tbuckley/cabot-search huggingface dataset:
Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed myeloma
Authors: P. G. Richardson, P. Sonneveld, M. W. Schuster, D. Irwin, E. A. Stadtmauer, T. Facon, J.-L. Harousseau, D. Ben-Yehuda, S. Lonial, K. C. Anderson
Journal: Journal of Clinical Oncology (2005)

6533 Background: Adverse prognostic factors in multiple myeloma (MM) include advanced age, increased β2-microglobulin (β2-M), and prior treatment (tx) failure. Bortezomib (VELCADE, Vc), a first-in-class proteasome inhibitor, provided improved time to progression (TTP) and higher response rates (RR) compared with high-dose dexamethasone (Dex) in patients (pts) with relapsed MM in a large randomized international multicenter phase 3 trial (APEX). The safety and efficacy of Vc were compared with Dex in elderly (≥ 65 y) and other high-risk pts in a subgroup analysis of this trial. Methods: 669 pts received either Vc 1.3 mg/m2 IV on d 1, 4, 8, and 11 for up to eight 3-wk cycles, followed by tx on d 1, 8, 15, and 22 for up to three 5-wk cycles, or Dex 40 mg po on d 1–4, 9–12, and 17–20 for up to four 5-wk cycles, followed by tx on d 1–4 for up to five 4-wk cycles. Pts were stratified at entry by therapeutic history (1 vs > 1 prior line), β2-M (≤ 2.5 vs > 2.5 mg/L), and response to last tx regimen (refractory vs not). EBMT criteria were used to evaluate RR (complete + partial response). Baseline high-risk was defined as age ≥ 65 y, > 1 prior line, β2-M > 2.5 mg/L, or refractory to prior tx. Results: Median TTP was significantly improved and RR were significantly higher with Vc than Dex in elderly and other high-risk pts (table). Rates of grade 3/4 adverse events (AE) were only slightly increased with Vc compared with Dex in pts overall (75% vs 60%), age ≥ 65 (75% vs 64%) and receiving > 1 prior line (75% vs 64%). Rates of serious AE were similar with Vc or Dex in pts overall (44% vs 43%), age ≥ 65 (46% vs 47%), and pts receiving > 1 prior line of therapy (47% vs 43%). Conclusions: Vc was significantly more effective than high-dose Dex in elderly and other high-risk pts with relapsed MM and should be considered an appropriate treatment choice in such pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium, Ortho-Biotech, Pharmion Amgen, Celgene, Millennium, Ortho-Biotech, Roche Millennium
Radiation-induced complications requiring surgical treatment
Authors: S. S. Mahid, M. Turina, C. Yashar, S. Galandiuk
Journal: Journal of Clinical Oncology (2005)

8266 Background: Radiotherapy is an invaluable therapeutic modality in the treatment of pelvic neoplasms. However, despite technical advances in the mode of delivery, an increase in the prevalence of radiation-induced complications may result from more widespread utilization. Methods: Retrospective analysis of 34 consecutive cases with complications following postoperative radiation for pelvic neoplasms within a 14-year period. Results: Among 34 patients, 23 received radiation for colorectal carcinoma, 6 for carcinoma of the cervix and 5 for prostate cancer. Complications fell into 4 broad categories: Radiation strictures (16 cases), small bowel radiation enteritis (15), fistulae (13), and radiation proctitis (7). These occurred either alone or in combination. Proctitis was initially treated with mesalamine suppositories, and enteritis with cholestyramine and antidiarrheals such as diphenoxylate, loperamide, and/or codeine sulfate. No cases of enteritis occurring alone required surgery. Anastomotic strictures were initially treated by dilation under sedation. 5 cases of refractory strictures and proctitis required rectal excision and coloanal anastomosis with temporary ileostomy for 8 weeks. Only 2 patients subsequently required permanent diversion due to failure of other surgical approaches. All cases of radiation-induced fistulae required surgery; including 6 enterovaginal fistulae, 4 enterocutaneous fistulae, 2 colovesical fistulae, and 1 rectourethral fistula. Conclusions: Adjuvant radiotherapy represents an essential therapeutic modality for a variety of pelvic neoplasms. However, the management of radiation-induced injuries poses a challenge to both radiation oncologists and surgeons. Determining the treatment for specific complications requires objective evaluation of the degree and type of injury, patient anatomy, and sphincter function. In most cases, complications can be treated without the need for permanent diversion with acceptable functional results. No significant financial relationships to disclose.
