tbuckley/cabot-search huggingface dataset:
Evaluation of the safety of C-1311 administered in a phase 1 dose-escalation trial as a 1-hour infusion once every 3 weeks in patients with advanced solid tumors
Authors: A. Thomas, A. Anthoney, S. Ahmed, M. Drouin, A. Major, R. L. Capizzi, C. Grieshaber, P. Loadman, C. Twelves
Journal: Journal of Clinical Oncology (2006)

12005 Background: C-1311 (Symadex) is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of existing cancer therapies. This clinical trial was designed to assess the safety profile of ascending doses of C-1311 and to determine the recommended dose when administered every 3 weeks (Q3W). Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases with different schedules. Initially, C-1311 was given as a 1-hour daily infusion over 5 consecutive days. Following review of pre-clinical data, coupled with preliminary results of a parallel weekly study, a day 1 only schedule was explored. The maximum tolerated dose (MTD) is defined as the dose at which 2/3 or 2/6 pts experience a dose-limiting toxicity (DLT). The recommended dose (RD) is defined as the dose level below the MTD, confirmed by expansion of the RD cohort to 9 pts. Results: The first 5 patients were treated at doubling doses of 6, 12, 24, 48 and 96 mg/m 2 on a schedule of 1-hour daily infusions over 5 consecutive days, repeated every 3 weeks; no DLTs were seen. The 6 th pt received the same total dose as the 5 th (480 mg/m 2 ) but on day 1 only, following which a modified Fibonacci design with cohorts of 3 pts and 33% dose increments was utilized. Subsequently, pts received C-1311 at doses of 640 mg/m 2 (3 pts), 850 mg/m 2 (3 pts) and 1100 mg/m 2 (5 pts); 2/5 pts treated at 1100 mg/m 2 experienced an identical DLT (grade 4 neutropenia for ≥7 days with grade 4 thrombocytopenia), defining this as the MTD. The 850 mg/m 2 cohort was expanded to confirm this as the RD. Neutropenia, thrombocytopenia, anemia and fatigue have been reported as drug-related grade 3 or 4 adverse events (AEs). Grade 1 or 2 AEs most commonly described as drug-related are fatigue, nausea, vomiting and diarrhea. Stable disease was observed in two patients with advanced malignancy. A pt had a stable disease over 8 cycles and one over 6 cycles. Plasma drug concentrations are linear and proportional to dose. Conclusions: A C-1311 dose of 850 mg/m 2 administered once every 3 weeks offers a predictable and tolerable safety profile. [Table: see text]
Molecular prognostic markers in squamous cell carcinoma of the head and neck: the role of E-cadherin
Authors: P. Kountourakis, E. Pectasides, B. A. Burtness, D. Pectasides, A. Psyrri, G. Fountzilas
Journal: Journal of Clinical Oncology (2008)

6040 Background: E-cadherin is a transmembrane glycoprotein which is localized on the surface of epithelial cells and mediates adhesion through Ca2+-dependent homotypic binding. Downregulation of E-cadherin expression correlates with increased invasiveness and metastasis in carcinomas of several anatomic sites. In the present study we investigated the relationship between membranous E-cadherin expression and outcome in patients with head and neck squamous cell carcinoma (HNSCC). Methods: A tissue microarray including 102 specimens from primary HNSCC cases was constructed. Protein expression levels for E-cadherin were analyzed using a system of in-situ protein expression analysis (AQUA). AQUA uses molecular methods to define subcellular compartments. It then quantifies the amount of protein expressed within the compartment by co-localization. Primary endpoints of this study were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed by Kaplan-Meier method with log-rank for assessing statistical significance. Results: Mean follow-up time for the cohort was 36 months. Seventy of 102 (68.6%) cases had sufficient tissue for AQUA analysis. In univariate analysis, the top quartile of membranous E-cadherin expression was associated with improved PFS (p=0.017) and OS (p=0.05). In multivariable Cox regression, high membranous E-cadherin expression was an independent predictor for better OS at 5 years. Conclusions: Our results indicate that high membranous E-cadherin expression levels as assessed by AQUA are predictive of improved survival rates. No significant financial relationships to disclose.
Psychostimulants for Cancer-Related Fatigue
Authors: William Breitbart, Yesne Alici
Journal: Journal of the National Comprehensive Cancer Network (2010)

