bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of aberrant drainage after sentinel lymph node mapping and its impact on staging and change of operation in colon cancer.
Authors: Saha S. , Sirop S. , Korant A. , Nalluri S. , Machek O. L. , Desai D. , Kaushal S. , Ganatra B. , Badin J. , Wiese D. 
Published: February 2017

500 Background: Sentinel lymph node mapping in colon cancer leads to the detection of micrometastasis in 15- 20% of patients leading to upstaging to stage III disease. Methods: Between 1996-2010, patients diagnosed with colon cancer were enrolled in our study and underwent SLNM at the tim of surgery plus standard oncological resection including regional LN resection. After initial years of experience, exact locations of the SLNs were mapped in relation to the primary tumor. Aberrant drainage was observed when a SLN was detected outside the standard lymph node basin. The primary objective of this analysis is to identify the frequency of detection of such aberrant drainage and the rates of positive aberrant SLNs leading to change of operation and staging. Results: Between 1996-2010, 304 patients were included in the study. The overall success rates of SLNM was 99.7%. The average number of resected LNs was 15.4. SLNM had a sensitivity, negative predictive value, accuracy and false negative rates of 85.3%, 91.7%, 94.4% and 14.6% respectively. Micrometastatic disease was detected in 15.1% of patients with node positive disease. Since 2001, 150 patients were evaluated for the presence of aberrant drainage and potential change of planned surgery. In 27 patients (18%), extended surgery was performed due to aberrant drainage. The nodal positivity in these 27 patients was 59.5%, compared to 46% in the whole group. The average number of lymph nodes in this group was 16 and the average number of SLNs was 4.3. The most common location of the primary tumor was the right colon in 55.6% of patients with aberrant drainage. In 13 patients (8.7% of case), change of operation led to the detection of positive SLNs leading to upstaging to stage IIIA/B diseases. All of these 13 patients had T3 or T4 disease. All node positive patients underwent adjuvant chemotherapy. Conclusions: SLNM in colon cancer is highly successful, sensitive and overall accurate staging procedure. It leads to detection of SLNs outside the regional lymphatic basin and change of surgery in 18% of patients. This results in higher nodal positivity and significant change of planned surgery in 8.7% of cases. No significant financial relationships to disclose.
Dasatinib (D) in previously treated metastatic colorectal cancer (mCRC) patients: A phase II trial of the University of Chicago phase II consortium.
Authors: Sharma M. , Wroblewski K. , Kozloff M. , Modi S. S. , Sleckman B. G. , Taber D. , Vokes E. E. , Stadler W. M. , Polite B. N. , Kindler H. L. 
Published: February 2017

506 Background: Dasatinib (Sprycel, Bristol-Myers Squibb), an oral inhibitor of SRC family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. Since treatment options for mCRC are limited after a fluoropyrimidine (F), oxaliplatin (O), and irinotecan (I), novel agents need to be explored in this setting. Methods: We conducted a phase II trial of D in unresectable, previously treated mCRC patients (pts) at 9 centers. No more than 2 prior chemotherapy regimens were permitted, which must have contained F, O and I. Disease progression on or after treatment was required. Eligible patients also had to have measurable disease per RECIST criteria; normal organ function; PS 0-2. Pts received D 70 mg PO BID continuously. CT scans were obtained every 8 weeks. The primary endpoint was progression-free survival (PFS) at 4 months. We employed a Simon, two-stage design with 19 pts enrolled in the first stage, and a second stage planned if ≥ 5 were progression-free at 4 months. 19 pts enrolled 10/07-11/08. Pt characteristics: male 58%; median age 64 (range 38-83); PS 0: 47%, 1: 53%. Results: The study was terminated after the first stage due to lack of efficacy. A median of two 4 week cycles were administered (range <1-8). 2 pts discontinued due to adverse events, 2 others withdrew, and 2 had early deaths before the first CT scan. Grade 3/4 toxicities (% pts): anemia 11%; fatigue 16%; anorexia 11%; dyspnea 11%; nausea/vomiting 11%; pleural effusion 5%; diarrhea 5%; pneumonitis 5%; dehydration 5%. There were no objective responses; 1 pt (5%) had stable disease for 7 months. PFS rate at 4 months was 5% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Conclusions: Dasatinib is inactive in previously treated mCRC pts. Novel agents are still needed for this patient population. Supported by NCI grant N01-CM-62201. [Table: see text]
Population pharmacokinetic (PPK) analysis for 5-FU, tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo) in the eight clinical studies of S-1 in Western patients with advanced solid tumors.
Authors: Yoshida K. , Ikeda K. , Yoshisue K. , Rodriguez W. , Bodoky G. , Moiseyenko V. , Lichinitser M. , Saito K. , Benedetti F. M. , Ajani J. A. ,   The FLAGS Trial Investigators Group
Published: February 2017