Quality-of-life measurements in patients receiving radiation therapy for colorectal malignancies as compared to other gastrointestinal malignancies.
Authors: B. T. Samuelson, E. K. Fromme, J. Waller, C. R. Thomas
Journal: Journal of Clinical Oncology (2011)

587 Background: Therapy for GI malignancies has long been known to have a marked impact on quality of life, yet this relationship remains poorly understood. Methods: A retrospective, IRB-approved chart review was performed of 722 patients receiving RT for any cancer diagnosis between 1/1/2006 and 12/31/2008. Subjects completed the Functional Assessment of Cancer Therapy General (FACT-G) questionnaire before and after RT. Pre- and immediately post-RT course scores were compared using student t-tests with Bonferroni correction for multiple comparisons (5 comparisons, alpha =.01). Results: 722 of 1369 (52.7%) possible patients participated in the database. Complete pre and post RT spirituality data were available for 73 (64.6%) patients with GI malignancies. Average age was 62 years, 58 (79%) were male and 52 (71%) received definitive treatment. 27 (37%) had esophageal or gastric cancer, 22 (30%) had colorectal cancer and 24 (33%) had other GI malignancies such as pancreatic or hepatobiliary. Colorectal cancer patients fared better in overall QOL as compared to esophageal and gastric patients, pancreatic and hepatobiliary patients and patients with GI malignancies as a whole, and were the only group in which decline in overall QOL as measured by the FACT-G (77.22 to 73.08, p=0.216) did not reach or approach significance. This appeared to be largely driven by differences in physical and especially functional well-being, in which colorectal patients demonstrated the smallest decline (16.14 to 15.59, p=0.466) of any group. Colorectal patients did, however, demonstrate a larger decline in physical well-being (22.35 to 18.05, p=0.010) and overall QOL than did all-comers with any primary malignancy (22.1 to 19.4, p&lt;.001) and (81.3 to 78.9, p&lt;.001) respectively. Conclusions: Physical and functional well-being, as well as overall quality of life are known to decline in patients with GI malignancies. Patients with colorectal disease appear to fare better than those with esophageal, stomach, pancreatic or hepatobiliary malignancies by these measures. Additional investigations are warranted to further define these differences. No significant financial relationships to disclose.
Genetic polymorphisms of metabolizing enzymes and transporters correlate with pharmacokinetics (PK) and pharmacodynamics (PD) of amrubicin.
