90–4.78, p=0.084) in WZ, while other cancers showed no statistically significant associations. Conclusions: Common allergic symptoms, even symptoms of allergic rhinitis of conjunctivitis, may be associated with increased risk of cancer in female adults. It supports the hypothesis that systemic inflammation mediators may trigger or promote cancer development in all parts of the body. However, prospective studies are required to validate our findings. No significant financial relationships to disclose.
A retrospective analysis to identify variables predictive of achieving a pCR after neoadjuvant chemoradiation therapy for locally advanced esophageal cancer
Authors: J. A. Brooks, E. Werner, N. P. Jain, P. R. Helft, R. T. Zon, N. S. Fineberg, J. Leblanc, L. McHenry, L. H. Einhorn, K. A. Kesler
Journal: Journal of Clinical Oncology (2004)

4061 Background: Patients achieving a complete pathological response (pCR) after neoadjuvant chemoradiation therapy (CRTx) for locally advanced esophageal cancer have a superior prognosis as compared to those who do not achieve a pCR. A retrospective, institutional review was conducted to identify variables potentially predictive of achieving a pCR. Methods: From 1992 through 2002, 86 patients with esophageal cancer were identified who met criteria for review including pretreatment transesophageal ultrasound (EUS) stage ≥ II and platinum-based CRTx followed by transthoracic esophagectomy including complete staging with celiac and mediastinal lymph node dissections. The cohort was mainly male (88.2%, n=75) with a mean age of 57.8 yrs and adenocarcinoma as the predominant histology (89.4%, n=76). Fifty-five (65.8%) patients demonstrated EUS stages III or IVa prior to CRTx. Results: Twenty-five (29.4%) patients demonstrated a pCR after CRTx. Although none of the 10 variables analyzed were significantly predictive of a pCR, trends emerged in patients demonstrating a pCR including lower body mass index (BMI mean 27.6 vs non-pCR 30.1; p=0.12) and squamous cell as compared to adenocarcinoma histology (55.6%, n=5 vs 26.7%, n=20; p=0.11). Pretreatment EUS T stages 1 and 2, EUS N stage 0 and overall EUS stages IIa and IIb all demonstrated a higher percentage of patients achieving a pCR (T 1 or 2 47.0%, n=8 vs T 3 or 4 25.4%, n=17, p=0.14; N0 40.0%, n=8 vs N1 26.6%, n=17, p=0.27; stages IIa or IIb 41.3%, n=12 vs III, IVa or IVb 23.6%, n=13, p=0.13). Age (p=0.35), amount of weight loss (p=0.81) and gender (p=0.99) were not predictive of achieving a pCR. Multivariate analysis with variable entry set at p<0.15 demonstrated squamous cell histology to be most predictive of pCR (p=0.04). Conclusions: A lower BMI, squamous cell histology, and earlier EUS T, N and overall EUS stage increased the likelihood of patients achieving a pCR after CRTx in this retrospective study. Continued study is indicated to avoid the costs and potential for additional risks of CRTx in patients who predictably will not achieve a pCR. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Prognostic factors for survival in the phase III TROPIC trial.
Authors: A. Oliver Sartor, Stéphane Oudard, Mustafa Ozguroglu, Steinbjorn Hansen, Jean-Pascal H. Machiels, Ivo Kocak, Gwenaelle Gravis, Istvan Bodrogi, Mary J. MacKenzie, Francisco Jorquera Orlandi, Liji Shen, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2012)

102 Background: In TROPIC ( NCT00417079 ) 755 men were randomized (378 cabazitaxel/prednisone [CbzP]; 377 mitoxantrone/prednisone [MP]). Treatment arms were well balanced; ECOG PS 0–1 (93% CbzP vs 91% MP), measurable disease (53% vs 54%), baseline pain (46% vs 45%) and ≤ 6 months from last dose of docetaxel (D) to randomization (62% vs 72%). CbzP significantly improved overall survival (OS) in mCRPC pts who progressed on or after D treatment compared with MP (HR 0.70; CI 0.59–0.83; P &lt; 0.0001). We investigated overall prognosis and performed a multivariate analysis of factors implicated in OS from this robust dataset. Methods: A univariate analysis of a variety of factors followed by a multivariate analysis of all factors was conducted. Interactions with treatment arms were explored. Cox proportional hazard models were used to examine the effect of treatment and prognostic factors on OS. Results: In addition to the significant effect of treatment received, the univariate analysis identified ECOG PS and measurable disease at baseline, time from last dose of D to randomization, time of progression after last D treatment and pain scores at baseline as significant prognostic factors for OS. Interactions of each of these factors with the treatment were not statistically distinct, suggesting that CbzP survival benefit was consistent among the subgroups defined by these factors. After adjustments for all prognostic factors, multivariate analysis identified ECOG PS 2, measurable disease, time of last dose of D to randomization (≤ 6 months vs &gt; 6 months) and presence of baseline pain as statistically significant prognostic factors. Following adjustments, the treatment effect on survival (CbzP vs MP) remained statistically significant (Table). Conclusions: ECOG PS, measurable disease at baseline, time from last D dose to randomization, baseline pain and CbzP treatment predicted OS in patients in the TROPIC study in a multivariate analysis. [Table: see text]
Correlation of blood levels of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor and hemoglobin with response to therapy in advanced non-small cell lung cancer patients (NSCLC)
Authors: V. Alberola, C. Camps, R. Sirera, R. M. Bremnes, P. Bayo, A. Blasco, A. Berrocal, M. J. Safont, M. Taron, J. J. Sanchez, R. Rosell
Journal: Journal of Clinical Oncology (2005)

