bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Cockcroft-Gault (CG) and abbreviated modified diet in renal disease (MDRD) formulae in dosing of cancer drugs other than carboplatin
Authors: Jennings S. A. , de Lemos M. L. , Levin A. , Murray N. 
Published: March 2020

2522 Background: Glomerular filtration rate (GFR) is often used to determine initial dosing of renally-excreted cancer drugs. Estimated GFR (eGFR) can be calculated using serum creatinine (SrCr) -based formulae such as CG and MDRD. MDRD is more accurate in non-cancer patients, does not require patient weight, and is reported automatically by all laboratories in British Columbia (BC). We previously showed that CG and MDRD have similar accuracy for carboplatin dosing in patients with gynecological malignancies. We now examine dosing of all renally-excreted cancer drugs in the general cancer population. Since this setting does not include routine measurement of GFR, we report the concordance of eGFR derived from CG and MDRD. Methods: Patient data were collected retrospectively at the BC Cancer Agency. The primary outcome was concordance of eGFR derived from CG and MDRD, using the method of Bland and Altman. A difference of ≥ 30% was assumed to be clinically significant because this difference would usually lead to dose adjustment based on reclassification of renal function. The secondary outcome was the proportion of patients who would have received a different initial dose due to difference in eGFR. Each patient’s dose was determined from dose adjustment tables stated in specific treatment protocols. Results: 313 patients were evaluated: 40% male, median 56y, 67.5kg, 166cm, SrCr 74micromol/L. Median eGFR derived from CG and MDRD were 86.8mL/min and 87.6mL/min, respectively. A difference of ≥ 30% in eGFR was found in 17.9% (56/313) of patients. 8.6% (27/313) of patients would have received a different dose due to difference in eGFR; of these, 67% (18/27) would have received a higher dose. Conclusions: There is good concordance of eGFR derived from CG and MDRD for most cancer patients, with less than 10% of patients expected to receive a different initial dose of chemotherapy. MDRD may be a reasonable alternative to CG for dosing of any renally-excreted cancer drug. No significant financial relationships to disclose.
Use of tumor gene expression signatures and drug-induced changes to discriminate early response in human breast cancer
Authors: Lee S. , Watson M. , Xu X. , Wong C. I. , Iau P. , Sukri N. , Lim S. E. , Chuah B. , McLeod H. , Goh B. C. 
Published: March 2020

2524 Background: To elucidate the genomics of tumor responses to different classes of chemotherapy, we analyzed breast cancer gene expression before and after in vivo treatment with adriamycin or docetaxel. Methods: Tumor biopsies were obtained before and 3 weeks after one chemotherapy cycle and tumor RNA amplified and hybridized on the Affymetrix HG-U133+2 array containing 33,000 genes. Results: Pre- and post-treatment tumors from 46 chemonaive patients with unresectable breast cancers were studied, of which 24 and 22 respectively received adriamycin and docetaxel in the first cycle, and 14 in each group had early response sensitive tumors (=25% shrinkage after 1 cycle). Comparison of our baseline gene signatures with drug-specific panels generated in vitro (Nevins, Nat Med 2006,12:1294) revealed 12 and 2 common genes (p<0.05) that predicted for adriamycin and docetaxel response respectively, with the 12 common adriamycin-response gene panel correctly predicting response in 76% of patients. Analysis of the relative change in tumor gene expression (ratio of post- and pre-treatment differential values to pre-treatment values) in our dataset revealed adriamycin to up- or down- regulate 209 transcripts (p<0.005) including genes that encode for nuclear protein, cell cycle regulation, aminopeptidases, and Ankyrin repeats, while docetaxel up- or down-regulated 469 transcripts (p<0.005) including genes that encode for extracellular matrix, transmembrane signaling, endocytosis, EGF-like calcium binding, tubulin and actin binding functions. Adriamycin and docetaxel concordantly up- or down-regulated 269 transcripts (p<0.01) that may be common response markers, including genes involved in cell cycle proliferation, mitosis, DNA damage, and carboxypeptidase activities. Adriamycin and docetaxel differentially induced 92 transcripts (p<0.01) that distinguished between the two drugs with 96% accuracy. 27 adriamycin- and 100 docetaxel-induced transcripts (p<0.005) predicted response to each drug with >90% accuracy. Conclusions: Drug-specific genomic changes can predict clinical response, and may yield insights to targets to overcome drug resistance. No significant financial relationships to disclose.