Fatigue is a highly prevalent and distressing symptom associated with significant psychological and functional morbidity and decreased quality of life among patients with cancer. Despite its impact on patients and caregivers, fatigue is underreported and underrecognized, and remains untreated among patients with cancer because of various patient- and clinician-related factors. In addition to assessment for potentially reversible medical causes or medications exacerbating fatigue, and the implementation of nonpharmacologic interventions, several pharmacologic treatment options have been considered for the treatment of cancer-related fatigue. Among traditional psychostimulants, methylphenidate has been studied the most and is effective and well tolerated among patients with cancer despite common side effects. Modafinil, a novel psychostimulant commonly referred to as wakefulness-promoting agents as a group, has also been studied and seems to be well tolerated among patients with cancer. A large placebo effect has been reported in most randomized controlled trials with psychostimulants. Thus, randomized placebo-controlled trials with large sample sizes are needed to further assess the efficacy and tolerability of psychostimulants in the treatment of cancer-related fatigue. This article presents a comprehensive review of the use of psychostimulant agents for fatigue among patients with cancer, including an overview of the clinical trials with psychostimulants and of the clinical guidelines available for treatment of cancer-related fatigue.
Sensitivity and specificity of osteopontin (OPN) versus prostate-specific antigen (PSA) in prostate carcinoma (PCa): A case- control study
Authors: R. Libener, F. Montefiore, F. Bonini, L. Ruggero, M. Maffezzini, M. Puntoni, L. Nanni, M. Paganuzzi, R. Puntoni, P. Betta
Journal: Journal of Clinical Oncology (2009)

e16082 Background: OPN is a secreted adhesive glycoprotein overexpressed in human cancers. A stimulatory effect of OPN on human PCa cells in vitro has been demonstrated. This study intends to determine if measuring serum OPN and PSA levels can provide informative markers for the detection of PCa. Methods: Serum total PSA using a chemiluminescent immunoassay system (Hybritech PSA, DxI Beckman Coulter, Inc.) and plasma OPN using an ELISA technique (R&amp;D Systems, Inc.) were measured in 263 male subjects referred for diagnostic prostate biopsy, including 167 control patients with benign prostate pathology (mean age: 65.30; median age: 66; SD: 6.80; range 46–83) and 96 PCa patients (mean age: 66.80; median age: 68; SD: 7.90; range 47–86). Sensitivity and specificity were determined for each marker. The relationship between sensitivity and specificity was profiled by receiver operating characteristic (ROC) curves of OPN and PSA. Results: Both markers levels were higher in PCa patients (OPN 51.98 ng/ml, SD 32.64, range 5.9–169.54; PSA 12.91 ng/ml, SD 14.73, range 1.69–90) than in controls (OPN 49.93 ng/m, SD 27.78, range 4.15–146.34; PSA 8.04 ng/ml, SD 5.94, range 0.46–45), although the elevation was significant (p&lt;0.001) for PSA but not for OPN (p=0.59). The increase of serum OPN level paralleled the increase of the tumour size, defined by the T stage, and was more striking for T ≥2 PCa than for T1 PCa. The increase of PSA, related to the tumour size, was less evident and was observed only in high stage (T3) tumours. The ROC curve showed that OPN was not a marker that enabled the discrimination between PCa and non-cancer patients. For PSA, a cut-off value of 4 ng/ml had a sensitivity of 93% with a specificity of 13%. A cut-off value of 5 ng/ml resulted with a sensitivity of 85% and specificity of 26%. Conclusions: OPN and PSA are not correlated and therefore their combined evaluation in a larger study group could provide a novel insight into the natural history of PCa. A follow-up of the patients involved is ongoing in order to assess a possible prognostic role of the two markers. (The study was funded by the Alessandria branch of the Italian League against Cancer through a grant from the Cassa di Risparmio di Alessandria Foundation) No significant financial relationships to disclose.
Toxicity and quality of life data from SCOT: An international phase III randomized (1:1) noninferiority trial comparing 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy.
Authors: Timothy Iveson, Rachel Kerr, Mark P. Saunders, Ashita Marie Waterston, Niels Henrik Hollander, Louise C. Medley, Josep Tabernero, Charles Wilson, Richard Ellis, Sharadah Essapen, Andrew Mark Haydon, Amandeep Singh Dhadda, Robert Hughes, Stephen Falk, Sherif Abdel-Raouf, Bengt Glimelius, Karen Allan, Winnie Barlow, Andrew Briggs, James Paul
Journal: Journal of Clinical Oncology (2015)

