tbuckley/cabot-search huggingface dataset:
Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy.
Authors: James M. G. Larkin, Christian U. Blank, Petri Bono, Svetozar Gogov, Ashok Panneerselvam, Carlos A. Garay, Viktor Grünwald
Journal: Journal of Clinical Oncology (2012)

391 Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE. Results: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.) Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population. [Table: see text]
Evaluation of publicly-sponsored lung cancer trials in US: Are experimental treatments better than the control ones?
Authors: H. P. Soares, B. Djulbegovic, A. Kumar, T. Tanvetyanon, G. Bepler
Journal: Journal of Clinical Oncology (2006)

7157 Background: Lung cancer is one of the leading causes of cancer deaths in the US. A considerable number of these patients are treated in randomized clinical trials (RCTs). However, how often experimental lung treatments are superior to control treatments is not known. To accurately assess this, three factors have to be taken into consideration: publication rate, methodological quality of trials and the choice of the comparator intervention. Methods: All phase 3 RCTs that were completed to date by 3 National Cancer Institute cooperative groups (ECOG, NCCTG and RTOG) were eligible for the analysis. We identified 50 RCTs enrolling 11,631 lung cancer patients. The methodological quality of the trials was assessed for possible effects of bias and random error on the outcomes of the trials. The possible impact of the choice of a comparator intervention was also assessed. To evaluate the outcomes, we extracted data on survival (OS), disease free survival (DFS), response rate (RR) and treatment-related mortality (TRM). In addition, the final investigators’ preference about experimental or control interventions was used to assess whether experimental treatments were better than controls. Results: In terms of OS, DFS and RR experimental treatments were as likely as control treatments to be successful—Hazard ratio [HR]= 0.96 (99%CI 0.92–1.01)], [HR = 0.98 (99%CI 0.98–1.17)] and [RR = 1.11 (99%CI 0.84–1.46)], respectively. TRM was worse with experimental treatments [HR = 1.61 (99% CI 1.10–2.36)]. Investigators’ preferences for experimental vs. control treatments were 30% and 70%, respectively (p &lt; 0.001). The quality of trials was high. We did not find any evidence that the methodological quality of trials/choice of comparator influenced the results. Conclusions: We found that there is no clear pattern that predicts which treatment will be better. In aggregate, there is about an equal chance for experimental and standard treatments to result in successful outcomes or that the outcomes may not differ between two types of the treatments, although TRM is slightly higher with experimental arms. This is a welcome finding because if one intervention (experimental or control) was consistently better, maintaining randomization will be difficult. No significant financial relationships to disclose.
Selective in vitro and in vivo anti-tumor activity of PRLX 93936 in biological models of melanoma and ovarian cancer
Authors: S. R. Sahasrabudhe, S. Lai, M. Pierce, C. Clemens, R. Venkat, M. Rebentisch, A. Senina, R. Becklin, S. K. Richards, T. Erkkila, P. B. Robbins
Journal: Journal of Clinical Oncology (2008)