Clinical impact of ERCC1 and TOPOIIα gene expression in small-cell lung cancer patients treated with platinum/etoposide
Authors: Selvaggi G. , Ceppi P. , Longo M. , Giaj Levra M. , Cappia S. , Volante M. , Novello S. , Papotti M. , Scagliotti G. V. 
Published: March 2020

2526 Background: Platinum/etoposide is a commonly used regimen both in limited (LS) and extensive stage (ES) small-cell lung cancer (SCLC). The study was aimed at testing retrospectively the predictive role of mRNA quantification of genes correlated to platinum/etoposide therapy: ERCC1, RRM1 and TOPOIIa. Methods: Total RNA was extracted from microdissected sections of 103 formalin-fixed, paraffin embedded bronchial biopsies. Relative quantification for ERCC1, RRM1 and TOPOIIa and an internal reference gene (β- Actin) was performed by Real-Time PCR using intron-spanning primers. ERCC1 expression was also evaluated by immunohistochemistry using a semi-quantitative score. Results: Eighty-five samples (83%) were successfully amplified. Overall median survival (MS) was 9.9 months, 45 patients had LS (MS=13.1 months) and 40 had ES (MS=7.1 months). Fifty-six (65%) had an objective (complete or partial) response to treatment. Immunohistochemical staining of ERCC1 evidenced a positivity in 2 out of 85 patients with no correlation with clinico-pathological factors. By contrast, a gene expression level was detectable in all samples and a significant correlation between ERCC1 and RRM1 levels (Rs=0.34, p=0.0011) was found. By segregating patients according to response to treatment, it was found that lower TOPOIIa expression was associated to a better response in LS patients (p=0.025) and, more interestingly, those who had a complete response had low TOPOIIa levels than both partial and non-responsive patients (p=0.015). By adopting cut-offs according to median values, univariate analysis of survival by Kaplan-Meier method showed that LS patients with low ERCC1 had a significantly longer survival (MS 14.9 vs. 9.9 months, p=0.012), while RRM1 and TOPOIIa levels showed no influence on outcome. In multivariate analysis, ERCC1 was an independent prognostic factor for survival of LS patients, together with PS and response to therapy. No significant role was found for ERCC1, RRM1 and TOPOIIa in patients with ES. Conclusions: ERCC1 and TOPOIIa represent reliable candidate markers in predicting clinical outcome and response to treatment in LS SCLC patients, who may benefit from a better individualized therapy. [Table: see text]
Age and body composition related-effects on the pharmacokinetic disposition of STEALTH liposomal CKD- 602 (S-CKD602) in patients with advanced solid tumors
Authors: Zamboni W. , Maruca L. J. , Strychor S. , Zamboni B. A. , Ramalingam S. , Edwards R. P. , Friedland D. M. , Stoller R. G. , Belani C. P. , Ramanathan R. K. 
