tbuckley/cabot-search huggingface dataset:
The impact of the irinotecan (IRI) schedule on quality of life in combination with capecitabine (CAP) in first-line treatment of metastatic colorectal cancer (MCC): A randomized phase II trial of the Swiss Group for Clinical Cancer Research
Authors: M. M. Borner, J. Bernhard, D. Dietrich, R. Popescu, M. Wernli, P. Saletti, D. Rauch, R. Herrmann, A. Roth
Journal: Journal of Clinical Oncology (2004)

8120 Background: Combining infusional fluorouracil with oxaliplatin (OXA) or IRI is the new standard for first-line treatment of MCC in patients with good performance status. Oral CAP might be more convenient than infusional fluorouracil. Single agent IRI can be administered in a weekly or a 3-weekly schedule. Methods: We performed a randomized phase II trial investigating weekly IRI at a dose of 70 mg/m2 d1, 8, 15, 22, 29 (arm A) and 3-weekly IRI at a dose of 300/240 mg/m2 d1 and d22 (arm B) in combination with CAP 1000 mg/m2 twice daily d1–14 and d22–35 q42. Based on newly available phase I trial results (Cassata et al, Proc ASCO 2001; 20: 144a, Abstr 573), the IRI dose was reduced from 300 to 240 mg/m2 after one third of the treatment cycles has been administered. Quality of life (QL) was assessed with various self-report indicators and evaluated over the first 6 months of treatment in 75 patients with good performance status (0–1). Results: The two treatment arms were well balanced for relevant patient and disease characteristics. Patients in arm A and B indicated comparable physical well-being, mood, functional performance, effort to cope and overall treatment burden. Patients with 3-weekly schedule reported more severe diarrhea (p<0.05) and hair loss (p<0.01). Response rates after review were 18% for treatment A and 35% for B. Patients with an objective tumor response reported better physical well-being (p<0.001), mood (p<0.05), functional performance (p<0.05) and less effort to cope (p<0.01) and treatment burden (p<0.05) compared to the non-responders and stable disease patients. Conclusions: Considering quality of life, the 3-weekly CAPIRI schedule had an overall impact on QL comparable to the weekly schedule. The potentially detrimental impact of more severe diarrhea and hair loss of the 3-weekly CAPIRI was outweighed by the beneficial impact of better anti-tumor activity. This schedule will be used for further comparative trials. No significant financial relationships to disclose.
Efficacy of CAB therapy in stage C prostate cancer: Exploratory analyses based on results of a double-blind, randomized, placebo-controlled phase III study of bicalutamide
Authors: H. Akaza, Y. Arai, H. Kanetake, S. Naito, M. Usami
Journal: Journal of Clinical Oncology (2007)

5154 Background: Although the efficacy of CAB in advanced prostate cancer (PC) has been demonstrated by the PCTCG and others, more evidence is required in locally advanced (Stage C) PC. The results of a Japanese P III study of bicalutamide in Stage C/D PC suggested the efficacy of CAB was better than monotherapy. When time to progression (TTP) was evaluated in Stage C and D separately, CAB had significant benefits in both stages and results in stage D were consistent with PCTCG data. Thus, this exploratory analysis was conducted to evaluate more thoroughly the efficacy of CAB in Stage C. Methods: 205 untreated PC patients with Stage C/D were randomized to CAB (goserelin 3.6 mg/4 weeks or leuprorelin 3.75 mg/4 weeks + bicalutamide 80 mg/day) or LHRHa monotherapy (same LHRHa + placebo). Among these patients, 99 had Stage C (52/47 on CAB/monotherapy). The median of the following parameters were calculated, and log-rank tests performed: TTP in all Stage C patients; TTP in Stage C patients by age, PSA value at diagnosis, and histopathological class; time to PSA normalization when normal level was defined as =4, =1 and =0.2 ng/mL. Results: The median observation period in Stage C patients was 144 weeks. The median TTPs by each parameter in Stage C are shown below. The median times to PSA normalization on CAB and monotherapy were 7 and 16 weeks (p&lt;0.01), 8 and 93 weeks (p&lt;0.01) and 20 weeks and NR (p&lt;0.01) with normal values defined as =4, =1 and =0.2 ng/mL, respectively. Conclusions: These results suggest that CAB with bicalutamide possesses superior efficacy to LHRHa monotherapy in Stage C regardless of age, PSA value at diagnosis, or degree of tumor differentiation. It is suggested that CAB in Stage C could decrease PSA to lower levels in a shorter period than with LHRHa monotherapy. The study is ongoing to assess long term survival outcome. [Table: see text] No significant financial relationships to disclose.
Serum and intracavitary soluble mesothelin-related peptide (SMRP) levels in pleural and peritoneal malignant mesothelioma
Authors: J. Leinwand, E. Hare, C. De Rosa, L. Batista, R. N. Taub
Journal: Journal of Clinical Oncology (2008)

