tbuckley/cabot-search huggingface dataset:
Outcomes of second targeted therapy in metastatic renal carcinoma: A retrospective chart review in the EU.
Authors: Daniel Yick Chin Heng, Jinhee Park, James E. Signorovitch, Hongbo Yang, Jinlin Song, Dony Patel, Chinjune Lin, Thomas Powles
Journal: Journal of Clinical Oncology (2016)

558 Background: This study describes the real-world outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus (EVE), sorafenib (SOR), and axitinib (AXI) as 2nd targeted therapy in the UK, Germany, and France. Methods: A retrospective chart review was conducted among oncologists and urologists in the UK, Germany and France. Charts were reviewed for adult mRCC patients satisfying the following eligibility criteria: 1) experienced disease progression on 1st targeted therapy with sunitinib or pazopanib; 2) initiated 2nd targeted therapy with EVE, AXI, or SOR between 10/2012 and 6/2013. Kaplan-Meier analysis was used to estimate overall survival (OS) after initiation of 2nd targeted therapy among all patients and stratified by type of 2nd targeted therapy. Results: A total of 281 charts were reviewed, with 99, 91, and 91 mRCC patients receiving EVE, AXI, and SOR as 2 nd targeted therapy, respectively. Mean age was 60.6 years old at initial mRCC diagnosis and 65.5% were male. The majority of patients used sunitinib (79.4%), with the rest using pazopanib (20.6%) as 1st targeted therapy. Median duration of 1st targeted therapy was 9.7 months. At the initiation of 2nd targeted therapy, 91.8% of patients had an ECOG score ≤ 2. The most common sites of metastases were lung (71.2%), bone (53.0%), and lymph nodes (47.0%). Median OS from the initiation of 2 nd targeted therapy among all patients was 21.8 months (95% CI: 16.5-26.2). The median OS was 23.0, 23.5, and 18.7 for EVE, AXI, and SOR respectively. The majority of patients (87.5%) initiated 2 nd targeted therapy on the recommended dose. Patients receiving AXI had a higher rate of dose increase (13.2%), compared to EVE (1.0%) and SOR (0.0%), while patients on EVE had a higher rate of dose decrease (12.1%), compared to AXI (5.5%) and SOR (8.8%). Conclusions: In this retrospective chart review study of several EU countries, the observed median OS was numerically comparable for EVE and AXI, but rates of dose adjustment differed by treatments. Retrospective chart reviews may be subject to selection bias and errors in data entry, and further analysis is underway to address confounding effects of unobserved patient characteristics.
Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.
Authors: Sten Nilsson, A. Oliver Sartor, Oyvind S. Bruland, Fang Fang, Anne-Kirsti Aksnes, Chris Parker
Journal: Journal of Clinical Oncology (2013)

19 Background: Bone metastases (mets), present in &gt;90% of patients (pts) with CRPC, may cause severe pain. In a phase II dose-response study with Ra-223 treatment, pain response (pain reduction and stable analgesic consumption) was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase III ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n=614; placebo, n=307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR=0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The hazard ratios for time to initial opioid use and time to external beam radiation therapy (EBRT) were analyzed using the Cox proportional hazards model. Pts with no opioid use at baseline were included in the pain analyses. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer in the Ra-223 group vs placebo (HR=0.670, 95% CI: 0.525-0.854). Fewer Ra-223 pts reported bone pain as an AE compared to placebo pts (50% vs 62%). 269 pts in the Ra-223 group and 139 pts in the placebo group had no opioid use at baseline. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38% compared to placebo (HR=0.621, 95% CI: 0.456-0.846). Fewer pts in the Ra-223 group (36%) than in the placebo group (50%) required opioid use for pain relief. Conclusions: These ALSYMPCA results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in patients with CRPC and bone metastases. Clinical trial information: NCT00699751.
A prospective translational study investigating molecular predictors of resistance and response to regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (mCRC): Initial magnetic resonance imaging (MRI) sub-study result.
Authors: Khurum Hayat Khan, Mihaela Rata, Dow-Mu Koh, Nina Tunariu, David J. Collins, Ian Chau, David J. Watkins, Naureen Starling, Sheela Rao, Clare Peckitt, Nicos Fotiadis, Ruwaida Begum, Claire Saffery, Janet Thomas, Marco Gerlinger, Nicola Valeri, David Cunningham
Journal: Journal of Clinical Oncology (2016)