53 Background: This analysis was performed to establish the PPK model of S-1, and to identify the intrinsic or extrinsic factors that influence S-1 exposure in the Western patients with advanced solid tumor. Methods: PK data obtained in seven phase I and one phase III (FLAGS) studies were combined for PPK analysis. The total number of patients was 315, and the number of data points for FT, CDHP, 5-FU and Oxo were 2,860, 2,625, 2,492, and 2,484, respectively. The two-compartment model was used for FT, CDHP and Oxo, whereas for 5-FU, inhibitory effect of CDHP on 5-FU clearance was incorporated into a two-compartment model to describe its non-linear PK. The final models were validated by visual predictive check and bootstrapping. Results: The individual fit and the stability of four models were acceptable. The predicted daily AUCs (at steady state) were calculated to evaluate the effect of covariates. The daily AUC of 5-FU strongly correlated with oral clearance (CL/F) of CDHP, but not with that of FT. The ethnic difference in exposure to 5-FU was not apparent despite the significantly lower CL/F of FT observed in the Asian patients. Co-administration with food delayed the absorption of S-1 but exhibited no or limited effect on the AUC of FT, CDHP and 5-FU, whereas the bioavailability of Oxo decreased to approximately 30%. Renal function primarily influenced CDHP exposure and, in turn, 5-FU. The model simulation suggested that the S-1 dosages of 30, 25 and 20 mg/m2 BID could achieve similar daily AUC of 5-FU in the Western patients with normal renal function (CLcr>80 mL/min), mild (50-80 mL/min) and moderate (30-50 mL/min) renal impairment, respectively. Other factors such as age, gender, liver function, serum albumin, PS, gastric cancer, gastrectomy, combination with cisplatin and liver metastasis, had little or minimal impact on the daily AUC of 5-FU. Conclusions: This analysis suggests that the daily AUC of 5-FU after S-1 administration is primarily affected by the CDHP levels, and hence renal function remains the primary factor for 5-FU PK in patients. Other factors as well as CL/F of FT had little impact on 5-FU. [Table: see text]
Modeling 5-FU AUC-dose relationship to develop a PK dosing algorithm.
Authors: Haregewoin A. , Kaldate R. R. , Hamilton S. A. , Saam J. R. , Wenstrup R. J. 
Published: February 2017

547 Background: 5-fluorouracil (5-FU) is an ideal candidate for pharmacokinetic (PK) dosing. 5-FU is administered based on standard BSA dosing. BSA administration results in highly variable PK and exposure, and potential underdosing in about 50% of patients. Patients with higher 5-FU AUC levels derive greater clinical benefit but with increased risk of toxicity. An immunoassay (OnDose) that measures 5-FU concentration in plasma and reports a computed AUC in mg·h/L has been developed to aid optimization of therapy using PK dosing. The results of an analysis to model the 5-FU AUC-dose change relationship from our clinical database are presented. Methods: A set of 585 sequential patients from our database receiving FOLFOX6 regimen with 5-FU continuous infusion (CI) over 41-48 hours, with or without bevacizumab, for the adjuvant and metastatic treatment of CRC was used for the preliminary analyses. A subset restricted to include only patients that had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 at the initial test cycle, and had blood sample collection times ≥ 18 hours was used to conduct regression modeling of change in AUC versus change in dose. Outliers such as AUC values < 5 mg·h/L and > 50 mg·h/L were excluded from the analysis. Results: Our analysis corroborates previous findings that large variability in 5-FU PK measurements exists during the early part of the infusion cycle. The following simple regression model with an R2=0.51 developed over N=307 cycle-pair observations characterizes the AUC-dose relationship as: change in AUC (mg·h/L) = 0.02063 * dose change (mg/m2). Conclusions: The above model suggests that dose changes ranging from 145 to 720 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg·h/L for most patients. Assuming a 2,400 mg/m2 baseline dose, a maximum 720 mg/m2 dose increase would correspond to a 30% increase, but would likely be needed only by 10% of the patient population with low AUC readings. Our data from the US clinical setting indicate that it is possible to optimize 5-FU therapy by adjusting the dose based on AUC measurement. [Table: see text] [Table: see text]
Biomolecular, biochemical, and radiologic evaluation of patients on anti-VEGF treatment for mCRC.
Authors: Rossi L. , Veltri E. , Di Seri M. , Vari S. , Colonna M. , Adua D. , Longo F. , Zoratto F. , Mottolese M. , Tomao S. 
Published: February 2017