14586 Background: PRLX 93936 is a novel small molecule exhibiting therapeutic potential in an array of in vitro and in vivo tumor models many with limited treatment options such as melanoma. Developed and characterized in cell-based phenotypic assays, PRLX 93936 is a product of extensive SAR work originating from a small molecule identified in a synthetic lethal screen against isogenic cell lines engineered to differentially express several genes including activated RasV12. Methods: Assays measuring cell survival, cytostasis, cell cycle activity and mechanisms of death were employed to characterize the biological activity of the compound. Structural analogs were designed and tested for antiproliferative activity against normal cells and lines derived from tumors with dissimilar causative mutations. Western blotting and mRNA analyses were used to characterize the Ras pathway activation status of the cell panel. In vivo testing of the compound was performed in mice harboring xenografts of human tumor origin. Results: Potent and selective in vitro activity was observed against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas. Ras pathway activation as evidenced by high mRNA levels and/or the presence of phosphorylated Mek and Erk proteins was observed in many sensitive lines. PRLX 93936 can rapidly affect ion flux, cell cycle, and mitochondrial membrane polarization ultimately inducing caspase dependent apoptosis. Mass spectrometry-based proteomics experiments indicated that both PRLX 93936 and its parent compound can bind to mitochondrial VDAC proteins. Results in multiple tumor xenograft models produced responses from complete regression to tumor-growth inhibition following PO, IV, or IP administration. Responsive in vivo tumor models include: OVCAR-5 (ovarian), SK-Mel28 (melanoma) as well as some derived from sarcoma, pancreas, colon, non small cell lung cancer and multiple myeloma. Toxicology studies indicated drug tolerance at potentially therapeutic levels based on body surface area scaling. Conclusions: Preclinical pharmacodynamic and toxicological studies, suggest that PRLX 93936 has great therapeutic potential and therefore, Prolexys initiated a Phase I clinical trial in August, 2007. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Prolexys Pharmaceuticals, Inc. Prolexys Pharmaceuticals, Inc.
GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate PAd Vs VCD Induction Prior To High Dose Treatment Followed By Lenalidomide Consolidation and Maintenance – Final Analysis On Induction Therapy
Authors: Hartmut Goldschmidt, Jan Duerig, Uta Bertsch, Christina Kunz, Thomas Hielscher, Mathias Haenel, Igor Wolfgang Blau, Dirk Hose, Anna Jauch, Baerbel Schurich, Kai Neben, Anja Seckinger, Barbara Huegle-Doerr, Maximilian Merz, Markus Munder, Walter Lindemann, Matthias Zeis, Christian Gerecke, Ingo GH Schmidt-Wolf, Katja Weisel, Christof Scheid, Hans Salwender
Journal: Blood (2013)
Effect of Hypophysectomy on the Lowering of Organ Catalase by a Transplanted Tumor
Authors: Rechcigl, Miloslav, Wollman, Seymour H.
Journal: JNCI Journal of the National Cancer Institute (1963)

Journal Article Effect of Hypophysectomy on the Lowering of Organ Catalase by a Transplanted Tumor Get access Miloslav Rechcigl, Jr., Miloslav Rechcigl, Jr. Laboratory of Biochemistry and Laboratory of Physiology, National Cancer Institute,3Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar Seymour H. Wollman Seymour H. Wollman Laboratory of Biochemistry and Laboratory of Physiology, National Cancer Institute,3Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 31, Issue 3, September 1963, Pages 651–669, https://doi.org/10.1093/jnci/31.3.651 Published: 01 September 1963 Article history Received: 13 March 1963 Published: 01 September 1963
Aromatase inhibitors (AI) for elderly patients: Efficacy, compliance and safety according to patient age in the BIG 1–98 trial
Authors: D. Crivellari, Z. Sun, A. S. Coates, K. N. Price, B. Thürlimann, H. Mouridsen, L. Mauriac, J. F. Forbes, M. Castiglione- Gertsch, A. Goldhirsch
Journal: Journal of Clinical Oncology (2007)

9033 Background: Because elderly patients (pts) are under-represented in clinical trials, care should be taken in extending overall results to that patient group. We compared letrozole (L) with tamoxifen (T) with respect to disease-free survival, treatment compliance, and adverse events (AEs) according to age in the continuous therapy arms of the BIG 1–98 trial. Methods: Between March 1998 and May 2003, 8,028 postmenopausal women with hormone receptor-positive breast cancer were enrolled in the BIG 1–98 trial. This report includes the 4,922 pts allocated to continuous therapy with either T or L for 5 years. Subpopulation Treatment Effect Pattern Plots (STEPP) were used to look at the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categorical age groups were defined: “younger postmenopausal” &lt; 65, “older” 65–74, and “elderly” = 75. Cox proportional hazards models were used to compare T and L according to time to first AE, adjusting for relevant pre-existing risk factors. The median follow-up was 40.4 months. Results: STEPP analysis showed the L provided consistent benefit compared with T irrespective of age. Pts 75 and older were less likely to complete trial treatment, but similarly in the two treatment groups. Adjusted treatment comparisons of AEs according to age groups are given below. (T,L: significantly more AEs on T,L; NS: no significant difference) Conclusion: Adjuvant treatment with L had superior efficacy compared with T in all age groups. Physicians should base clinical decisions on the individual patient profile with respect to reduction of risk of recurrence from L as well as existing comorbidities. [Table: see text] No significant financial relationships to disclose.
Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: a randomized trial.
Authors: S Cascinu, A Fedeli, S L Fedeli, G Catalano
Journal: Journal of Clinical Oncology (1993)