22103 Background: Mesothelin is a 40kDa cell surface protein known to be overexpressed in mesothelioma. Soluble mesothelin related protein (SMRP) is theorized to be a useful blood test marker of mesothelioma tumor load. We examined whether serum SMRP is related to site (pleural or peritoneal), histological subtype (epithelioid, sarcomatous, biphasic), or CRP levels, and whether SMRP is detectable in cavitary effusions. Methods: Serum SMRP and CRP were measured on 1 or more occasions from May to December 2007 in 69 patients with malignant mesothelioma of the pleura (n = 20), peritoneum (n = 43), or both (n = 6); of epithelioid (n = 58), sarcomatoid (n = 5), or biphasic (n = 6) histology. Pleural effusion or peritoneal fluid SMRP was measured in 12 of these patients. These were grouped by site and histology and compared by 2-tailed Welch t-test, with levels below limit of detection (0.3 nM) recorded as 0. Results: Serum SMRP were higher in pleural (6.2 ± 1.1 nM) than peritoneal (4.3 ± 1.1 nM) patients (p = 0.015). 42% of pleural patients had an average serum SMRP within normal limits (<1.5 nM), vs 57% of peritoneal patients. Differences between epithelioid (4.5 ± 0.8 nM) and the small subset of sarcomatoid/biphasic (5.7 ± 3.8 nM) patients were not statistically significant (p = 0.574). Cavitary SMRP was higher than serum in all 3 pleural patients and in 5 of 9 peritoneal patients. Serial samples from individual treated patients, often but not always paralleled increased or decreased tumor burden after surgery or chemotherapy. No correlation was found between SMRP and CRP in any group. Conclusions: Changes in SMRP levels in individual patients, especially with pleural disease, can reflect tumor burden after operation or chemotherapy, and might be explored as a means of detecting residual or progressive disease in pleural effusions. The relationship between cavitary and serum SMRP is less predictable in abdominal ascites than in pleural effusions. SMRP elevations are distinct from elevated CRP, and may reflect different processes. No significant financial relationships to disclose.
Treatment patterns of chronic myelogenous leukemia patients with suboptimal responses to imatinib
Authors: A. Guérin, A. Guo, D. Williams, A. P. Yu, E. Wu, D. Latremouille-Viau, M. Tsaneva, J. Signorovitch, J. D. Griffin
Journal: Journal of Clinical Oncology (2009)

7090 Background: Imatinib is the first-line therapy for Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Patients with suboptimal responses may have the dose of imatinib escalated or may be switched to an alternative kinase inhibitor such as dasatinib. The aim of this study is to examine the real-world treatment patterns of imatinib and dasatinib in CML patients. Methods: Two large U.S. administrative claims databases from January 1999 to March 2008 were combined (MarketScan and Ingenix Impact) to extract de-identified information of patients diagnosed with CML (ICD-9 code: 205.1) who were initiated on imatinib. Patients were followed from the first observed imatinib prescription to the end of data availability. Patients who increased imatinib dose to &gt;400 mg/day were defined as dose escalators, while patients who initiated on imatinib and further switched to dasatinib were considered as switchers. Rates of imatinib dose escalation and switching to dasatinib were estimated. Kaplan-Meier (KM) survival analyses were used to estimate the rate of imatinib discontinuation, defined as a lack of imatinib supply for at least 90 days. Among switchers, the rate of switching back to imatinib was also estimated using KM survival analysis. Results: Among the 5,159 CML patients initiated with imatinib, 1,144 patients either had dose escalation of imatinib (839) or were switched to dasatinib (305) during the study period. Of the 5,159 patients, 12.1% patients discontinued imatinib by the end of the first year, and 25.4% discontinued by the end of the third year. Among the 305 switchers, 115 (37.7%) had an imatinib dose increase prior to the switch, and 66 (21.6%) were escalated to 800 mg of imatinib before switching. 51 patients (16.7%) had used imatinib for &lt;6 months before switching, and 17.1% switched back to imatinib within 6 months of dasatinib treatment. Conclusions: This study showed that great variability was observed in the real world treatment pattern of CML patients. Most CML patients who initiated on imatinib did not dose increase or switch during the study period. Of those who switched to dasatinib, most did not attempt to increase the dose before switching, and a sizeable portion of patients had to switch back to imatinib. [Table: see text]
Radiofrequency ablation (RFA) of pulmonary colorectal metastases
Authors: D. L. Morris, D. Glenn, J. King, R. Lencioni, D. Regge, R. Suh, A. Gilliams, T. Helmberger, C. Dereskewitz
Journal: Journal of Clinical Oncology (2004)