556 Background: K-ras mutation is a negative predictor of clinical benefit (CB) from anti-EGFR treatment in mCRC. Bevacizumab combined with chemotherapy prolongs both PFS and OS in first-line treatment of mCRC. Previously data suggested that this results are independent of K-ras status. We conducted a study to investigate the CB of Bevacizumab in treatment of mCRC according to K-ras status and to evaluate timing of response to treatment trough the correlation between tumor markers values and clinical responses. Finally we evaluated CB in patients affected by mCRC with only hepatic metastases vs patients with multiple metastasis sites. Methods: 82 patients were enrolled and underwent first-line chemotherapy with Folfiri or FolFoX and bevacizumab. Tissue samples were analyzed for DNA sequencing in order to identify K-ras mutations in codons 12 and 13. Before therapy all patients were investigated with CT scan and with a blood sample to define tumor markers values; a new evaluation of tumor markers after 2 months of chemotherapy was performed and a CT scan after 3 months. Results: An overall objective response rate (RR) of 40% and a CB of 79% were obtained, with a correlation between tumor markers values and clinical response of 89%. 49% of population presented only hepatic metastases while other 51% showed multiple metastatic sites. RR in exclusive hepatic metastatic group was 45% vs 33% multiple metastatic sites group, CB was 90% vs 66% respectively. No grade 3 or 4 bevacizumab associated toxicity was showed in patients. K-ras mutations were investigated in 75 of 82 patients. 49 patients were wild-type (wt 65%) while 26 patients were mutated (mut 35%). RR in wt group was 45% vs 35% in mut group, while CB was 82% vs 81% respectively. Correlation between tumor markers values and clinical response was 90% in wt group vs 93% in mut group. Conclusions: RR in two K-ras groups was different with an advantage in K-ras wt group, but this difference does not observe in CB. Bevacizumab provides significant RR and CB after a short time of treatment and tumor markers values could be an optimal correlative parameters of early clinical response. Bevacizumab provides significant CB in patients with only hepatic metastases vs patients with multiple metastatic sites. No significant financial relationships to disclose.
A randomized cross-over trial comparing single-agents capecitabine (C) and UFT plus leucovorin (LV) in patients (Pts) with advanced colorectal cancer (CRC): Preliminary data of a patient preference study.
Authors: Peugniez C. , Fournier C. , Guerin-Meyer V. , Berger S. , Gasnault L. , Girault C. , Rad E. , Lam Y. , Maes P. , Adenis A. ,   Noroncomed Network - France
Published: February 2017

558 Background: Oral fluoropyrimidines such as C and UFT plus LV (U) are widely used pro-drugs dedicated to the care of CRC. Although their toxicity profile may slightly differ, no direct comparison between these treatments has been done as both molecules are converted into fluorouracil. To help the physicians to choose between C and U, we initiated this randomized cross-over trial aimed to assess patient's preference. Methods: Pts with advanced CRC received either a first cycle of C (1,250mg/m2 x 2/d for 14 days, q3 wks) or a first cycle of U (UFT 300mg/m2/d plus LV 75 mg/d in 3 divided doses every 8 hrs for 28 days, repeated at 35-day intervals). Patients were randomized to receive C at cycle 1 followed by U (arm A) or U at cycle 1 followed by C (arm B). After 2 cycles, pts were asked which treatment they preferred. Treatment was then continued with the chosen regimen. Preferences rates are presented with 95% confidence intervals and the two groups are compared with the chi-squared test. Results: 89 pts were enrolled from 10/2005 to 6/2010. Treatment arms were well balanced for baseline characteristics: male 57%; median age 66 years; PS 0-1 81%. Most of the pts were heavily pretreated (0/1/2/ and >2 previous chemotherapy lines: 6/2/15/66). 64 (arm A: 35, arm B: 29)/89 pts received at least 2 cycles of chemotherapy and were evaluable for preference. At cycle 1, 21% and 43% of the pts presented at least 1 severe toxic event with C and U, respectively. Pts with U at cycle 1 presented more likely with severe fatigue and anorexia. There was 1 toxic death under C (gr. 3 diarrhea, gr.4 neutropenia) at cycle 1. Overall, 66% (95%CI: 52-77%) of evaluable pts expressed preference for C, and there was a statistically significant difference between arms A and B (p<0.02) with more pts preferring C in arm A: 79% (95%CI: 61-91%), as compared to arm B: 50% (95%CI: 31-79%). Conclusions: Pts with advanced CRC preferred C over U, especially when given during the first cycle. No significant financial relationships to disclose.
The role of postoperative PET-CT in the evaluation of patients with high-risk stage III colorectal cancer (CRC).
Authors: Purim O. , Asman Y. , Bard S. , Kundel Y. , Wasserberg N. , Gordon N. , Brenner B. 
Published: February 2017