580 Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (K trans ) derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and K trans were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour K trans was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median K trans change (-36 to + 17%). Overall, the cohort average K trans decreased from 0.17 to 0.07 min -1 (58%). No significant ADC changes were observed at day 15. Of the 4 pts with K trans reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no K trans change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with K trans reduction were classified as responders. Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings. Clinical trial information: EUDRACT No: 2014- 003579-51.
Cost comparison of treating low- and intermediate-risk endometrial cancer using time-derived, activity-based costing (TDABC) in a large regional cancer network delivery model.
Authors: Nicole D. Fleming, Karen H. Lu, John D. Calhoun, Anuja Jhingran, Isidora Arzu, Pamela T. Soliman
Journal: Journal of Clinical Oncology (2016)

9 Background: Value-based and quality health care delivery has become an important focus for many health care systems. The purpose of this study was to assess the cost differences in treating low and intermediate risk endometrial cancer using time-derived activity based costing (TDABC) in a large regional cancer network model. Methods: Process mapping and TDABC was performed in treating endometrial cancer patients at a large tertiary cancer center (main) with a regional cancer network program. Clinical visits and adjuvant therapy including high-dose rate vaginal cuff brachytherapy (VBT) and pelvic radiation (PRT) were performed in ambulatory treatment centers at each location. Surgery for endometrial cancer was performed at the main cancer center. Costs for each process point was determine by cost-capacity rates, and compared by treatment center location. Results: TDABC costing determined a 28.3% cost difference in ambulatory clinic visits for endometrial cancer patients, favoring treatment at the regional network location. There was no cost difference in surgery for endometrial cancer patients since all procedures were performed at main. Delivering adjuvant VBT was 44.2% more in the ambulatory regional center compared to main, primarily due to the radiation quality assurance checks at the regional site. TDABC costing determined a 39.8% cost difference in delivering PRT for intermediate risk endometrial cancer patients, favoring treatment at the regional network location. Overall, there was a 13.2% cost savings, favoring treatment at the regional cancer network location. Conclusions: Delivering care for low and intermediate risk endometrial cancer in a regional network model may represent a cost effective health care delivery method. Quality assurance checks at the regional locations are required for quality treatment delivery, however, may represent an area for cost effective process improvements or need to stratify treatment location based on complexity.
Correlation of progression-free and overall survival with level of survivin, FoxP3, and OX40 in colorectal cancer patients treated with bevacizumab.
Authors: K. R. Shell, S. Sahota, G. C. Bohac, W. T. Leslie, L. M. Watkins, I. Lamzabi, S. Basu, J. M. Plate
Journal: Journal of Clinical Oncology (2011)

e14115 Background: We investigated the association between levels of survivin expression, presence of OX40+ and FoxP3+ T-cells in colorectal tumors with disease progression and survival in patients treated with bevacizumab and chemotherapy. Our hypothesis is that the presence of OX40 in tumor T-cells correlates with an active anti-tumor immune response and may be augmented by bevacizumab. In addition we explored whether expression of survivin or FoxP3 regulator T-cells, which lead to decreased apoptosis and immunity, correlates with poorer outcomes. Methods: Tumor specimens from 23 patients diagnosed with colorectal cancer and treated with bevacizumab were submitted for analysis. Tumors were stained for intratumoral and peritumoral lymphocyte expression of FoxP3 and OX40, and for cytoplasmic and nuclear survivin. The intensity of FoxP3 and OX40 expression was graded 0 (negative) to 3 (strong). Survivin was scored 0 to 4, based on number of cells and intensity. Clinical data included were stage at diagnosis, tumor histology, CEA levels, progression free survival (PFS), and overall survival (OS). Results: 15 subjects had level ≤3 and 8 had level 4 nuclear survivin expression. The median OS for patients with less nuclear survivin (≤3) was strongly significant at 31 months, compared to 13.5 months for a greater expression of 4 (p=0.007). Subjects with no intratumoral OX40 (n=14) had significantly longer OS compared with those with level ≥1 (n=9), 31 months versus 17 months respectively (p=0.036). Fewer peritumoral FoxP3+ cells correlated with longer PFS; level ≤2 with 8 months and level 3 with 5 months (p=0.046), but did not correlate with OS. Conclusions: Subjects treated with bevacizumab and chemotherapy who had increased survivin expression had shorter OS, consistent with our previous studies of other targeted therapies. Increased expression of FoxP3 correlated with a shorter PFS but did not seem to affect OS. Contrary to our previous study and hypothesis, an increased expression of OX40 resulted in a shorter OS. Further studies with targeted therapies to these molecules should be considered to evaluate the role of immune T cell responses and survivin in colorectal cancer.
Factors associated with use of preoperative chemoradiotherapy for rectal cancer.
Authors: M. E. Charlton, D. Jiang, C. Lin, K. B. Stitzenberg, J. F. Pendergast, E. A. Chrischilles, R. B. Wallace
Journal: Journal of Clinical Oncology (2011)

