tbuckley/cabot-search huggingface dataset:
Results of a phase II clinical trial to evaluate a re-challenge of intraperitoneal catumaxomab for treatment of malignant ascites (MA) due to epithelial cancer (SECIMAS).
Authors: Klaus Pietzner, Ignace Vergote, Armando Santoro, Frederik Marme, Per Rosenberg, Hilke Friccius-Quecke, Jalid Sehouli
Journal: Journal of Clinical Oncology (2013)

5582 Background: Catumaxomab is approved in Europe for the i.p. treatment of MA. With a growing number of patients (pts) treated, the question arises, if a re-challenge is feasible and effective despite the immunogenicity of this non-humanised antibody. Methods: Pts were eligible if they received 4 i.p. applications of catumaxomab in the CASIMAS study and benefitted with a puncture free interval of &gt; 60 days. Primary endpoint was to determine the proportion of pts who were able to receive at least 3 catumaxomab applications. Secondary endpoints were the development of human anti-drug antibodies (ADA) as well as the safety profile of a second catumaxomab cycle including a composite safety score (CSS) summarizing the worst CTCAE grades for the main adverse reactions (pyrexia, nausea, vomiting, abdominal pain). Efficacy endpoints were time to puncture (TTPu), overall survival (OS) and puncture-free survival (PuFS). Results: Median age was 59.0 years. 8 out of 9 screened pts were treated with a second cycle of catumaxomab. The primary tumor was ovarian cancer in 5 (62.5%), breast cancer in 2 (25%) and urachal cancer in 1 (12.5%) pts. All 8 (100%) pts received all 4 infusions within 20 days. Median CSS was 3.0 after the second cycle while it was 3.4 after the first cycle in the CASIMAS study for these 8 pts. Only less pts had AEs with CTC &gt;3 (SECIMAS 25%; CASIMAS 70.1%). All 8 (100%) pts were ADA-positive at study entry. ADA levels were consistently higher in the plasma than in the ascites fluid. During treatment, highest ADA values were found on day 10 for ascites and day 11 for plasma up to values of &gt; 1 mg/ml. PuFS was 47.5 days and TTPu 60 days after the second cycle, and 37 days and 102 days, respectively after the first cycle. Median OS was 406.5. Conclusions: This first experience with a re-challenge of catumaxomab in MA, demonstrates a tolerable safety profile without acute allergic reactions, in spite of the high immunogenicity of catumaxomab and the repeated application. Efficacy was not impaired despite ADA response and the advanced disease of the pts. A re-challenge seems feasible for selected pts suffering from recurrent MA after a first cycle of catumaxomab. Clinical trial information: NCT01065246.
Circulating endothelial microparticles (EMP) modifications as predictive biomarkers of resistance to chemotherapy for breast cancer (BC).
Authors: Elisa Garcia-Garre, Gines Luengo-Gil, Silvia Montoro-Garcia, Marta Zafra, Enrique Gonzalez-Billalabeitia, Pilar de la Morena, Elena Garcia-Martinez, Gregory Y Lip, Vicente Vicente, Francisco Ayala
Journal: Journal of Clinical Oncology (2013)

3042 Background: Growing evidence indicates that EMP may both modulate angiogenesis and endothelial injury in cancer and cardiovascular disease. However, it has not been shown whether in vivo release of EMP might reflect the tumor response or the antiangiogenic effects of chemotherapy (CT). The aim of this work was to evaluate the relationship between the levels of small-size EMP (sEMP) and resistance to CT in locally advanced and metastatic BC. Methods: Citrated platelet-free plasma was obtained from BC patients before and after 3-4 cycles of chemotherapy. Small-size CD144+ sEMP (0.1-0.5 μm diameter) were prospectively quantified using a high resolution Apogee A50 flow cytometer. Association of EMP with clinical variables, response to CT and survival was analyzed. Response (partial or complete) was defined by RECIST criteria. Results: 45 BC patients were included (20, metastatic; 25, locally advanced). Treatment included anthracyclines in 66.7% of patients and taxanes in 15.5%. Small-size EMP baseline counts were higher in premenopausal women (p=0.008), but no association with other clinical or pathological characteristic was found. A significant decrease of circulating sEMP was observed after treatment with CT in the whole group of patients with paired samples available (n=33): pre-CT: 416.2 ± 365 vs. post-CT: 340.7 ± 458 (p=0.005). Lower chemotherapy-induced sEMP decrease was associated to treatment resistance: ROC analysis demonstrated a 66.7% sensitivity and 72.2% specificity of lower sEMP decrease for lack of response to CT using a decline cut-point of -40 sEMP (close to median decrease: -47). With the same cut-point of low sEMP decrease, odds ratio for treatment resistance was 5.2 (95% confidence interval, 1.17-23.04; p=0.03). No clear association of the degree of sEMP decrease was found for disease or progression free survival in the neoadjuvant or in the metastatic setting. Conclusions: This study suggests that circulating sEMP decrease after CT and are tightly associated with treatment resistance in BC patients. These findings indicate pathophysiological roles for sEMP in BC and support their potential role as treatment resistance biomarkers.
Predicting outcome based on minimal residual disease (MRD) using multiparameter flow cytometry (FC) in acute myeloid leukemia (AML) patients (Pts).
Authors: Sagar D Sardesai, Wei Tan, Laurie Ann Ford, George Deeb, Anne Marie W. Block, Sheila N.J. Sait, Philip L. McCarthy, Carlos E Vigil, Elizabeth A. Griffiths, James E Thompson, Eunice S. Wang, Paul K Wallace, Meir Wetzler
Journal: Journal of Clinical Oncology (2012)