3732 Background: Surgical resection is known to improve survival in patients with pulmonary colorectal metastases (CRPM) to the lung, but the majority of patients are not surgical candidates. Methods: Local control of pulmonary CRM was evaluated as part of two ongoing studies of percutaneous radiofrequency ablation (RFA) of both primary lung tumors or metastatic tumors to the lung in 96 enrolled patients. Fifty patients had 66 RFA procedures for 109 CRPM tumors. Image-guided RFA was performed and follow-up included computed tomography (CT) imaging at 1, 3, 6 and 12 months. Results: There were 2.2±1.6 CRCPM tumors (mean±SD) per patient with mean longest diameter of 1.4±0.7 cm. Patients had undergone prior chemotherapy (62%), or radiation therapy (4%) for their lung tumors. Mean lesion longest diameter decreased from 3.1±1.2 cm following RFA to 2.1±1.1, 1.6±1.0, and 1.4±1.3 at 3, 6 and 12 months, respectively. At 3, 6 and 12 months 30%; 44% and 62% of treated tumors showed a positive response (RECIST: CR; PR; SD). There were 33 pneumothoraces following 66 procedures (50%) with chest drain insertion required after 12 (18%) treatments with 3 (4.5%) of those required for pleural effusion. Procedure-related complications included self-limiting hemorrhage (3) and atelectasis/pneumonia (2). Patient median follow-up is 11.6 months (range 0 to 37.6 months). Conclusion: RFA provides effective local tumor control with low morbidity and may prove an important adjuvant therapy in patients with colorectal pulmonary metastases who are not surgical candidates. No significant financial relationships to disclose.
Validation of a multi-marker test that predicts recurrence in patients diagnosed with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS)
Authors: Steven P. Linke, Troy M. Bremer, Pat Whitworth, Alfred Lui, Jess Savala, Yelina Noskina, Todd Barry, Stephen Lyle, Stephanie C. Walters, Cherie Taglienti, Karl Simin, Wenjing Zhou, Karin Jirstrom, Rose-Marie Amini, Fredrik Wärnberg
Journal: Cancer Research (2015)

Validation of a multi-marker test that predicts recurrence in patients diagnosed with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS)
Final results of phase I/II studies of IL13-PE38QQR administered intratumorally (IT) and/or peritumorally (PT) via convection-enhanced delivery (CED) in patients undergoing tumor resection for recurrent malignant glioma
Authors: M. Prados, S. Kunwar, F. F. Lang, Z. Ram, M. Westphal, G. Barnett, J. H. Sampson, D. Croteau, R. K. Puri
Journal: Journal of Clinical Oncology (2005)