Authors: Y. Makino, R. Ando, N. Yamamoto, H. Sato, H. Nokihara, I. Sekine, H. Kunitoh, F. Koizumi, T. Tamura, H. Yamamoto
Journal: Journal of Clinical Oncology (2010)

2577 Background: Amrubicin (AMR) is an active agent for lung cancer; however, substantial variability of its hematological toxicity has been observed. Genetic polymorphisms that correlate with PK/PD variabilities of AMR have not been elucidated. The aim of this study was to assess whether genetic polymorphisms correlate with PK/PD of AMR. Methods: AMR (40mg/m2) was administered on days 1-3 every 3-4 weeks with full PK samplings. DNA samples were extracted from peripheral blood mononuclear cells before treatment and 1,936 SNPs in 225 genes coding for a wide category of drug metabolizing enzymes and transporters were analyzed (DMET Plus Premier Pack). Results: Twenty-one patients with lung cancer were enrolled. Major toxicity was hematological and grade 4 neutropenia was observed in 13 out of 21 (61.9%) patients. Grade 4 neutropenia was significantly correlated with AMR (p=0.022) and its active metabolite amrubicinol (AMR-OH) clearance (CL) (p=0.004). Body-weight and serum total bilirubin were significantly correlated with AMR-CL (p<0.0001 and p=0.001, respectively), and serum albumin was also correlated with AMR-OH-CL (p=0.038). Of 1,936 SNPs analyzed, FMO2 gene (rs2020861) was significantly correlated with grade 4 neutropenia (AA+AG [7/15] and GG [6/6], p=0.032 and minor allele frequency = 0.44). The AMR-CL in the FMO2 GG group [16.3L/hr, n=6] was significantly lower compared with AA+AG groups [22.1L/hr, n=15] (p=0.014). NQO1 gene (rs1800566), one of the important metabolic enzymes of AMR, was correlated with both AMR-CL and AMR-OH-CL, and showed a moderate trend for grade 4 neutropenia (CC+CT [10/18] and TT [3/3], p=0.215, and minor allele frequency = 0.22). SLC22A1 gene (rs1867351), that is, an organic cation transporter-1, was significantly correlated with the %-decrease in hemoglobin level in the first treatment cycle (CC+CT [n=13] and TT [n=8] were 18.7 and 11.7%, respectively, p=0.028, and minor allele frequency = 0.354). Conclusions: This is the first report of detailed AMR PK/PD analysis and suggestion of correlation between AMR PK/PD and genetic polymorphisms. Further studies to confirm these results in larger population are highly warranted. No significant financial relationships to disclose.
Analyses of plasma cytokine/angiogenic factors (C/AFs) profile during preoperative treatment with pazopanib (GW786034) in early-stage non-small cell lung cancer
Authors: P. Nikolinakos, N. Altorki, M. Guarino, H. Tran, D. Rajagopalan, S. Swann, W. Bordogna, L. Ottesen, D. Yankelevitz, J. V. Heymach
Journal: Journal of Clinical Oncology (2008)

7568 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. In a single-arm phase II trial (NCT00367679; VEG105290), patients received pazopanib 800 mg QD for 2–6 weeks before scheduled surgery. Tumor volume measurements were performed using high resolution CT images before and after treatment. An exploratory analysis was planned to describe the modulation of C/AFs during pazopanib treatment and identify potential predictive plasma markers. Methods: Plasma samples were collected pre- treatment and on the last day of pazopanib dosing. Levels of 52 C/AFs were measured by suspension bead multiplex assays (BioRad) or ELISA. Results were correlated with change in tumor volume. Statistical analyses included Wilcoxon tests and Pearson correlation tests. Results: 19 paired samples have been analyzed. Pazopanib treatment was associated with a significant modulation of 13 C/AFs, including a decrease in soluble VEGFR-2 (p<0.001) and increases in PlGF, IFN-α2 and HGF; chemokines/monokines: SDF1-α, CTACK, CXCL-10, CXCL-9, RANTES; and further factors: IL-12; M-CSF and TRAIL (all with p<0.05). PlGF showed the highest up-regulation during treatment with an average 15.9 fold increase, whereas changes compared to baseline for the remaining factors varied between 5 and 60%. The exploratory correlation of C/AF changes with tumor changes indicated an association with 6 factors (sVEGFR-2 (r = 0.77), VEGF (r = - 0.68), IL-16, IL-1RA, MCP-3, and IL-4; all with p<0.05). A significant correlation between baseline levels of C/AFs and tumor reduction was observed for 8 factors (PlGF, IL-2R, IL-12, IL-16, TRAIL, SCF, IL-3 and CTACK). Conclusions: Pazopanib treatment was associated with decreases in sVEGFR2 and increases in an additional 12 C/Afs, with PlGF demonstrating a particularly striking increase. The exploratory analysis identifies that baseline levels of several C/Afs may have predictive value for pazopanib treatment. Moreover a strong correlation between sVEGFR-2 changes during pazopanib treatment and tumor shrinkage was observed making this factor a potentially attractive marker of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Pneum Rx, General Electric GlaxoSmithKline, Pneum Rx GlaxoSmithKline GlaxoSmithKline