6565 Background: Most AML pts will experience relapse caused by persistent leukemic cells during complete remission (CR). The aim of our study was to predict outcome in AML pts in CR by assessing their MRD using standard 4-colour FC panels available at our institute. Methods: We queried our AML database between 1/2004 to 10/2010 for newly diagnosed untreated AML pts &gt;18 years of age who achieved CR after one induction regimen. Treatment included 7+3 or similar intensive approaches. The gating strategy used a series of Boolean regions that best defined the diagnostic abnormal population based on its expression patterns using three 4-colour FC panels (F7-CD38,CD10,CD19,CD34; F9-C11b,CD33,CD13,CD34; F38-CD15,CD56,CD7,CD34). The same regions were applied to post-induction samples, and the number of residual events was determined. Results: 140 AML patients with a median age of 64 (range 24-93) years, including 74 females (52.8%) were analyzed; 67 (47.8%) patients relapsed. Eighty-eight (62.8%) pts were CD34-positive (CD34+) at diagnosis. Normal karyotype was detected in 27 (30.7%): FLT-3 ITD was detected in 4/23 (17.4%) and NPM-1 mutation was detected in 1/15 (0.07%) samples. Median follow-up for CD34+ pts was 17.9 months. Forty-two (30%) pts underwent stem cell transplantation (SCT) in first CR: 31 (22.1 %) were allogeneic and 11 (7.9%) autologous. In multivariate analysis, a detectable MRD in any of the 3 panels at or beyond week 16 among CD34+ AML pts in CR was significantly associated with inferior relapse free survival (F7: P=0.035 , F9: P=0.027, F38: P=0.042). In addition, MRD ≥ week 16 using panel F9 was also significantly associated with inferior overall survival (P=0.0224). In pair-wise comparison, those who were MRD-negative ≥ week 16 did not benefit from SCT compared to the non-SCT group. Similar analyses among CD34– AML pts did not achieve statistical significance. Conclusions: MRD+ by FC in CD34+ AML is an independent prognostic factor and can identify pts who may benefit from SCT/more intensive therapy to maintain remission. However, the value of studying MRD in CD34– AML requires further consideration. More effort is needed to identify stem cells in CD34– AML.
Applicability of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial results in invasive lobular carcinoma.
Authors: Jun Wang, Elizabeth Ann Mittendorf, Aysegul A. Sahin, Min Yi, Abigail Suzanne Caudle, Kelly Hunt, Yun Wu
Journal: Journal of Clinical Oncology (2013)

1103 Background: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that, for patients with clinical T1-T2, N0 breast cancer and one or two positive sentinel lymph nodes undergoing breast conserving therapy, there was no difference in local-regional recurrence (LRR), disease-free survival or overall survival (OS) between patients who underwent sentinel lymph node dissection (SLND) alone or completion axillary lymph node dissection (ALND). However, there were a limited number of invasive lobular carcinoma (ILC) participants (7%) in the study. In addition, it is known that ILC has a different pattern of metastases, frequently presenting as small foci requiring immunohistochemistry for detection. Together, these considerations raise concern regarding the applicability of the ACOSOG Z0011 data to patients with ILC. Methods: Patients with ILC who met the ACOSOG Z0011 eligibility criteria were identified from the Surveillance, Epidemiology, and End Results database (1998-2009). Patients were evaluated based on the extent of axillary surgery: SLND alone or ALND. Clinicaloutcomes of the two groups were compared. Results: At a median follow-up of 71 months, there were no LRRs in the SLND arm, and only 4 (0.45%) in the ALND arm. There were no differences in OS or disease-specific survival between the two groups. Conclusions: Omission of completion ALND is appropriate in patients with ILC who fulfill the ACOSOG Z0011 eligibility criteria.
Doxorubicin 75mg/M<sup>2</sup> followed by cyclophosphamide, methotrexate, and fluorouracil (A=&gt; CMF) in the adjuvant treatment of node positive breast cancer: Outcome and toxicity in 136 patients
Authors: S. Rizel, M. Ben-David, H. J. Brenner, S. M. Stemmer
Journal: Journal of Clinical Oncology (2004)