Published: March 2020

2528 Background: STEALTH liposomes (SL), which contain lipids conjugated to polyethylene glycol (PEG), prolong the circulation time of a drug in plasma, achieve high and extended drug exposure in tumor, and are eliminated via the reticuloendothelial system (RES). S- CKD602 is a SL formulation of CKD-602, a camptothecin analogue. CKD-602 released from S-CKD602 is eliminated by the kidney. There is significant interpatient variability in the pharmacokinetic (PK) disposition of S-CKD602. Thus, there is a need to identify factors associated with the PK variability. We hypothesize that older patients (pts) have a reduced capacity to eliminate SL agents due to age-related impairment of the RES and that body composition alters the disposition of SL. Methods: PK studies of S-CKD602 were performed in a phase I study of S-CKD602 at 0.1 to 2.5 mg/m2 IV q 21 d in pts with solid tumors. Concentrations of encapsulated (E), released (R), and sum total (E + R) CKD-602 in plasma and CKD-602 in urine were measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated and normalized by dose (AUC/dose). The ratio of total body weight to ideal body weight (TBW/IBW) was calculated as a measure of body composition. Results: Mean ± SD S-CKD602 sum total AUC/dose in pts < 60 (n = 13) and = 60 (n = 17) years of age (yo) were 4.5 ± 5.0 and 11.2 ± 11.0 (μg/ml·h)/(mg/m2), respectively (P<0.05). Controlling for age, there was a statistically significant inverse relationship between TBW/IBW and S-CKD602 AUC/dose where low TBW/IBW was associated with high AUC/dose in both age groups (P<0.05). The cumulative amount of CKD-602 recovered in the urine was 2.2-fold higher in pts < 60 yo compared with = 60 yo. Conclusions: These data suggest that pts = 60 yo have a reduced clearance of S-CKD602 and reduced release of CKD-602 from S- CKD602 compared with pts < 60 yo. In addition, pts < 60 and = 60 yo with a lean body composition may have a reduced tissue distribution and an increased plasma exposure of S-CKD602. The clinical significance of these differences and the factors associated with them need to be evaluated for S-CKD602 and other liposomal and nanoparticle anticancer agents. No significant financial relationships to disclose.
Biomarker and in vitro chemoresistance profiles of undifferentiated ovarian cancers
Authors: Chan J. K. , Kapp D. S. , Mechetner E. , Yu I. 
Published: March 2020

2532 Background: To determine the biomarker expression and drug resistance patterns of undifferentiated ovarian cancers. Methods: Biomarker expression was determined by immunohistochemistry. In vitro drug resistance profiles were analyzed by assays exposing tumors to suprapharmacologic doses of chemotherapy. Results: Of 177 ovarian cancer specimens, 63 were classified as undifferentiated tumors and 114 well-differentiated cancers were used for comparison. Of the undifferentiated tumors, 46.7% were primary cancers and the remainder were recurrent cancers. Most of the well-differentiated tumors were obtained from primary (82%) vs. recurrent disease specimens. The average DNA index and S-phase fraction were significantly higher in the undifferentiated vs. well-differentiated tumors (1.42 vs. 1.23, p=0.025 for DNA index; 1.69 vs. 3.06, p<0.0001 for S phase fraction). In addition, the percent of tumors with p53 mutations was also higher in the undifferentiated compared to the well-differentiated tumors (47.8% vs. 17.8%; p=0.005). The mean percent cell inhibition was significantly lower in the undifferentiated tumors compared to well-differentiated cancers after exposure to etoposide (54%±21 vs. 80%±18; p=0.0002), doxorubicin (59%±28 vs. 80.0%±21; p=0.07), and topotecan (61.7%±20 vs. 71%±21; p=0.015). Compared to well-differentiated tumors, undifferentiated tumors tended to be more resistant to etoposide (40% vs. 11%), doxorubicin (22% vs. 9%), and topotecan (19% vs. 16%). However, the drug resistance patterns after exposure to taxanes (paclitaxel and taxotere) and platinums (carboplatin and cisplatin) were similar. Conclusions: Undifferentiated tumors of the ovary have a significantly different biomarker expression and drug resistance profiles compared to well-differentiated tumors. Given that undifferentiated cancers provide a treatment challenge for the clinician, this data can provide additional prognostic and therapeutic information, and warrants further investigation. No significant financial relationships to disclose.
Positron-emission tomography reveals early flare in uptake of FLT in tumors following chemotherapy with gemcitabine
Authors: McArthur G. A. , Hicks R. M. , Shalinsky D. R. , Binns D. , O’Kane C. , Hogg A. , Fisher R. , McCarthy T. J. , Anderes K. A. 