3514 Background: Oxaliplatin/Fluoropyrimidine combination chemotherapy is an established adjuvant treatment for colorectal cancer (CRC). Neurotoxicity from Oxaliplatin is cumulative, dose limiting, and potentially irreversible. Methods: SCOT is designed to determine whether 3 months of adjuvant chemotherapy with OxMdG or XelOX (physician/patient choice) in Stage III /high risk Stage II CRC is as effective as 6 months, with less toxicity. In the initial 867 patients toxicity was graded during treatment using NCI-CTCAE. Quality of life was assessed using EORTC QLQ-C30/EQ-5D (n = 1681) and neuropathy using GOG-Ntx4 (n = 1776). Results: From May 2008 to Nov 2013, 6087 patients were randomized from 237 centers/6 countries. Median age was 65 years. 4972 (82%) were Stage III, 4983 (82%) had colon cancer and 4105 (67%) received XelOx. There were 31 toxic deaths (0.5%) equally distributed between the randomized arms. Toxicity profiles depended on the FU backbone with more grade 3/4 neutropenia on OxMdG (23% v 5%) and more grade 3/4 diarrhea (9% v 15 %) on XelOx. 16% overall did not complete 3 months of treatment mainly citing toxicity (56%). Peripheral neuropathy was cumulative, (24% grade 2/3 toxicity by 3 months; 56% by 6 months) and as measured by GOG-NTX4 persisted and was much higher at 1 year on the 6 month compared to the 3 month randomized arm (mean difference = 19 [se = 1.3]). QLQ-C30 global health status worsened during treatment and stayed more depressed in months 4-6 in the 6 month arm. By12 months the mean difference between the arms was small (2.2[0.9]); a similar pattern was seen with the QLQ-C30 functional scales. The pattern for the EQ-5D health score were also similar with small differences at 12 months (.03 [.02] respectively). Conclusions: Both OxMdG and XelOx were safe and well tolerated. As expected, the main toxicities did vary according to FU backbone (but this was not randomized). Quality of life worsened while patients were on treatment but recovered by 1 year despite persistent peripheral neuropathy, suggesting that current quality of life tools may not adequately capture the morbidity associated with this toxicity. Clinical trial information: ISRCTN59757862.
Analysis of epidermal growth factor receptor (EGFR) downstream proteins in metastatic colorectal cancer patients: Comparison between primary tumor and related metastatic sites
Authors: P. Saletti, F. Molinari, V. Martin, A. Bordoni, S. Crippa, L. Mazzucchelli, M. Frattini
Journal: Journal of Clinical Oncology (2008)

11075 Background: EGFR expression by immunohistochemistry (IHC) is not predictive of response to cetuximab in metastatic colorectal cancer (mCRC). EGFR gene status (fluorescent in situ hybridization, FISH) and alterations in EGFR downstream proteins (K-Ras, PTEN) represent independent predictive markers of cetuximab efficacy. These data have been obtained analysing primary tumors (PT) of mCRC patients. However, PT and metastatic lesion (M) might share different patterns. Methods: We analyzed PT and M in 32 consecutive mCRC patients. We evaluated EGFR gene status and protein expression by IHC and FISH, K-Ras mutations in codons 12 and 13, and PTEN expression by IHC. Results: EGFR expression in PT was classified as score 1+ in 5 cases, score 2+ in 4, and score 3 in 21. In PT and M we observed the same pattern of EGFR expression in 26/30. Three patients showed score 3+ at PT and score 1+ at M, and 1 score 1+ in PT and score 2+ in M. We found in PT chromosome (Chr) 7 loss in 1 case, Chr 7 disomy in 9, Chr 7 polysomy in 14, and EGFR gene amplification in 6. The same pattern between PT and M was observed in 19 cases. A trend in favour of deregulation was observed in 7 cases (from disomy to polysomy in 5 cases, and from polysomy to gene amplification in 2 cases), whereas 4 patients showed gene amplification or polysomy in PT and polysomy or disomy in related M. K-Ras mutations were observed in 14 PT (47%). Only one patient showed the GtT change. The same mutational pattern between PT and M was observed in 26 cases. In 3 cases the mutation was restricted to PT, in 1 case to M. Loss of PTEN expression was found in 7 cases. The same PTEN expression pattern between PT and M was observed in 29 cases. Three cases showed a loss of PTEN expression limited to M. Conclusions: 1) PT and paired M may exhibit different gene and protein profiles. 2) A trend in favour of gene or protein expression deregulation most likely reflects a malignant progression of metastatic cells. The loss of deregulation in M with respect to paired PT may be explained by not representative biopsies. 3) EGFR and K-Ras gene status, and PTEN expression analysis should be performed on PT and possibly on representative (multiple) biopsies of M. 4) We confirm that GtT K-Ras mutation confers an indolent phenotype. No significant financial relationships to disclose.
Intratumoural injection of the toll-like receptor-2/6 agonist ‘macrophage-activating lipopeptide-2’ in patients with pancreatic carcinoma: A phase I/II trial
Authors: A. Marten, P. F. Mühlradt, D. Jäger, J. Schmidt
Journal: Journal of Clinical Oncology (2008)