e14079 Background: Studies of patients with stage II/III rectal cancer have demonstrated that preoperative (preop) chemoradiotherapy (CRT) improves local control, reduces toxicity and is associated with more sphincter preserving surgeries than postoperative (postop) CRT. While preop CRT has been recommended as the standard of care, many still receive postop CRT. We determined the proportion and associated characteristics of those who received preop CRT among our sample. Methods: We identified patients with stage II/III rectal cancer who had primary site resection and CRT in the population-based cohort studied by the Cancer Care Outcomes Research and Surveillance Consortium, and used data from patient surveys and abstracted medical records to construct patient variables (age, gender, marital status, race, education, income, insurance status, stage, comorbidity, patient treatment preferences, research site, types and sequence of providers seen) and determine sequence of CRT and surgery. Multivariable logistic regression was used to model the association between predictors and receipt of preop CRT. Results: Of the 220 patients meeting inclusion criteria, 64% received preop CRT and 36% received postop CRT. A multivariate model showed those visiting a medical oncologist (MO) or radiation oncologist (RO) prior to receiving any treatment had a 91% (95% CI, 86% to 97%) probability of receiving preop CRT, whereas those who did not had a 30% (95% CI, 19% to 41%) probability. Subjects visiting a RO prior to a surgeon had a 91% (95% CI, 79% to 100%) probability of receiving preop CRT, whereas those visiting a surgeon first had a 65% (95% CI, 57% to 73%) probability. No other patient characteristics remained significant in the multivariate model. Conclusions: Early visits to an oncologist and sequencing of provider visits appear to be more important predictors of receiving preop CRT than the extensive list of patient characteristics evaluated in this study. Further evaluation of provider characteristics, referral patterns and health system processes that determine treatment should be undertaken to help design targeted interventions to reduce variation from recommended care.
Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin, and cyclophosphamide as adjuvant chemotherapy for early-stage breast cancer
Authors: H. Abe, T. Umeda, Y. Kawai, M. Tanaka, T. Shimizu, H. Chou, Y. Kubota, E. Mekata, Y. Kurumi, T. Tani
Journal: Journal of Clinical Oncology (2009)

604 Background: As adjuvant chemotherapy for breast cancer, the addition of docetaxel to regimens containing anthracyline has been shown to be effective. However, tolerance and safety associated with the administration order of the two drugs have not been evaluated. Methods: Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The treatment completion rate and toxicity were evaluated in 2 arms who underwent a total of 6 courses of the following regimens: Arm A: 3 courses of fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 and cyclophosphamide 500 mg/m 2 (FEC100: q3w) followed by 3 courses of docetaxel (DOC100: 100 mg/m 2 , q3w); and Arm B: 3 courses of DOC100 (q3w) followed by 3 courses of FEC100 (q3w). Results: June 2006 to April 2008, 42 patients were registered. To the present, analysis has been completed in 21 patients in arm A and 21 in arm B. The mean age of patients was 49.1 years and 53.8 years, respectively. In arm A, the stage of cancer was 1 in 4 patients, 2a in 10, and 2b in 7, in arm B, the stage of cancer was 1 in 3 patients, 2a in 9, and 2b in 9. The adjuvant chemotherapy completion rate was 100 % for arm A and 95.2 % for arm B. The relative dose intensity (RDI) was 94.2 % for FEC100 and 97.8 % for DOC100 in arm A, and 98.9 % for DOC100 and 95.2 % for FEC100 in arm B. In arm A, grade 3 or higher hematological toxicity was observed in 9 patients, and febrile neutropenia developed in 3 patients with FEC100. In arm B, grade 3 or higher hematological toxicity was observed in 7 patients, but febrile neutropenia was not noted in any patients. Grade 3 or higher non-hematological toxicity was observed with FEC100 in 2 patients each in the two arms. Grade 1 or 2 edema developed in 11 patients with DOC100 in the two arms. Conclusions: In both arm A and B, adverse events associated with FEC100 were frequently observed but spontaneously recovered, or adequate management was possible by supportive therapy. Adverse events associated with DOC100 were mild. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early stage breast cancer. However, DOC100 followed by FEC100 may be more tolerable and effective. No significant financial relationships to disclose.
A phase II study of imatinib with pioglitazone, etoricoxib, dexamethasone, and low-dose treosulfan: Combined anti-inflammatory, immunomodulatory, and angiostatic treatment in patients (pts) with castration-refractory prostate cancer (CRPC).
Authors: A. Reichle, M. Vogelhuber, S. Feyerabend, T. Suedhoff, M. Schulze, J. Hubner, R. Oberneder, M. Baier, A. Ruebel, K. Birkholz, A. Bakhshandeh-Bath, R. Andreesen
Journal: Journal of Clinical Oncology (2011)