1506 Background: IL13-PE38QQR (IL13PE) is a recombinant cytotoxin which binds selectively to the IL13 receptor that is over-expressed on malignant glioma cells. CED utilizes positive pressure infusion to achieve loco-regional delivery of therapeutic agents via intracerebral catheters. Given the infiltrative nature of malignant glioma, two approaches were examined in three Phase I/II studies. Methods: IL13PE was infused IT before resection, and/or PT after resection. Safety and tolerability of IL13PE, different dosing regimens, catheter positioning, and efficacy as measured by overall survival (OS) were evaluated. The distribution of an imaging tracer co-infused with IL13PE was also assessed by SPECT. Results: Enrollment is complete; 74 adult patients received IL13PE. Dose-limiting toxicity consisted of non-specific necrosis of tumor-infiltrated and normal brain parenchyma which occurred at 1.0 μg/mL with PT administration. The maximum tolerated dose for PT infusions was 0.5 μg/mL. Higher concentrations (up to 3 μg/mL) were tolerated in the IT setting. The most common drug related adverse events were headache (31%), hemiparesis (16%), and fatigue (11%). SPECT imaging showed that distribution was confined to the solid tumor with IT infusion, but distribution to parenchyma at risk for tumor infiltration could be achieved with PT infusion. Improved OS was observed in patients with glioblastoma multiforme (GBM) receiving PT infusions (45.9 wks, n=45) as compared to patients given IT infusion (37.1 wks, n=22). In the PT setting, OS was 70.3 weeks (n=26) for patients with ≥2 optimally placed catheters compared to 41.4 weeks (n=19) for those with <2 optimally placed catheters. Deferred catheter placement led to a greater percentage of optimally placed catheters. Conclusions: CED of IL13PE has a favorable risk/benefit profile for treatment of patients with GBM undergoing tumor resection. Based on these results, the design of the ongoing Phase III study incorporates deferred catheter placement and PT infusion of 0.5 μg/mL of IL13PE. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm
Molecular determinants of capecitabine efficacy in colorectal cancer
Authors: D. Vallbohmer, H. Kuramochi, D. Shimizu, K. D. Danenberg, J. N. Nielsen, J. Lindebjerg, A. Jakobsen, P. V. Danenberg
Journal: Journal of Clinical Oncology (2006)

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]
A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CRPC) (CA180085)
Authors: E. Yu, C. Massard, M. Gross, G. Wilding, E. Posadas, S. Culine, M. A. Carducci, G. Trudel, P. Paliwal, C. Sternberg
Journal: Journal of Clinical Oncology (2009)

5147 Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory function of dasatinib in pre-clinical models supports its potential as a targeted therapy for prostate cancer. Previously we presented results on BID dosing of dasatinib in the treatment of CRPC (ASCO. 2008 Abstract 5156). A second group of patients (pts) was enrolled to investigate the activity, safety and bone effects of 100 mg once daily dosing. Methods: Male pts with progressive metastatic CRPC, rising PSA, castrate levels of testosterone (&lt; 50 ng/dL) and no prior chemotherapy were enrolled. Dasatinib dose was 100 mg QD. Continuation of bisphosphonates was permitted. Primary endpoint was a composite of: PSA responses, bone scans and disease control by RECIST. Urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP) were determined Q 4-weeks as indicators of bone metabolism. Results: 47 pts were treated (median treatment duration was 2.3 months). 11 patients were evaluable by RECIST; of these 64% achieved SD. The composite response rate was (8/47) 17%. Of 22 pts with bone scans, 50% were stable at 12 weeks and 3/9 (33%) were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 pts (82%), including one pt with a PSA response. Of the pts with evaluable bone markers, including those who continued on bisphosphonate therapy, 20/41 (49%) had a ≥ 35% decrease in uNTX and 21/42 (50%) had a decrease from baseline in BAP. Grade 3/4 adverse events (AEs) were experienced by 13% of pts (diarrhea, asthenia, and pleural effusion [n=1]). Grade 1/2 AEs (≥ 15% of pts) were diarrhea, nausea, headache, fatigue, asthenia, anorexia and dyspnea. Conclusions: Fewer and less severe AEs were observed in all categories for the QD dosing group compared to the previously reported BID dosing cohort. In addition, preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing. These data support the relevance of further studies of dasatinib in metastatic CRPC. [Table: see text]
A phase II study of gemcitabine and vinorelbine combination followed by sequential gefitinib monotherapy in elderly patients with non-small cell lung cancer
Authors: K. Kasahara, T. Kita, K. Shibata, K. Nishi, Y. Ishiura, T. Araya, Y. Tambo, A. Sakai, H. Kimura, M. Fujimura
Journal: Journal of Clinical Oncology (2009)