15604 Background: This phase I/II trial examined safety and efficacy of the toll-like receptor 2/6 agonist MALP-2 in combination with gemcitabine in patients with incompletely resectable pancreas carcinomas. MALP-2 is a toll-like receptor-2/6 agonist, acts an immunological adjuvant and has been described recently to prolong survival in a mouse model of an orthotopic, syngeneic pancreas tumor. Methods: Men and women with incompletely resectable pancreas carcinomas were eligible while patients with R0 or R1 resections or with peritoneal carcinosis were excluded. Ten patients were injected intratumorally during surgery with 20–30μg MALP-2 followed by postoperative chemotherapy. Samples were taken from peripheral blood and wound secretion, and assayed for cell content, cytokine and CRP levels, and NK activity. Results: A MALP-2 dose of 20 μg was well tolerated. Clear signs of local MALP-2 effects were: influx of lymphocytes and monocytes in wound secretions, and abolishment of inhibition of NK activity. The actual mean survival is 17.9 ± 4.6 months (CI 8.9, 26.9); the median survival being 9.3 months. Two patients are still alive after 34 months. Conclusions: Up to 20μg MALP-2 were well tolerated, and no systemic effects were noted. The mean survival of 17.9 months is remarkably high. No significant financial relationships to disclose.
Comparison of the cost per distant disease-free year gained for upfront letrozole or anastrozole, or switched exemestane compared to tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: The UK perspective
Authors: J. Karnon, F. di Trapani, S. Kaura
Journal: Journal of Clinical Oncology (2007)

557 Background: Due to subsequent poor prognosis, prevention of distant recurrence (DR) is a primary aim of adjuvant hormonal therapy for early breast cancer. Compared to 5 years TAM in hormone receptor positive (HR+) postmenopausal women, DR relative risks are 0.73 (95% CI 0.6 - 0.88) for 5 years letrozole (LET), 0.84 (95% CI 0.7 - 1.0) for 5 years anastrozole (ANA), 0.73 (95% CI 0.59 - 0.9) for 2–3yrs exemestane after 2–3 years (EXE/TAM). This analysis evaluates the incremental cost per distant disease free year gained from a UK NHS perspective of LET, ANA, EXE/TAM versus 5 years TAM using the same health economic model. Methods: A Markov model described pathways through relevant health states over the remaining lifetime of a cohort of HR+ women aged 61 yrs. Probabilities of breast cancer events (contralateral; locoregional; soft tissue, bone, and visceral metastases) adverse events (endometrial cancer, hip and other fractures, cardiovascular disease, thromboembolic events, and arthralgia) were based on the latest early breast cancer overview, published results of the BIG 1–98, ATAC, and IES trials, and UK population-based studies as appropriate. Conservatively, no carry-over effect was assumed for the AIs after therapy discontinuation. Costs (2005 UK£) of breast-cancer care were obtained from a primary costing study in Scotland, and treatment costs for AEs were obtained from published studies. Costs and DR-free years were discounted at 3.5% annually. Results: The mean durations of DDFS were estimated to be 12.81, 12.66, 12.57, and 12.35 years for LET, ANA, TAM/EXE, and TAM, respectively. The incremental cost per distant disease free year gained of LET vs TAM is £10,379 (95% CI £5,286-£17,818), of ANA vs TAM is £11,428 (95% CI £5,071- £48,856), and of TAM/EXE vs TAM alone is £11,020 (95% CI £4,820-£36,947). Conclusion: Compared to 5 years TAM, adjuvant treatment of postmenopausal HR+ women with an AI is a cost-effective use of UK NHS resources. Based on the mean results, LET appears to be the most cost-effective of the three AIs, despite its higher acquisition cost compared to ANA in the UK, though the confidence intervals are wide. [Table: see text]
A national cancer plan for the UK
Authors: D.J. Kerr
Journal: Annals of Oncology (2000)