4599 Background: Therapeutic options for pts with CRPC are still limited. Continuous production and release of pro-inflammatory cytokines may account for its resistance towards cytotoxic drugs. Therefore, a phase II study was implemented in pts with CRPC to assess tumor response to combined biomodulatory agents. Primary objective was the PSA-response rate in pts with CRPC. Methods: 69 pts with histologically confirmed CRPC (according to EAU guidelines) were enrolled in 11 German centers. In the 6 months core phase and thereafter, pts were treated continuously with daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone until PSA progression. During the study, PSA-values, ECOG performance status and QoL were continuously assessed. Pts responsive to study medication were allowed to enter the extension phase until disease progression or intolerable toxicity occurred. Results: The core phase of this study was finished in July 2009. Six pts are currently under treatment in the extension phase. At baseline the median PSA value was 45.3 (5 to 3603) ng/ml. The majority of pts had PSA doubling times of 50 to 100 days. Of the 61 evaluable pts, 23 pts (37.7%) were considered as PSA responders with a confirmed PSA decline of at least 50%. During the treatment period PSA decreased from 278.9 (± 784.1) to 8.8 (±11.6) ng/ml in the responders.. Median time to PSA response and to progression as well as overall survival was not achieved. In some pts the therapy led to complete resolution of bone lesions. Of the 38 non-responders, 14 pts showed a stable disease ≥ 6 months. The increase of imatinib doses in case of progressive disease did not result in a further PSA response of the pts. Conclusions: The study evaluated a new multi-targeted approach for pts with CRPC. Although the substances show limited efficacy in single therapeutic use, this multi-targeted approach led to an impressive response rate of 37.7%. Given the good response and the comparatively low and manageable toxicity, this combination treatment might be a good alternative to present treatment regimens.
IHC-based predictive biomarker for irinotecan response.
Authors: Koji Ando, Ankur K. Shah, Vibhu Sachdeva, Julian Taylor-Parker, Eiji Oki, Ajit Bharti
Journal: Journal of Clinical Oncology (2016)

548 Background: For gastro-intestinal cancers, irinotecan is used as first or second line, either as single agent or in combination therapy. The patient response rate is low and drug resistance mechanism is not understood. Irinotecan like other topoisomerase I inhibitors (camptothecin and their analogues, CPTs) are not MDR substrates, topoI mutations are rare and other potential mechanisms have not been validated. One of the most distinct cellular responses to CPT is the proteolytic degradation of topoI by the ubiquitin proteosomal pathways (UPP) and the rate of topoI degradation determines the drug response. Using a functional proteomic approach we have defined the mechanism of UPP mediated topoI degradation and have identified the molecular determinant of CPT resistance. We have demonstrated that higher basal level of topoI-pS10 drives rapid topoI ubiquitination and degradation in response to CPT. Methods: We have raised mouse monoclonal antibody that specifically binds with topoI-pS10 for immunohistochemistry (IHC) staining of the formalin fixed paraffin embedded (FFPE) slides. In our first cohort of retrospective study, 48 metastatic colorectal cancer tissues were immunostained with anti-topoI-pS10 and nuclear staining was quantitatively analyzed. Results: Data were summarized with descriptive statistics. ROC analysis was used to assess diagnostic characteristics across different thresholds. Mean and median positive nucleation values correlated strongly with drug response. Median nucleation level among non-responders was 69% compared to 9% for responders (Wilcoxon p = 0.0006). ROC analysis demonstrated an optimal threshold between 30-40% nucleation. Using a threshold of 35%, the estimated sensitivity was 82% (95% CI 56-95) and specificity was 77% (57-89). Estimated positive and negative predicted values were 67% (43-85) and 88% (69-97) respectively. We have also got similar results in 80 patient gastric cancer retrospective studies. Conclusions: Basal level of topoI-pS10 can be used as a predictive biomarker for topoI inhibitors. Our IHC based test can be adopted in clinical pathology settings to determine the topoI-pS10 level and stratify the patient population for CPT based therapy.