566 Background: Routine PET-CT evaluation is still not indicated for stage III CRC patients; however accumulating data suggest that it may modify these patients' staging and treatment. We hence evaluated the role of PET-CT in high risk stage III CRC patients and to characterize positive predictors. Methods: Retrospective chart review of stage III CRC patients who underwent PET-CT for being at high risk for systemic disease attributable to: early T stage (T < 3), grade > 3, < 12 lymph-nodes examined, > 3 involved lymph-nodes, elevated postoperative CEA and/or CA-19.9. The demographic and clinicopathological characteristics of patients found to have metastatic disease were compared to those who were negative. Results: Seventy-three patients (33 males [45%], median age 67 years [range: 29-88 years]) were included. Pathologic FDG-uptake was observed in 33 (45%) patients. Of them, 16 (22%) were upstaged with altered treatment protocol, 13 (18%) required further work-up and 4 (5%) were found to have post operative changes. Elevated post-operative CEA and CA-19.9 levels correlated with positive PET-CT (p = 0.002 and p = 0.015, respectively). None of the other examined parameters differed between the groups. With a median follow-up of 26 months (range:1-63 months), overall survival was 88% in patients with positive PET-CT and 92% in patients with negative PET-CT. Eight patients in the positive group were disease free following metastectomy, five were alive with disease, two patients died of disease and one patient died of other cause. Conclusions: Selective postoperative PET-CT influenced staging/therapy in 22% of high risk stage III CRC patients. Postoperative CEA and CA-19.9 levels may play a role in selecting eligible patients. Failure to identify other parameters may be related to the preexisting selection bias and the small cohort. No significant financial relationships to disclose.
Phase I/II study of transcatheter arterial chemoembolization with cisplatin powder and degradable starch microspheres for unresectable hepatic metastases from colorectal cancer refractory to systemic standard chemotherapy.
Authors: Nishiofuku H. , Tanaka T. , Anai H. , Sueyoshi S. , Matsuoka M. , Otsuji T. , Yamamoto K. , Inaba Y. , Sakaguchi H. , Kichikawa K. ,   Nara 1
Published: February 2017

577 Background: We conducted a phase I/II study of novel transcatheter arterial chemoembolization with cisplatin powder and degradable starch microspheres (DSM) to determine the recommended dose (RD) and to assess the efficacy and safety. Methods: Cisplatin powder and DSM mixing solution was administered followed by the injection of DSM alone via hepatic artery every 4 weeks. In phase I, cohorts of 3 patients received escalating dose of cisplatin (50, 65 and 80mg/m2), and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response, toxicity, hepatic progression free survival (H-PFS) and 6-month overall survival (OS) rate. Results: A total of 24 patients (male 16, female 8; mean age 63.0, range 45-79; colon 15, rectal 9) were enrolled in this study. FOLFOX had previously been administered to all patients, irinotecan-containing regimen to 12 and bevacizumab and/or cetuximab to 14. During phase I (n= 9 patients), maximum tolerated dose was not reached and cisplatin 80 mg/m2 was recommended for a phase II. Phase II enrolled 15 patients. The following grade 3 toxicities were observed: platelets reduction 16.6%, aspartate transaminase elevation 38.8%, alanine transaminase elevation 16.6%, hyponatremia 11.1%, cholecystitis 5.5%. The tumor response rate was 53.3% (CR 0, PR 8, SD 6, and PD 1). The median H-PFS was 6.3 months (95% CI; 2.71 to 9.88) and 6 -month OS rate was 86.7%. Conclusions: This phase I/II study demonstrates that novel transcatheter arterial chemoembolization with 80 mg/m2 cisplatin powder and DSM is well tolerable, and can produce a high response rate with encouraging survival duration. Further clinical trials are warranted. No significant financial relationships to disclose.
Patients' perspective on palliative chemotherapy of colorectal and non-colorectal tumors.
Authors: Rehm M. , Rentsch A. , Trautmann K. , Hornemann B. , Schuler U. , Ehninger G. , Folprecht G. 
Published: February 2017