STA-4783 in combination with paclitaxel induces heat shock protein 70 (hsp70) in a phase I trial
Authors: A. Berkenblit, J. Supko, D. P. Ryan, M. V. Seiden, M. Nagai, J. Bertin, T. Dahl, B. Dezube, J. P. Eder
Journal: Journal of Clinical Oncology (2005)

2011 Background: STA-4783 (S) is a bis-thiobenzoylhydrazide that promotes induction of hsp70 and enhances paclitaxel (P) antitumor efficacy in xenograft models. Its mechanism appears to be immunologic, involving stimulation of cytotoxic responses. Methods: A phase 1 trial was conducted in combination with P in advanced solid tumor patients. S and P were coadministered iv over 3 h every 3 weeks. Starting doses were 44 mg/m2 S and 135 mg/m2 P. P was then increased to 175 mg/m2, followed by escalation of S to establish the maximum tolerated dose based upon first cycle toxicity in 3–6 patients at each dose level. Pharmacokinetic (PK) studies were performed during cycle 1 using LC/MS assays to measure both compounds in plasma. Hsp70 was measured in plasma before and after treatment. Results: 35 patients have been evaluated at 8 dose levels. The S dose was escalated from 44 to 525 mg/m2 in combination with P 175 mg/m2. No serious adverse events specifically attributable to S have been observed. P related dose limiting toxicities occurred in a single patient in each of the top three dose levels (neutropenia, arthralgia, and febrile neutropenia with mucositis) resulting in cohort expansion. S exhibited linear PK that was unaffected by P dose. It was rapidly eliminated from plasma with terminal-phase half-life of 0.94 ± 0.23 h and total body clearance of 28 ± 8 l/h/m2. Its apparent volume of distribution was comparable to total body water (Vss, 23 ± 16 l/m2). P PK appeared to be moderately dependent on the S dose, as indicated by a significant trend toward decreasing clearance, an increase in peak plasma concentration and Vss, but without affecting the terminal phase half-life. These observations are consistent with competitive inhibition of P hepatic metabolism. Increased toxicity at higher dose levels was consistent with moderate increase in systemic exposure to P. Induction of hsp70 protein in plasma was dose-dependent peaking at 8 h after dosing. Conclusions: The S/P combination was well tolerated, with adverse events consistent with those expected for P alone. Phase 2 clinical trials are underway in NSCLC, melanoma, and soft-tissue sarcoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta Synta
Efficacy of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) versus doxorubicin in advanced HCC: Updates on the EACH study.
Authors: S. Thongprasert, S. Qin, H. Lim, V. Bhudhisawasdi, X. Yin, W. Gang, B. Kim, Z. Jian, T. Yang, K. Rau
Journal: Journal of Clinical Oncology (2011)

160 Background: In Asia, where hepatitis B is very common, patients often present with locally advanced or metastatic hepatocellular carcinoma (HCC), and their prognosis is poor. The EACH study was designed to evaluate the efficacy and safety of FOLFOX4 vs. doxorubicin as palliative systemic chemotherapy in advanced HCC. Methods: The open-label, randomized, multicenter phase III study was conducted in 371 patients in China, Taiwan, Korea and Thailand, who had locally advanced or metastatic HCC and were ineligible for resection. Patients were randomized 1:1 to receive either FOLFOX4 (oxaliplatin 85 mg/m 2 i.v. d1; LV 200 mg/m 2 i.v. h0–h2 d1 and d2; 5FU 400 mg/m 2 i.v. bolus h2, then 600 mg/m 2 over 22 hours d1 and d2 q2w) or doxorubicin (50 mg/m 2 i.v. q3w). The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate (RR) by RECIST and safety. Data from final and follow-up analyses of the intent-to-treat (ITT) population and selected subgroup analyses are presented. Results: At the final analysis, median OS with FOLFOX4 (N = 184) was 6.40 months (95% CI: 5.30, 7.03) vs. 4.97 months (95% CI: 4.23, 6.03) with doxorubicin [N = 187; p = 0.0695 using a stratified log-rank