849 Background: After the 1991 publication from Milan showing the advantage of A=> CMF compared to alternating CMF/A therapy, we elected to treat women with intermediate risk stage II breast cancer, with a similar combination. The objective of the study was to assess the effectiveness and tolerability of a modified A=> CMF regimen. Methods: From August 1991 till January 2003, 136 breast cancer patients, median age 45y (range 24–70) with T 1–2 N>3 (66 pts) or if less (70 pts), have at least two out of the following bad prognostic markers: very young age, negative receptors, grade III and vascular invasion. Grade I, II or III Infiltrating duct was noted in 8, 70 and 33 of the specimens respectively and positive receptors were detected in 78 of the tumors. The modified treatment was Doxorubicin (A) 75mg/M2 Q 21D × 4 followed by Cyclophosphamide 600mg/M2, Methotrexate 40mg/M2 and 5 Fluorouracyl 600mg/M2 day 1,8 Q 28D × 4. 122 patients were treated with local radiotherapy: All pts after conservative surgery and post mastectomy when 4 or more axillary nodes were positive. Hormone therapy was recommended based on receptor status. Results: There was no treatment related death. 16 patients were hospitalized for neutropenic fever and 3 for other infectious complications (<2% of the cycles). 1 pt developed secondary leukemia 24 months from end of chemotherapy. No clinical cardiac toxicity was noted. After a median follow up of 77 months from diagnosis (10 -146) 36 patients relapsed and 21 died. The disease free survival is 73% and the overall survival is 84%. Conclusions: The use of A=> CMF for node positive breast cancer is feasible, safe and very effective when compared to other modern regimens. In parts of Europe this regimen remains the standard of care for the treatment of intermediate risk breast cancer. No significant financial relationships to disclose.
Natural history of glioblastoma in the modern era: Longitudinal results from a large prospective Italian register.
Authors: Alba Ariela Brandes, Enrico Franceschi, Mario Ermani, Roberta Depenni, Rosalba Poggi, Anna Pisanello, Norina Marcello, Antonella Valentini, Fiorenzo Albani, Marina Faedi, Graziano Guiducci, Benedetta Urbini, Girolamo Crisi, Isabella Dascola, Claudia Mucciarini, Claudio Dazzi, Luigi Cavanna, Stefania Bartolini, Michele Cavallo, Agostino Baruzzi
Journal: Journal of Clinical Oncology (2012)

2057 Background: The role of temozolomide (TMZ) concurrent with and adjuvant to radiotherapy (RT) in the treatment of glioblastoma (GBM) has been demonstrated by the EORTC 22981/26981-NCIC CE.3 (EORTC/NCIC) randomized trial, and has been widely accepted as the standard treatment. The impact of RT/TMZ in the general patient population was assessed in the context of the Registry of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), that represents the first italian prospectic observational population-based study in neuro-oncology. Methods: Approvals from local Ethical Committees were obtained by 8 participating centres. Patients (pts) who met the following inclusion criteria were evaluated: age ≥18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant non glial tumoral disease, resident in Emilia Romagna region. The data were prospectively collected. Results: From January 2009 to January 2011, 194 GBM pts were enrolled. The median age was 62.5, with 26% of pts over 70 years. After surgery pts received RT/TMZ (73%), RT alone (19%), TMZ alone (5%) or no further treatment (3%); 22% were included in clinical trials. Median overall survival (OS) was 12.9 months. Pts &lt;70 years received RT/TMZ in 85% of cases. In this group of pts mOS was 17 months (95%CI: 15.4–18.6). Interestingly, pts &lt;70 years included in experimental clinical trials showed a significant OS improvement (p=0.04). In multivariate analysis, only extent of surgery (p=0.047), KPS (p=0.01) and RT/TMZ (p&lt;0.001) were associated with OS in pts &lt;70 years. Conclusions: Our population data reproduces the beneficial effect of RT/TMZ from the EORTC/NCIC randomized trial, confirming how this successful approach as been widely incorporated in daily practice. Interestingly, our data suggest that the survival of GBM pts treated with RT/TMZ could be greater than patients treated with RT/TMZ in the EORTC/NCIC trial at the beginning of this century.
Baseline subclinical sensory deficits and the development of pain and numbness in patients with multiple myeloma (MM) being treated with chemotherapy.
Authors: Elisabeth G. Vichaya, Xin Shelley Wang, Jessica A. Boyette-Davis, Zijing He, Sheeba K. Thomas, Nina Shah, Tito R. Mendoza, Loretta A. Williams, Charles S. Cleeland, Patrick M. Dougherty
Journal: Journal of Clinical Oncology (2012)