Published: March 2020

2537 Background: Strategies to monitor molecular & cellular responses to novel cell cycle targeting agents are vital to provide proof of their mechanism & biological activity. In developing biomarkers for the novel chk1 inhibitor, PF-477736, we demonstrated that gemcitabine chemotherapy induced a significant increase, or flare, in uptake of the PET tracer, 3’-deoxy-3’flurothymidine (FLT), into tumor xenografts 24 h after dosing (Proc ASCO 24:A3045, 2006). We postulated that an early flare in FLT may also occur following gemcitabine therapy in human tumors. Methods: Eligible patients had at least 1 malignant lesion identified by CT scan outside of a previous radiation field. Patients received a baseline FLT-PET scan day-1 to -4 relative to 1st dose of gemcitabine at 1,000 mg/m2, and a post dose FLT- PET scan 22–26 h after gemcitabine. Endpoints were FLT uptake as assessed by: SUV; a qualitative scoring system; and tumor-to-background (T:B) ratios using liver, mediastinum and bone marrow as references. Results: Six of 8 planned patients with 14 index lesions have been accrued in this pilot study. 4/6 patients demonstrated increased uptake of FLT as defined by >50% increase in SUV or T:B ratio in at least 1 lesion. Analysing all index lesions showed an increase in FLT-uptake post gemcitabine as assessed by a 4 point qualitative scoring system from 1.6±0.2 to 2.7±0.1 (p=0.01) or T:B 1.1±0.2 to 2.0±0.3 (p<0.01) using liver as a reference. Interestingly in contrast to increased uptake in tumors, uptake of FLT in bone marrow was reduced from an SUV of 6.4±0.6 to 3.4±0.7 (p<0.01) following gemcitabine. Conclusion: Following treatment with gemcitabine there was an early flare in uptake of FLT into many tumors. In contrast, uptake in bone marrow was reduced. FLT-PET appears to be a promising tool to monitor the cell cycle response of both tumor and bone marrow to cytotoxic chemotherapy. No significant financial relationships to disclose.
A phase I/II, pharmacokinetic (PK) and pharmacogenomic (PG) study of weekly irinotecan (CPT-11) therapy for elderly patients with advanced non-small cell lung cancer
Authors: Isobe H. , Yamamoto N. , Kunikane H. , Masuda N. , Eguchi K. , Shibuya M. , Takeda Y. , Ogura T. , Yokoyama A. , Harada M. , Watanabe K. 
Published: March 2020

2539 Background: CPT-11 is commonly used to treat lung cancer, but there is little evidence about its efficacy in elderly patients. The aim of this study was to determine the recommended dose (RD) of CPT-11 for weekly administration to elderly patients, and to assess its efficacy and safety. In addition, a PK and PG study was performed to investigate the influence on the clinical outcome. Methods: CPT-11 was infused intravenously on Days 1 and 8 (every 21 days). In the phase I study, the dosage of CPT-11 was escalated from 60 (Level 1) to 80 (Level 2) and 100 mg/m2 (Level 3). PK of CPT-11 and SN-38, and UGT1A1 polymorphism were analyzed during the first treatment cycle in the phase II study. Results: In the phase I study, 12 patients were enrolled (level 1/2/3=6/3/3) and the RD was determined to be 100 mg/m2. The 37 patients in phase II had the following characteristics: male/female=25/12, median age=77 (71–88), IIIB/IV=10/27, PS 0/1=12/25. The overall response rate and the disease control rate (PR+SD) was 8% and 73%, respectively. The median survival time was 441 days and the 1-year survival rate was 54.0%. Grade 3/4 neutropenia and diarrhea occurred in 27% and 8%, respectively. The AUCs for both CPT-11 and SN-38 were significantly correlated with neutropenia (P=0.0095, P=0.0004). Both the UGT1A1*6 and UGT1A1*28 genotypes were significantly correlated with the AUC ratio, leukopenia, and neutropenia ( Table ). Conclusion: CPT-11 monotherapy is considered to be effective for non-small cell lung cancer in elderly patients because good survival with tolerable adverse events were achieved. The UGT1A1*6 and UGT1A1*28 genotypes might both influence the toxicity of irinotecan in Asians. [Table: see text] [Table: see text]
Relationship between persistent neurotoxicity and long-term platinum exposure after treatment with cisplatin
Authors: Brouwers E. E. , Huitema A. D. , Boogerd W. , Beijnen J. H. , Schellens J. H. 