PURPOSE Diarrhea is a prominent feature of fluorouracil (5FU) gastrointestinal toxicity, especially when 5FU is combined with leucovorin (LV) or interferon (IFN). No treatment for this condition has been well defined, although drugs, such as diphenoxylate or loperamide, generally are used. The efficacy of octreotide in the treatment of 5FU-induced diarrhea recently has been reported. We performed a randomized trial that compared octreotide with loperamide, the drug most commonly used for therapy for this disorder. PATIENTS AND METHODS Forty-one patients with grade 2 (four to six stools per day) or grade 3 (seven to nine stools per day; National Cancer Institute toxicity criteria) diarrhea after chemotherapy with a 5FU-containing regimen for colorectal cancer in 28 cases, gastric cancer in six cases, pancreatic cancer in five cases, and breast cancer in two cases, were entered onto the study. Twenty-one patients received octreotide at a dosage of 0.1 mg subcutaneously twice per day for 3 days, and 20 patients received loperamide 4 mg orally initially and then 2 mg every 6 hours for 3 days. The two arms were comparable for age, sex, and primary tumor. Patients were evaluated for response each treatment day; all patients were assessable. RESULTS Diarrhea resolved in 19 patients in the octreotide arm (one within the first day; four within the second day; and 14 within the third day) versus only three (all after the third day of therapy) in the loperamide arm (P &lt; .005). Median frequency of stools in the 3 days of therapy was four, three, and zero in the octreotide arm and five, five, and five in the loperamide arm. No side effects were observed in both arms. Ten patients on the loperamide arm and only one on the octreotide arm required hospitalization for parenteral replenishment of fluids and electrolytes. CONCLUSION Octreotide seems to be more effective than loperamide in control of diarrhea and elimination of the need for replenishment of fluids and electrolytes.
Predictors of dose limiting toxicities in phase I clinical trials: The impact of age, comorbidity, and other clinical and non-clinical factors
Authors: N. K. LoConte, J. F. Cleary, J. Bozeman, G. Wilding, D. Alberti, A. Setala, J. Liou, M. Smith, K. D. Holen
Journal: Journal of Clinical Oncology (2008)

9525 Background: There are no clear predictors clinicians use to predict dose limiting toxicity (DLT) in phase I chemotherapy clinical trials. Many providers are reluctant to refer older adults to phase I trials because of concerns about the development of toxicity. The goal of this study was to identify clinical and nonclinical factors which were associated with the development of DLT in phase I studies. Methods: Patients (pts) were included if they were treated at maximally tolerated dose (MTD) and above. Studies were included only if MTD was reached. Data collected included age, comorbidity (Cumulative Illness Rating Score-Geriatrics), labs at enrollment, height, weight, performance status, cancer type, duration of diagnosis, prior treatment, drug level, smoking status, marital status, mean income and % high school educated by ZIP code. Those who did and did not have DLT were compared by univariate and then multivariate analysis. Results: 242 charts were reviewed, from 24 cytotoxic chemotherapy studies, and 27 different types of cancer were represented. On univariate analysis, higher mean age, being married, lower weight, dose of drug, alkaline phosphatase, hemoglobin, and LDH were significantly associated with DLT (p<0.05). CIRS-G score was not associated with DLT, mean total CIRS-G score was 7.5. In multivariate analysis being married or partnered, higher household income (mean $50,299 versus $45,872), weight (mean 75 versus 82 kg), dose level and LDH (mean 23 versus 290) were still significant predictors of DLT (see table). Conclusions: Age and comorbidity did not predict for development of DLT in phase I chemotherapy trials. Many of these pts were very fit, with relatively low CIRS-G scores, so the impact of comorbidity may not have been fully evaluated. Several social and clinical factors may predict for development of DLT. A prospective model is being planned to confirm these results. Supported by an ASCO/John Hartford Foundation Award and NCI U01 CA062491. Adjusted Odds Ratios and 95% Confidence Intervals for Factors Predicting Presence of DLT (N=242) Characteristic OR of DLT (N=65) 95% CI p- value Currently married or partnered (partnered versus not) 2.75 (1.02, 7.43) 0.046 Median household income by census tract (higher versus lower) 1.00 (1, 1) 0.013 Weight (kg, higher versus lower) 0.98 (0.96, 0.99) 0.009 Dose of chemotherapy (above MTD versus MTD) 2.57 (1.33, 4.94) 0.01 LDH (U/L, higher versus lower) 1.10 (1.02, 1.19) 0.02 No significant financial relationships to disclose.
Long survival of never smoking non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib HCl (OSI-774) and chemotherapy: Sub-group analysis of TRIBUTE
Authors: V. A. Miller, R. Herbst, D. Prager, L. Fehrenbacher, R. Hermann, P. Hoffman, B. Johnson, A. B. Sandler, M. G. Kris, D. Ramies
Journal: Journal of Clinical Oncology (2004)