9082 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity experienced by patients with MM. Patients may develop painful and non-painful (e.g., numbness) symptoms that impair function and often persist after therapy is terminated. This study examined the predictive value of baseline subclinical sensory deficits on the development of treatment-related pain and numbness. Methods: Patients (N=56) who had two or fewer cycles of induction therapy and no obvious neuropathy were assessed for sensory deficits using quantitative sensory testing (QST). Patients reported the severity of pain and numbness (on a 0-10 scale) at least weekly via the MD Anderson Symptom Inventory during induction (up to 16 weeks); 15 of 56 patients provided data for up to 16 additional weeks of maintenance therapy. These values correlate to patient reported pain and numbness in the hands/feet. Based on data collected from healthy controls, patients were classified as being with or without a sensory deficit at baseline on each QST domain. We fit linear mixed models for pain and numbness with each sensory deficit and time, controlling for cumulative cycles, diabetes, age, and treatment agent. Data is shown as mean ± standard deviation. Results: Patients who showed baseline deficits in sharpness detection (20%) reported significantly lower levels of pain (1.2±1.9 vs 3.1±2.9, p=.004) and numbness (0.4±0.8 vs 2.4±2.6, p&lt;.001) during induction therapy and less numbness (0.0 vs 3.5±2.8, p=.001) during maintenance therapy. Further, those who showed deficits in warmth detection (40%) reported higher levels of pain (5.2±2.8 vs 1.7±2.3, p&lt;.001) and numbness (5.8±2.2 vs 1.6±1.8, p&lt;.001) during maintenance therapy. Finally, those with lower skin temperature (47%) reported higher levels of pain (4.5±2.3 vs 1.7±2.9, p=.005) during maintenance therapy. Conclusions: Our results suggest that subclinical sensory deficits may be useful in determining a patient’s risk for developing CIPN prior to initiation of induction therapy. This information could be used to provide patients with more-personalized chemotherapy plans that take into account their neuropathy risk.
IGF-1R inhibition effect on a yes/SFK bypass resistance pathway: Rational basis for cotargeting IGF-1R and yes/SFK kinase in rhabdomyosarcoma.
Authors: Xiaolin Wan, Choh Yeung, Christine Heske, Arnulfo Mendoza, Lee J. Helman
Journal: Journal of Clinical Oncology (2014)

10045 Background: The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. Thus, identifying the mechanisms of acquired resistance to IGF-1R blockade is a major goal. The aim of this study was to identify the molecular mechanisms responsible for acquired resistance to IGF-1R targeted therapy in rhabdomyosarcoma. Methods: Expression profiles of IGF components and Src family kinases (SFKs) were analyzed by cDNA microarray. Antiproliferative effects of anti-IGF-1R agents and SFK inhibitors alone or in combination were tested in vitro in multiple rhabdomyosarcoma (RMS) cell lines and in vivousing xenografts. Western blot and immunoprecipitation were performed to identify protential resistance mechanisms to IGF-1R inhibition. Results: We identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor against IGF-1R/IR. In both cases, resistance was associated with increased activation of Yes/SFK in RMS. Combining anti-IGF-1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition induced activation of Yes/SFK and displayed enhanced antitumor activity in vitro and in vivo. Conclusions: Our data provide evidence that IGF-1R blockade results in activation of the Yes/Src family kinases (SFKs) by-pass resistance pathway in vitro and in vivo, and that co-targeting both IGF-IR and SFK shows advantageous antitumor activity in vitro and in vivo. Our preclinical data support consideration of clinical trials to test this combination in pediatric sarcomas.
Differential changes in tissue biomarkers after bevacizumab (BEV) alone in a neoadjuvant study of BEV and chemotherapy in ER+ breast cancer (BC) versus triple-negative breast cancer (TNBC) patients (pts).
Authors: Yves Boucher, John D. Martin, Sara M. Tolaney, Marek Ancukiewicz, Giorgio Seano, Shom Goel, Eren Yeh, Jack E Meyer, Steven J. Isakoff, Dan G. Duda, Eric P. Winer, Ian E. Krop, Rakesh K. Jain
Journal: Journal of Clinical Oncology (2013)