581 Background: In contrast to trials investigating treatment efficacy, patients perspective on given chemotherapy is less studied. Known surveys indicate that patients accept therapy for very limited benefit. Methods: Patients who had received 3 or more months of systemic, palliative therapy for colorectal (CRC) or non-colorectal (upper GI, NSCLC, SCCHN) cancer were eligible. They completed a questionnaire including their retrospective report on symptomatic toxicity (according to NCI-CTC) and using numeric ranking scales their burden from the toxicity and the comparison to the informed consent. Depression and anxiety was measured by HADS. Finally, the patients were asked for the minimal gain in life expectancy they would feel it worth to repeat the therapy for. Results: Between August 2008 and December 2009, 134 patients were enrolled. Median age was 63 (32-86); 71% of patients were male. Colorectal cancer patients would repeat their therapy for a minimal gain of life expectancy of 36.0 mo (14.0-57.0 mo), non-CRC patients for 15.9 [12.3-19.5] months (p = 0.01). Considering additional time with best supportive care, the minimal expectation from treatment trended to be longer than the actual survival of the same patients (39.3 [33.6-45.0] and 19.9 [16.3- 23.5] months for CRC and non-CRC patients, respectively), p = 0.08. Depression, diarrhea and tumor entity (CRC vs. non-CRC) were an independent factors for the minimal expected life expectancy in a multivariate analysis. Most frequent self reported toxicity (grade 3/4) was fatigue (9.0%), nausea (8.1%), diarrhea (8.5%) and stomatitis (8.3%), severe burden was felt from fatigue (14.3%) followed by neuropathy (12.0%), diarrhea (11.1%), nausea (9.8%) and stomatitis (8.8%). Fatigue was felt ′a little bit more′ or ′much more′ than in the patient information in 29.9%, followed by neuropathy (20.5%), acne (18.4%) and diarrhea (17.6%). Conclusions: Patients' expectations of life-prolonging systemic therapy are higher than expected from previous studies or the median survival in phase III studies. Compared to their actual survival it may be regarded as realistic. Fatigue might deserve more attention when toxicity of treatment and symptoms of disease are explained. [Table: see text]
The optimal dose period of indisetron tablets for preventing chemotherapy-induced nausea and vomiting (CINV) induced by mFOLFOX6: An exploratory trial HGCSG0703.
Authors: Yuki S. , Nakatsumi H. , Tateyama M. , Uehata Y. , Kudo M. , Kato K. , Miyagishima T. , Uebayashi M. , Asaka M. , Komatsu Y. 
Published: February 2017

589 Background: Indisetron is a 5-HT3 receptor antagonist which shows also 5-HT4 antagonistic activity, that had approved in 2004 by Japan's PMDA. There are no recommendations of prophylactic regimens for preventing nausea and vomiting induced by FOLFOX therapy. To explore the optimal dose period of indisetron tablets during mFOLFOX6, we designed the study to compare the antiemetic efficacy and safety of 3-day regimen of indisetron with a single dose regimen. Methods: Advanced colorectal cancer patients who were treated with mFOLFOX6 (+/- bevacizumab) as first-line chemotherapy were enrolled in this study. They were randomly assigned to Group A (3-day of indisetron) or Group B (a single dose of indisetron). Dexamethazone (8mg) was also administered intravenously in both groups before administering of oxaliplatin. The follow-up period was 5 days from the start of chemotherapy. The primary endpoint was complete protection from vomiting, and secondary endpoints were complete protection from nausea, no use of rescue therapy, and severe adverse events. Results: Of 45 patients enrolled in this trial, 42 (93.3%) were assessable. The proportions of patients with complete protection from vomiting were 85.7% in Group A, and 81.0% in Group B (p=1.000; Fisher's exact test). The proportions of patients with complete protection from nausea were 47.6% in each group (p=1.000; chi-square test). The no rescue therapy rates were 66.7% in Group A, and 57.1% in Group B (p=0.525; chi-square test). No severe adverse events were observed in both groups. Conclusions: We suggested that the efficacy of a single dose of indisetron might be equivalent of 3-day regimen for preventing from nausea and vomiting induced by mFOLFOX6. [Table: see text]