test; statistical significance (p = 0.0425) was achieved at the post hoc follow-up analysis conducted 7 months later]. Median PFS with FOLFOX4 was 2.93 months (95% CI: 2.43, 3.53) vs. 1.77 months with doxorubicin (95% CI: 1.63, 2.30; p = 0.0002). The RR was 8.2% vs. 2.7% of patients with FOLFOX4 and doxorubicin, respectively (p = 0.0233), and the disease control rate (DCR) was 52.2% vs. 31.6% (p &lt; 0.0001). In the Chinese sub-population, OS, PFS, RR and DCR were significantly improved with FOLFOX4 vs. doxorubicin at both the final and follow-up analyses. In the other subgroups analyzed, the OS and PFS benefits of FOLFOX4 vs. doxorubicin were generally consistent. Conclusions: In the ITT population, median OS was greater with FOLFOX4 than doxorubicin throughout the study and statistical significance was achieved after continued follow-up. FOLFOX4 can benefit patients with advanced HCC, as it significantly increases median OS, PFS, RR and DCR compared with doxorubicin. [Table: see text]
Burdensome Research Procedures in Trials: Why Less Is More
Authors: Jonathan Kimmelman, David B. Resnik, Jeffrey Peppercorn, Mark J. Ratain
Journal: JNCI Journal of the National Cancer Institute (2016)

A large volume of trials involve invasive, nontherapeutic research procedures, like organ biopsy or sham surgeries, that can pose risks comparable with the experimental treatment itself but that have no direct benefit for volunteers. Though such procedures can enhance the value of clinical investigations, recent studies suggest that many studies involving invasive, nontherapeutic research procedures are not well planned and reported; some studies suggest that their results are often not utilized in the planning of new investigations. This commentary offers recommendations for how investigators, sponsors, and ethics committees might improve evaluation and implementation of studies involving invasive nontherapeutic procedures. We conclude by urging more demanding scientific standards for the rationale, design, and reporting of burdensome, nontherapeutic research procedures—particularly where they involve risk of serious complications.
Prediction of the probability of breast cancer-related lymphedema after axillary lymph node dissection.
Authors: Atilla Soran, Ahmad Ibrahim, Lori DeGore, Ronald Johnson
Journal: Journal of Clinical Oncology (2013)

140 Background: Early detection and timely intervention demonstrate the greatest promise of reducing incidence of late-stage lymphedema (LE) in breast cancer patients undergoing axillary lymph node dissection (ALND). A nomogram was developed for predicting the risk of arm LE in this group. This study’s aim was to test the preoperative prediction model for the early diagnosis of clinical and subclinical LE in ALND including patients prospectively monitored by bioimpedance spectroscopy (BIS). Methods: Patients with pre-existing clinical LE were selected from our existing database. In addition, data on subclinical LE was prospectively collected through our LE monitoring program. This program tracks patients from a baseline, using an L-Dex U400 measurement preoperatively or postoperatively (if no clinical LE), and at 3-6 month intervals. The 5 year probability of LE after ALND was calculated using The Cleveland Clinic Risk Calculator. The discrimination of the nomogram was assessed by calculating the area under (AUC) the receiver operating characteristic curve (ROC); AUC values between 0.7–0.8 represent considerable discrimination. Results: A total of 334 patients who underwent ALND were included in this study; 116 patients with previously diagnosed clinical LE and 218 patients at-risk of LE (monitored with BIS since 2010). Since BIS monitoring began, a total of 58 patients were diagnosed with subclinical LE; a total of 174 patients with clinical or subclinical LE (LE group). The mean age was 60.6+11.4 years in LE group and 57.8+12.03 years in No-LE group (p=0.03). BMI was higher in LE group compared with no LE group (29.8 + 7.4 vs.28.3+6.3 kg/m 2 (p=0.05). The AUC value was calculated from the nomogram (AUC=0.609). Conclusions: The recently created preoperative prediction model for the diagnosis of LE in ALND is not accurate in predicting who will develop clinical or subclinical LE. Periodic monitoring of women at high risk for LE, with modern technology, helps early detection and timely intervention for LE, which can minimize or eliminate more advanced LE among women undergoing ALND.