Published: March 2020

2546 Background: We aimed to assess relationships between the severity of persistent neuropathy and long-term platinum exposure in patients previously treated with cisplatin. Methods: Twenty patients, treated with a cisplatin containing regimen 18 to 75 months before participating in this study, were included. Sensory nerve function in hands and feet was evaluated using vibration threshold (VT) determination. Platinum levels in plasma and plasma ultrafiltrate were assessed using inductively coupled plasma mass spectrometry (ICP- MS). Possible factors affecting sensory nerve function or platinum retention were collected, including cumulative dose, follow-up time, route of administration, renal function, glutathione S-transferase (GST) genotypes, co-administration of sodium thiosulfate (STS with intra-arterial (i.a.) cisplatin), and co-morbidity (alcoholism and diabetes). Results were evaluated using non linear mixed effects modelling. Results: Patients (9 testis, 8 head-neck, 1 NSCLC, 1 SCLC, and 1 yolk sac) were treated with a cumulative dose of 300–600 mg·m-2. Five patients received STS. Platinum plasma concentrations ranged between 142.4–1154 ng·L-1of which on average14.8% was recovered in ultrafiltrate. Platinum levels decreased with a half-life of 21.7 months and were related to the cumulative dose. Platinum levels were reduced by 60% with i.a. cisplatin and co-administration of STS (p=0.002). The hand-VT decreased with time (t1/2=19.9 months) and was related to cumulative dose and to alcohol use (p=0.06). Moreover, the half-life of recovery of the hand-VT was related to the elimination half-life of platinum, albeit non-significant. In contrast, the feet-VT did not improve over time and did not show an association with cumulative dose or any of the other factors. GST genotypes and renal function were not related to VT and platinum levels. Conclusions: Our data suggest that plasma platinum levels are related to follow-up time, cumulative dose, and STS use. The data show that neuropathy in the feet might be irreversible in contrast to the hand-VT, which was also related to cumulative dose and alcohol use. Whether recovery of neuropathy was related to platinum elimination remains to be established. No significant financial relationships to disclose.
A phase I trial of E7974 administered on days 1 and 15 of a 28-day cycle in patients with solid malignancies
Authors: Madajewicz S. , Zojwalla N. J. , Lucarelli A. G. , Hentschel P. , Giardelli J. , Schuck E. L. , Krivelevich I. , Wong B. Y. , Vogelzang N. J. , Sharma S. 