7228 Background: VEGF and EGFR are important angiogenic factors involved in cell proliferation and tumor growth. We have investigated the association of serum VEGF and EGFR and hemoglobin levels with clinical outcome in patients with advanced NSCLC. Methods: In 100 patients with stage IIIB and IV NSCLC, treated with gemcitabine/cisplatin, blood was collected before chemotherapy. Serum VEGF and EGFR levels were assessed by commercial ELISA. Anemia was defined as hemoglobin level below 11 g/dl. Results: 91% of the patients were males and the mean age was 61 years [35–82]. 86% had ECOG PS 0–1 and 14% PS 2. 71% had stage IV disease. The histological subtypes were: 38% squamous cell carcinoma, 37% adenocarcinoma, 5% anaplastic large cell, and 20% undifferentiated. Patients received a median of 6 cycles chemotherapy [1–7]. 42% had objective response (4% CR and 38% PR), 25% stable disease (SD) and 30% progressive disease (PD). VEGF and EGFR serum levels were not significantly different with respect to stage, histology or PS. Besides, there were no differences with regard to response rates; In CR and PR patients median EGFR was 63.5 ng/ml [7.5–302] and VEGF 364.4 pg/ml [51–4015] versus a median EGFR level at 62.6 ng/ml [15.3–227.8] and VEGF 570.8 pg/ml [143–1452] in the SD/PD group. Patients with local metastasis had lower median EGFR levels that patients with distant metastasis, 55.5 ng/ml [7.5–85.7] vs 68.7 ng/ml [12.8–302] (p<0.05), respectively. In multivariate analyses, EGFR and VEGF levels were not found to be predictors for anaemia, time to progression, or survival. Conclusions: In advanced NSCLC patients we have not found serum VEGF and EGFR levels to correlate with stage, histology, response, time to progression or survival. VEGF levels were not associated with anaemia after therapy, however, higher EGFR levels were associated with the presence of distant metastasis. No significant financial relationships to disclose.
Evaluation for cardiac toxicity with MRI in young adult survivors of acute lymphoblastic leukemia (ALL)
Authors: J. A. Wright, S. C. Reimold, N. J. Winick, A. Turoff, S. Brooks, D. Eshelman, K. C. Oeffinger
Journal: Journal of Clinical Oncology (2006)

18604 Background: Long-term survivors of childhood cancer treated with a moderate to high cumulative dose (≥300mg/m 2 ) an anthracycline are known to be at risk for cardiac toxicity. It remains unclear what cardiac risk exists for survivors who received a low cumulative dose (&lt;300mg/m 2 ) of an anthracycline. Methods: We are conducting an NIH sponsored trial in 120 young adult survivors of ALL to determine the prevalence of cardiovascular risk factors and to determine the effectiveness of an exercise intervention. As part of their cardiovascular risk assessment, participants undergo cardiac MRI, a tool with excellent reproducibility in assessing left ventricular (LV) size and function. The aim of this component of the study is to determine the prevalence of cardiac toxicity in survivors treated with low dose anthracycline in comparison to those who did not receive any anthracycline. Descriptive statistics, chi-square analysis, and spearman correlation coefficients were used to examine the relationship between anthracycline dose and measures of cardiac function. Results: This study represents a work in progress. Preliminary results from the first 22 participants who have had a cardiac MRI do not show a significant difference in ejection fraction, LV mass, cardiac output, or mass to volume ratio between those treated with low cumulative dose anthracycline versus no anthracycline. Available cardiac MRI data for all participants will be presented at the meeting. Conclusions: With the continued use of an anthracycline at cumulative low doses, particularly in upcoming ALL standard risk trials, it is particularly important to determine if there is a risk of cardiac toxicity after low doses with aging. No significant financial relationships to disclose.
INTERMEDIARY METABOLISM OF THYROID TISSUE AND THE ACTION OF DRUGS
Authors: FARAHE MALOOF, MORRIS SOODAK
Journal: Pharmacological Reviews (1963)

It is clear from this review that some progress has been made in defining thyroid function at a basic level. A stumbling block to the precise localization of various mechanisms is the anatomical structure of the thyroid, i.e. , a division into two major components—foilicular cells and follicular colloid. Detailed observations of isolated functional follicular cells should help solve this dilemma. Nevertheless, it appears likely that the follicular cell with its complement of cytostructural components is the initiating locus of the important reactions in the thyroid.

Progress has been made regarding carbohydrate and lipid metabolism in thyroid tissue. Further studies along these lines should be forthcoming and will be invaluable in defining the energetics of thyroid tissue. Similar progress in protein synthesis, in particular, thyroglobulin synthesis, is lacking.

New and systematic methods of study are contributing greatly to the evaluation of the iodide-concentrating mechanism. A maze of data concerning the iodination reaction has been published and it is difficult to evaluate them critically because of the wide variety of techniques and systems employed by various investigators. Although the weight of evidence suggests that a peroxidase is involved in the iodinating system, the precise role of the peroxidase remains to be elucidated. It will be important to acquire knowledge concerning the endogenous hydrogen peroxide-generating system within the thyroid. Furthermore, the actual concentration of peroxide as well as the factors which control its level must be determined. The nature of the iodinating intermediate remains an enigma, but on the basis of preliminary studies, a sulfenyl iodide (RSI) suggests itself as a likely possibility.

This review of antithyroid drugs has been largely limited to specific compounds, the metabolic pathways of which have been studied. This obviously has limited the report. Observations involving the thiocarbamides continue to play a crucial part in evaluating thyroid function. Recent studies with the thiocarbamides, thiourea in particular, have been informative and have led to a new concept in thyroid physiology, i.e. , the possible role of a disulfide bond in thyroid tissue, not only as a locus for the inhibitory action of these compounds but as an initiating site for the iodination reaction.