Impact of neoadjuvant chemotherapy following chemoradiation on tumor response, adverse events, and surgical complications in patients with advanced rectal cancer treated with TME.
Authors: J. Garcia-Aguilar, J. Marcet, T. Coutsoftides, P. Cataldo, A. Fichera, L. E. Smith, S. Oommen, S. R. Hunt, D. Herzig, D. Dietz, M. G. Varma, C. A. Ternent, M. J. Stamos, K. Avila, D. D. Smith
Journal: Journal of Clinical Oncology (2011)

3514 Background: A pathologic complete response (pCR) to pre-operative chemoradiation (CRT) is associated with improved prognosis in rectal cancer patients treated with total mesorectal excision (TME), but the proportion of patients who achieve a pCR is relatively small. We investigated the effect of adding increasing cycles of pre-operative neoadjuvant chemotherapy after CRT followed by surgery on pCR rate, adverse events (AEs) and surgical complications. Methods: Three sequential phase II trials or study groups (SGs) were conducted in patients with endorectal ultrasound or MRI Stage II and III rectal cancer. All patients were treated with neoadjuvant 5-FU-based CRT, followed by 0, 2 or 4 cycles of mFOLFOX-6 followed by TME. Tumor response was assessed by pathology according to RECIST criteria. AEs and surgical complications were reported according to CTCAE 3.0. Results: Demographics were similar between SGs. Clinical characteristics, treatment compliance, pathological tumor response, AEs and surgical complications are shown below (Table). Conclusions: Advanced rectal cancer patients who receive pre-operative CRT and increasing cycles of chemotherapy before surgery have a higher pCR rate without increasing AEs or surgical complications. Studies assessing delivering all chemotherapy before rather than after TME are underway. SG1 n=60 SG2 n=67 SG3τ n=48 Clinical stage II 19 (32%) 12 (18%) 13 (27%) III 41 (68%) 55 (82%) 35 (73%) Treatment compliance CRT 44 (73%) 53 (79%) 42 (88%) mFOLFOX-6 --- 58 (87%) 41 (85%) Median CRT-to-surgery timeÔ 40 77 106 R0 resection 58 (97%) 64 (96%) 32 (97%)* Sphincter saving surgery 46 (77%) 50 (75%) 38 (79%) Temporary ileostomy 38 (63%) 43 (64%) 38 (79%) Nodes examined 13±7 15±7 14±7 Pelvic fibrosis† 2.4±1.7 4.0±2.6 4.1±2.4 Surgical difficultyψ 4.5±2.7 5.1±2.7 4.9±2.6 Tumor response pCR 11 (18%) 17 (25%) 15 (31%) pPR 43 (72%) 50 (75%) 32 (67%) Stable disease 6 (10%) 0 (0%) 1 (2%) Grade 3+ AEs 26 (43%) 23 (34%) 19 (40%) Grade 3+ surgical complications 9 (15%) 4 (6%) 5 (12%)** Based on 33* and 42** patients; ÔDays; †1=none-10=max; ψ1=easy-10=difficult; τ60 patients accrued, 48-surgery; pPR: pathologic partial response.
Direct RNA Target Analysis Identifies Signatures That Define Msi2's Role in Sustaining HSC Cell Fate.
Authors: Sun Mi Park, Raquel Deering, Yuheng Lu, Patrick Tivnan, Varun Shenoy, Steve Lianoglou, Fatima Al-Shahrour, Christina Leslie, Benjamin L. Ebert, Christopher Lengner, George Q. Daley, Michael G Kharas
Journal: Blood (2012)