7061 Background: Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor (TKI). Monotherapy trials of EGFR-TKIs have suggested never smokers and pts with bronchioloalveolar cell carcinoma (Shah, Proc ASCO 2003 #2524; Miller, Proc ASCO 2003 #2491) are more likely to benefit from these agents. TRIBUTE was a placebo-controlled study randomizing pts with previously untreated advanced NSCLC to receive erlotinib, 150 mg/d, or placebo (PBO) with 6 cycles of carboplatin/paclitaxel (CP) followed by maintenance monotherapy. Methods: Pts with performance status (PS) of 0 or 1 were eligible. Randomization was stratified by stage, >5% weight loss (WL) prior 6 mos., measurable disease (MD), and study site. The primary endpoint was overall survival (OS). Other endpoints included time to progression (TTP), objective response (OR) and duration of response. Results: 1059 pts randomized/treated (526 erlotinib; 533 PBO). No difference was observed in OS (p=0.95), OR (p=0.36) or TTP (p=0.36) with erlotinib and CP vs CP alone. Univariate analyses with pre-specified factors at entry (stage, WL, MD, age, gender, race, smoking hx, PS, EGFR status and histology) were used to see if any were predictive of OS. Smoking history as recorded on Case Report Forms was available on all pts in the intent-to-treat analysis. Pts who reported never smoking in the erlotinib arm (n=69) had an improved OS versus never smoking pts who received CP alone (n=44) (median survival 23 versus 10 months; HR 0.49 95%CI 0.28–0.85). This subgroup was well-balanced for known prognostic features between the 2 arms. None of the other factors were predictive for OS. Conclusions: Although erlotinib with CP did not confer an advantage in OS over CP alone in all enrolled NSCLC pts, the addition of erlotinib to CP markedly prolonged survival in pts who reported never smoking. This latter observation is consistent with results of prior studies of EGFR-TKIs and warrants confirmation in a randomized trial. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech; OSI Pharmaceuticals, Inc. Genentech AstraZeneca; Genentech Genentech
Recombinant bispecific antibodies (bsMAb) to carcinoembryonic antigen (CEA): Promising new agents for pretargeted radioimmunotherapy (RAIT) of solid tumors
Authors: R. M. Sharkey, H. Karacay, E. A. Rossi, C. H. Chang, W. McBride, I. D. Horak, H. J. Hansen, D. M. Goldenberg
Journal: Journal of Clinical Oncology (2004)