A national cancer plan for the UKThere has been increasing awareness that delivery of cancer care in the UK is patchy and sub-optimal.This is manifest by unacceptable regional and international variation in cancer survival figures.Publication of a discussion document by an Expert Advisory Group on Cancer Services (so called Calman-Hine plan) in 1995 offered a model for an improved framework for service delivery, but neither funding nor a national implementation plan.Nevertheless, this did prompt health professionals to start developing local, cancer action plans [1].The change of government in 1997 brought a renewed energy and much stronger vision for how the NHS should be funded and managed.Development of a Cancer Control Strategy was given the highest priority and Professor Mike Richards and the Cancer Action Team were given the task of preparing a National Cancer Plan [2].This was announced, recently by the Prime Minister and Secretary of State for Health, Alan Milburn, both of whom have identified themselves strongly with this commitment to improve the quality of cancer care and research in the UK.The plan shows how cancer services will benefit from increased investment in staff, equipment and research, right across the spectrum of cancer prevention to provision of palliative care, summarised as follows.
Phase II trial of imatinib mesylate in patients with metastatic unresectable pancreatic cancer
Authors: M. M. Gharibo, P. Juvidian, L. Patrick-Miller, L. Zheng, J. Craig, L. Guensch, C. Wojtaszek, E. Poplin
Journal: Journal of Clinical Oncology (2005)

4183 Background: Chemotherapy treatment of metastatic pancreatic cancer remains quite limited. Platelet-Derived Growth Factor and its tyrosine kinase receptor (PDGFr) are overexpressed in pancreatic tumor cells. Imatinib (Gleevec) is a tyrosine kinase inhibitor that inhibits PDGFr, bcr-Abl, and c-kit. It is a well tolerated oral agent with clinical activity in CML and GIST tumors.Thus, given the evidence of increased PDGFr in pancreatic cancer and the few treatment options for patients with pancreatic cancer, we conducted a phase II trial of Imatinib in patients with metastatic pancreatic cancer. Methods: Previously treated or untreated patients with histologically proven, unresectable pancreatic adenocarcinoma with adequate organ and bone marrow function were enrolled. Patients received Imatinib 400 mg po BID for a 28 day cycle continuously. Response was evaluated every 4 weeks by imaging scans. Response was defined as lack of tumor progression at 3 months. Sample size was based on a Simon two-stage design with p0:0.5 and p1: 0.7. The study is closed for enrollment if 8 or more (of 15) patients have progressive disease. Results: Eleven patients were enrolled between 2/03 and 10/04. Patient characteristics: median age 66 years (range 50–81); M/F 6/5, PS of 0–1, and 10 patients had prior chemotherapy. One patient was enrolled but did not receive any treatment. The first three patients received Imatinib 400 mg po BID. Due to unexpected grade 2 and 3 toxicities (edema, hyponatremia and alkaline phosphatase), the Imatinib dose was reduced to 600 mg daily for subsequent patients. Median number of weeks on study was 4 weeks (range 1–9 weeks). Three patients came off study due to toxicities. No response was seen in any patient by imaging scans. All patients had progressive disease. Nine patients were evaluable for toxicity. 9 patients experienced grade 1–2 edema. Two patients had grade 2 rash, grade 3 hyponatremia and grade 3 alkaline phosphatase. Other toxicities include grade 1–2 nausea, fatigue, anorexia, and diarrhea. Conclusion: Single agent Imatinib does not have significant activity in pancreatic cancer. Supported by a grant from Novartis. No significant financial relationships to disclose.