Published: March 2020

2550 Background: E7974 is a synthetic hemiasterlin analogue exhibiting binding to a and β tubulin. It induces disruption of spindle formation and mitotic arrest characteristic of anti-tubulin cancer drugs. Unlike taxanes and vincas, E7974 is a poor substrate for the PgP drug efflux pump, potentially overcoming this common mechanism of drug resistance. E7974 demonstrates broad anti-tumor activity against a variety of human tumor xenografts. Methods: An accelerated phase I dose escalation design was used to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of E7974 administered IV over 2–5 minutes on Days 1 and 15 of a 28-day cycle. Results: Seventeen patients (14 male, 3 female) with a median age of 59 yrs. (range: 42–77 yrs.) were treated at doses of 0.18 mg/m2, 0.25 mg/m2, 0.31 mg/m2, and 0.39 mg/m2. Patients with colorectal (6), esophageal (3), prostate (2), urothelial (2), NSCLC (2), and other (2) cancers were enrolled. At the 0.39 mg/m2 dose level, one patient experienced grade 3 neutropenia and 2 patients experienced grade 4 neutropenia. The 0.31 mg/m2 dose was declared the MTD. Additional drug related toxicities (grade 1–2) included fatigue (8 pts.), constipation (4 pts), neuropathy (3 pts.), diarrhea (2 pts.), flushing (2 pts.) and myalgia (1 pt.). One patient with esophageal cancer had a partial response at the 0.39 mg/m2 dose level and one patient with prostate cancer had >50% decline in PSA and significant clinical benefit for >4 months at the 0.31 mg/m2 dose level. Stable disease was seen in two patients, one with esophageal cancer (8 cycles) and one with colorectal cancer (4 cycles). The PK profile of E7974 was characterized by moderate to large distribution (Vss = 55 - 187 L), slow clearance (CL = 1.99 - 8.77 L/hr) and moderate to slow elimination (t1/2 = 11.9 - 31.6 hr). Approximately 26 - 85% of the administered dose of E7974 was recovered unchanged in the urine 48 hours post-dose. Conclusions: The recommended phase 2 dose of E7974 on days 1 and 15 of a 28-day schedule is 0.31mg/m2. Observed toxicities were manageable and reversible. No significant financial relationships to disclose.
The 2-13C-5-fluorouracil breath test (FUBT) as a novel, rapid method for assessment of dihydropyrimidine dehydrogenase (DPD) activity in cancer patients: Initial characterization and comparison to the 2-13C-uracil breath test (UraBT)
Authors: Fourie J. , Mattison L. K. , Wood T. E. , Posey J. A. , Modak A. , Diasio R. B. 
Published: March 2020

2551 Background: The UraBT is currently in development as a phenotypic test to screen for DPD deficiency. Following an oral dose of 2-13C-uracil, the UraBT shows a significant relationship between breath 13CO2 metabolite formation and plasma 2-13C-uracil and 2-13C-dihydrouracil pharmacokinetics. We herein describe a novel, potentially more clinically relevant test in which a small oral dose of 2-13C-5-fluorouracil (5-FU) is administered, followed by assessment of breath 13CO2 metabolite formation as previously described for the UraBT. We hypothesize that the FUBT can rapidly assess interindividual variability in 5-FU catabolism and predisposition to 5-FU toxicity. Methods: Over two sessions separated by a seven day washout, a single dose (6mg/kg, p.o.) of 2-13C-uracil or 2-13C-5-FU was administered to patients with stage III-IV colorectal cancer (n = 4). Subsequent to drug administration, in each session, 13CO2 catabolite formation was quantified in the breath over eight hours. In a separate investigation over two sessions separated by a seven day washout, a single dose (3mg/kg, p.o.) of 2-13C-uracil or 213C-5-FU was administered to colorectal cancer patients with previously documented severe (n=2) or moderate (n=2) 5-FU dose-related hematological/gastrointestinal toxicity. Following drug administration 13CO2 catabolite formation was quantified over eight hours. 13CO2 concentration was expressed as Delta Over Baseline (DOB) in all sessions. Results: Compared to the UraBT, the FUBT showed an increased Cmax (50.7 ± 6.6 DOB/mg vs. 36.8 ± 7.8 DOB/mg; mean ± SD) and decreased Tmax (25 ± 4 min vs. 45 ± 6 min) for 13CO2 formation (p<0.05). The FUBT was able to distinguish patients with previously reported severe and moderate 5- FU toxicity, with 13CO2 Cmax values of 35.5 ± 9.5 DOB/mg (mean ± SD) and 59.8 ± 7.3 DOB/mg, respectively. Importantly, FUBT Cmax values positively correlated with DPD activity (rs=1.00, p<0.01). Conclusions: These data lend support to further development of the FUBT as a rapid and informative test to assess DPD activity and to predict susceptibility to severe dose-related 5-FU toxicity. [CA116964] No significant financial relationships to disclose.