e19040 Background: Gemcitabine (GEM) and vinorelbine (VNR) combination have demonstrated activity as a 1st-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). Gefitinib (GEF) is effective as a 2nd-line treatment for NSCLC. We conducted a multicenter phase II trial to evaluate the efficacy and toxicity for treatment of GEM+VNR followed by sequential GEF in elderly patients (pts) with advanced or metastatic NSCLC. Primary endpoint is response rate, secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Methods: Eligibility required hitologically or cytologically comfirmed NSCLC, no prior therapy, measurable lesion(s), ECOG PS 0–2, age equal to or over 70 years, and adequate organ functions. Patients were received 3 cycles, each at 4-week intervals, of GEM (1000 mg/m 2 , d 1, 15) and VNR (25mg/m 2 d 1, 15), followed by 250 mg of GEF daily until disease progression or unacceptable toxicity. Results: Between June 2004 and November 2007, 60 pts were enrolled and 2 pts withdrew consent. Fifty-eight pts (35 male and 23 female, median age 77 years) were evaluated. Median number of GEM+VNR administrations was 3 (range 1–3). Median duration of GEF was 101 days (range 9–652 days). Grade 3/4 toxicities included leucopenia (29%), neutoropenia (40%), anemia (12%), febrile neutropenia (9%), and anorexia (9%) during GEM+VNR, anorexia (2%), and constipation (2%) during GEF. Best response rate of GEM+VNR was 17% and that after sequential GEF was 31%. Median PFS and median OS were 4.2 months and 12.6 months, respectively. Response rate, PFS, and OS were significantly favorable in female and never-smoker. Conclusions: Sequential treatment consisted with GEM+VNR and GEF was feasible with acceptable toxicities in elderly patients with NSCLC. [Table: see text]
Antitumor effects of combined bortezomib and tipifarnib in head and neck squamous cell carcinoma (HNSCC) cells
Authors: C. M. Klass, Z. G. Chen, X. Zhang, S. Lonial, F. R. Khuri, D. M. Shin
Journal: Journal of Clinical Oncology (2006)

5581 Background: The dysregulation of the NF-κB and Ras/PI3K/AKT pathways in HNSCC supports our hypothesis that combined treatment with the proteasome inhibitor (PI) bortezomib (B) and the farnesyl transferase inhibitor (FTI) tipifarnib (T) leads to synergistic growth inhibition of HNSCC cells. Methods: Growth inhibitory effects of single agents (B 2.5–100 nM; T 0.625–5μM), combination (B+T) (B 12.5–17.5 nM; T 0.625–5 μM) or sequential treatment (B→T after 2h or T→B) were examined in three HNSCC lines (Tu212, 686LN and Sqcc/Y1) using a sulforrhodamine B assay after 72 h of drug exposure. Combination effect in cells treated concomitantly or sequentially was assessed using the combination index (C.I.: &lt; 1.0, synergy; &gt;1.0, antagonism; ≈1.0, additivity). Apoptosis was measured by flow cytometry. Relevant protein markers were evaluated by Western blot. Cell cycle analysis after flow cytometry used FlowJo software. Statistical analysis was done using a two-sided t-test. Results: Growth inhibition by B alone is very effective in all three lines (IC50 = 9–22nM). T used alone is active only in μM range (IC50 = 0.625–5 μM). The inhibitory effects of B and T were sequence dependent. Simultaneous treatment with 12.5 nM B and 5μM T showed synergistic growth inhibition in all 3 lines [C.I., 0.281–0.54]. B→T showed synergistic effects in all three cell lines [C.I., 0.36–0.76]. However, T→B was less synergistic in two of the three lines [Sqcc/Y1 C.I. = 0.404; Tu212 C.I. = 0.748]. Apoptosis was also sequence dependent with B+T or B→T treatment showing significantly more apoptosis than T→B (p = 0.03). Apoptosis induced by T→B was not different from treatment with single agent B (p = 0.22). Sqcc/Y1 cells treated with B and T showed accumulation in G2M phase and an increased percentage of cells in sub-G1. The observed synergistic inhibitory effect of B+T was associated with downregulation of p-AKT. Conclusions: We conclude that treatment with B+T and B→T synergistically enhances HNSCC growth inhibition and results in both significantly increased apoptosis and G2M arrest. These studies strongly support the clinical development of the sequential combination of a PI and a FTI. (Supported by Millenium Pharm. and the Georgia Cancer Coalition). [Table: see text]