1065 Background: The benefit of the anti-VEGF antibody BEV—despite its confirmed activity with chemotherapy—remains unclear in BC pts. This may reflect that its benefit is limited to an unknown subset of BC pts. Methods: We previously reported the outcome and circulating biomarker data of a phase II study of neoadjuvant BEV with chemotherapy in ER+ BC and TNBC pts (NCT00546156; ASCO 2012 abstr 1026). In the present study we evaluated tissue biomarkers after 1 run-in cycle of BEV treatment alone. Patients then received BEV with standard dose-dense doxorubicin/cyclophosphamide/paclitaxel. We analyzed the changes in tissue biomarkers in ER+ BC versus TNBC pts after BEV alone and their correlation with outcome at surgery. The primary endpoint was pathologic response, measured by the Miller-Payne (MP) score (MP5=pCR). Results: Mean MP score was 3.1 for ER+ BC pts versus 4 for TNBC pts (area under ROC=0.60, P&lt;0.001). This supports the hypothesis that the activity of BEV with chemotherapy may depend on BC subtype. In TNBCs, BEV significantly decreased mean microvascular density (MVD) by 33% (p&lt;0.05). MVD was inversely correlated with the fraction of tissue positive for the hypoxia marker CAIX post-BEV (p&lt;0.01). Moreover, a high pre-treatment MVD correlated with an increase in CAIX+ fraction post-BEV (p&lt;0.05). In addition, a drop in MVD associated with increased CAIX+ fraction post-BEV (p=0.05). Finally, high (&gt;60%) pericyte coverage post-BEV—ie, more mature vessels—was inversely correlated with CAIX+ fraction (p&lt;0.05). MP score was more favorable for TNBC pts with lower CAIX+ fraction at baseline (p=0.058) and post-BEV (p&lt;0.05), and higher MVD at baseline (p&lt;0.05) and post-BEV (p&lt;0.05). In contrast, BEV reduced MVD non-significantly by 15% in ER+ BC (p=0.25). There was no correlation between MVD and CAIX+ fraction in ER+ BCs. In contradistinction to TNBC, in ER+ BCs the fraction of CAIX+ tumor was directly correlated with MP score (p&lt;0.01). Conclusions: Our exploratory study suggests that vascular pruning post-BEV may reduce vascular function and increase hypoxia, and reduce the effectiveness of chemotherapy in TNBC. Clinical trial information: NCT00546156.
The use of health-related quality of life outcomes in oncology practice: An international study.
Authors: Julie Rouette, Jane M. Blazeby, Madeleine King, Melanie Calvert, Yingwei Peng, Ralph M. Meyer, Jolie Ringash, Melanie Walker, Michael Donald Brundage
Journal: Journal of Clinical Oncology (2014)

6524 Background: Although health-related quality of life (HRQL) outcomes are often reported in randomized controlled trials (RCTs), research has identified challenges to their clinical application. The current perspectives of experienced oncologists on the use of HRQL outcomes, and how these perspectives vary between countries and specialties, are unknown. Methods: A cross-sectional e-survey of oncologist members of the NCIC Clinical Trials Group in Canada, the UK National Cancer Research Institute Clinical Studies Groups, and the network of the Australia/NZ cancer clinical trials groups was conducted. Respondents reported their perceptions of the usefulness of HRQL outcomes, use of HRQL outcomes in clinical practice, barriers/facilitators to their use in practice, and preferences for presentation of HRQL data in RCT publications. Chi-square tests were used to compare responses between countries and specialties. Results: Of the 396 participating oncologists (est. r. rate: 31%), 53% were medical oncologists in Canada and the UK and 61% were radiation oncologists in Australia. HRQL outcomes were reported to be useful in all types of trials (range 76-97%), particularly non-inferiority (89%) and palliative (97%) trials. More than 50% of oncologists reported not using HRQL outcomes with the majority of their patients to guide clinical decisions. Perceived barriers were lack of time (67%) and understanding (57%), and concerns about generalizability of results (68%). Identified facilitators included a summary of clinical implications of the HRQL results in RCT publications (76%), clear description of missing data (86%) and joint publication of HRQL and clinical outcomes (96%). Use of HRQL outcomes in practice, perceived barriers/facilitators, and presentation preferences did not differ by country or specialty. Conclusions: Oncologists support HRQL outcomes but perceive important barriers to their use in clinical practice, regardless of their country or specialty. Publishing HRQL and clinical outcomes jointly or simultaneously in the same journal, a clear description of missing data, and a clear summary of the clinical implications of the HRQL results, may facilitate the clinical application of HRQL outcomes.