3105 Background: Although radiolabeled antibodies are effective treatments for lymphoma, to be effective for solid tumors, the radiation dose needs to be increased. Streptavidin-biotin pretargeting methods have been reported to increase the radiation dose to tumors and improve therapeutic responses in lymphoma and solid tumor models. Because of the high immunogenicity of streptavidin, we have developed a pretargeting method that will use recombinant, humanized anti-CEA bsMAbs to localize either 90Y or 177Lu. Methods: Recombinant bsMAb monovalent (bispecific diabody; 40 kD) or divalent (trivalent bsMAb; 80 kD) to CEA and monovalent binding to a novel hapten, histamine-succinyl-glycine (HSG), were tested in nude mice bearing a human colon tumor xenograft, GW-39. Results: When the bsMAb dose and interval between the bsMAb and111In-DOTA-di-HSG peptide were properly adjusted, tumor targeting within 3 h after the 111In-peptide could achieve levels of nearly 30 percent injected dose per gram (% ID/g), which rivaled the maximum tumor uptake achieved with an 111In-labeled anti-CEA IgG 2 days after its injection. Tumor/blood ratios were as high 30:1 for the pretargeting at 3 h after the peptide injection. Analysis of time-activity curves over 5–7 days, comparing targeting of 90Y-radioactivity, using the trivalent bsMAb pretargeting method with a 90Y-peptide, to a 90Y-anti-CEA IgG, showed pretargeting had a 1.7-fold higher AUC with a 3-fold higher dose rate advantage than the IgG at equitoxic toxic injected activity. Preliminary studies using the 90Y-peptide pretargeting method have shown complete arrest of the growth of established (0.35 cm3) colonic cancer xenografts in nude mice over a 14-week period, whereas tumors in untreated or animals receiving the same dose of the 90Y-peptide progressed rapidly. Conclusions: These studies indicate that pretargeting using these recombinant bsMAb could potentially provide sufficient targeting enhancement to be an effective therapeutic in solid tumors. (Supported in part by the Office of Science (BER), U.S. Department of Energy grant DE-FG01–95ER62028.) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration IBC Pharmaceuticals, Inc.; Immunomedics, Inc. IBC Pharmaceuticals, Inc.; Immunomedics, Inc.
Osteosarcoma of the jaw/craniofacial bones: Outcomes following multimodality treatment
Authors: B. Guadagnolo, G. K. Zagars, A. K. Raymond, R. S. Benjamin, E. M. Sturgis
Journal: Journal of Clinical Oncology (2009)

10511 Purpose: To evaluate outcomes for patients with osteosarcoma of the jaw/craniofacial bones treated with surgery or combined modality therapy (CMT) consisting of surgery and radiation therapy (RT). Methods: Retrospective analysis was performed on data for 119 patients with osteosarcoma of jaw/craniofacial bones who underwent definitive resection with or without RT between 1960 and 2007. Median age was 33 years (range, 7–77 years). Ninety-two (77%) underwent surgery alone while 27 (23%) were treated with CMT. Median RT dose was 60 Gy (range, 50–66 Gy). Kaplan-Meier method was used to calculate the actuarial curves for survival (OS), disease-specific survival (DSS), local recurrence (LR), distant metastatic relapse (DM), and complication rates; and the log-rank statistic was used to test for significance of differences between curves. Results: Median follow-up was 5.8 years (range, 0.25 to 44.5 years). The OS rates at 5 and 10 years were 63% and 55%, respectively. Corresponding DSS rates were 67% and 61% respectively. Surgical margin status (positive/uncertain vs. negative) was adversely prognostic for OS (p=0.0001) and DSS (0.0001). Stratified analysis by margin status showed that CMT compared to surgery alone improved OS (80% vs. 31%, p=0.02) and DSS (80% vs. 35%, p=0.02) for patients with positive/uncertain margins. Multivariate analysis showed that CMT for patients with positive/uncertain margins improved OS (p&lt;0.0001). Forty-four patients (40%) experience LR and 25 (21%) developed DM. There was no difference in DSS if relapse was isolated LR vs. DM (26% vs. 29%, respectively at 5 years, p=0.48) Local control (LC) rates were 59% and 57% at 5 and 10 years, respectively. The use of CMT vs. surgery alone significantly improved LC for patients with positive/uncertain margins (75% vs. 24%, p=0.006). The rate of surgical complications was 28% at 5 years. Rates of RT-associated complications were 40% and 47% at 5 and 10 years, respectively. Conclusions: RT in addition to surgery improves OS, DSS, and LC for patients with osteosarcoma of the jaw/craniofacial bones who have positive/uncertain surgical margins. Complication rates from surgery and RT are high, but LR is lethal in this disease. Morbidity risks must be weighed against the need to eradicate disease with primary local managmement. No significant financial relationships to disclose.