tbuckley/cabot-search huggingface dataset:
Examining the adherence to CONSORT guidelines and the reporting of the enrollment process in clinical oncology randomized controlled trials: A review of trials published between 2013 and 2015.
Authors: Sophie Audet, Catherine Doyle, Christopher Lemieux, Julie Lemieux
Journal: Journal of Clinical Oncology (2017)

e14026 Background: Due to eligibility criteria, most, if not all, randomized controlled trials (RCTs) exclude patients at the outset, before randomization. Understanding which patients are excluded is important to evaluate the external validity of the results. The proportion of trials that report the entire flow diagram of patient enrollment, in accordance with the CONSORT 2010 statement, is unknown. Failure to do so makes it more difficult to discuss the generalizability of the trial findings. Methods: We performed the systematic retrieval and analysis of all phases II and III RCTs published in paper form between 2013 and 2015, in four high impact factor journals, in the field of clinical oncology. Our main objective was to determine the proportion of trials that report the number of patients assessed for eligibility before randomization. We further aimed to identify the variables that affect this reporting as well as the reasons for patient exclusion, to calculate the recruitment fraction and the number needed to screen and to determine the proportion of trials that include a discussion on the generalizability of the trial findings. Results: 462 RCTs were reviewed. Among them, 426 (92.2%) included the flow diagram in the article and 224 (48.5%) reported the number of patients assessed for eligibility. This proportion varied significantly between the journals studied, but it did not increase over time. A total of 116 (25.1%) included a discussion of generalizability. Among the trials that reported the entire enrollment process, the reason for patient exclusion could not be found in 50 (22.3%). Conclusions: There is still room for improvement in the reporting of the determinants of external validity in clinical oncology RCTs. Increasing the reporting of the enrollment process could help clinicians and health policy makers establish to whom the results of a trial apply.
Correlation of indoleamine 2,3-dioxygenase expression in primary cutaneous melanoma with Breslow thickness and peritumoral inflammation.
Authors: Dagmar von Bubnoff, Felicia Rubel, Johannes Kern, Kristin Technau-Hafsi, Frank Meiss
Journal: Journal of Clinical Oncology (2016)

9580 Background: Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immunosuppressive properties because this enzyme degrades the essential amino acid tryptophan and T cells undergo proliferation arrest when exposed to tryptophan shortage. Cutaneous melanoma is a highly immunogenic cancer entity with a marked tumor-associated inflammation. This local inflammation fails to stimulate T cell immunity and may thus contribute to disease progression. It is very likely that both the inflammatory infiltrate and the tumor itself can determine whether the immune system fights or supports tumour growth. Peri-tumoral IDO expression in human melanoma and IDO positivity in sentinel lymph nodes has been shown to be linked to negative outcome in melanoma. Methods: We analyzed cellular IDO expression together with the expression of markers of T cells (CD3), myeloid DCs (S100, CD11c) and macrophages (CD68, CD11c) in low-risk primary cutaneous melanomas with tumour thickness of < 0,75mm (n = 32), melanomas with 0,75 -1mm thickness (n = 31) and in high risk melanomas with > 4mm in thickness (n = 36). Immunofluoresence studies were done to identify the IDO expressing cells in the inflammatory infiltrate. Results: IDO-expression in melanoma cells was positively correlated with Breslow thickness (p = 0.003) and intensity of the melanoma-inflammatory infiltrate (p = 0.001). Importantly, IDO may be present already in very thin melanomas directly at the site of tumor development. Immunohistochemistry analyses further showed that IDO-positive inflammatory cells are aligned along the border between the developing tumor and the inflammatory infiltrate. IDO-expression in myeloid cells correlated with the strength of the inflammatory infiltrate (p = 0.001). Two-color immunofluorescence showed that it is primarily the CD68+ macrophages and, to a much lesser extent, the large myeloid CD11c+S100+CD68-dendritic cells (DCs) that express IDO in the microenvironment of melanoma progression. Conclusions: These results demonstrate that IDO-expression is prominent already in early melanoma tumours and may be a key component of immune escape in primary human cutaneous melanoma growth.
Supportive oncology collaborative: Initial impact on supportive oncology screening and care across cancer centers.
Authors: Julia Rachel Trosman, Rosa Berardi, Jennifer Carrie Obel, Frank J. Penedo, Sofia M Garcia, Catherine Deamant, Patricia A. Robinson, Urjeet Patel, Paramjeet Khosla, William Dale, Oana Cristina Danciu, Joanna Martin, Colleen Savory, Aidnag Diaz, Christine B. Weldon
Journal: Journal of Clinical Oncology (2016)

e18191 Background: The IOM 2013 report recommends supportive oncology care from diagnosis through survivorship to end of life, but large gaps and variations exist. Funded by the Coleman Foundation, the Coleman Supportive Oncology Collaborative (CSOC) is making consistent improvements in supportive oncology care across Chicago, using a best of breed set of metrics from CoC, ASCO-QOPI and NQF. Methods: We compared data from consecutive medical records at 6 cancer centers (3 academic, 2 safety-net, 1 public) between 2014 (n = 843) and Q1 2015 (n = 313), to determine feasibility of the consolidated metrics and assess initial CSOC impact. We included solid and hematologic malignancies. Results: Sites completed two rounds of data collection; 6 of 8 core metrics showed initial improvement (Table). Conclusions: A consolidated, best of breed set of metrics is feasible in assessing supportive oncology quality. Early data indicate effectiveness of the collaborative approach. However, large supportive oncology gaps remain. Collected data will guide further CSOC improvements. Metric Patients dx in 2014 % (#) Patients dx in Q1 2015 % (#) Documented discussion on understanding of illness, treatment expectation, or quality of life within 30 days of diagnosis (QOPI 2 NQF 0386) 54 (453/ 843) 67 (210/ 313) Patients provided prognosis timeframe (days to weeks, weeks to months, months to years, years+) within 30 days of diagnosis (QOPI 2 NQF 0386) 24 (205/ 843) 23 (71/ 313) Documented health care agent / validated POA within 90 days of diagnosis (QOPI 25a) 5 (42/843) 18 (58/313) Stage IV patients with a documented advance directive / POLST discussion within 90 days of diagnosis (QOPI 25a) 1 (10/452) 10 (10/103) Stage I, II, III patients with supportive oncology needs screening within 30 days of diagnosis (QOPI 24, CoC 3.2) 38 (148/ 391) 34 (72/210) Stage IV patients with supportive oncology needs screening within 14 days of diagnosis (QOPI 24, CoC 3.2) 6 (27/452) 10 (10/103) Stage IV patients with documented palliative care referral (QOPI 43 NQF 0215) 15 (68/452) 30 (31/103) Stage I, II, III patients who received treatment summary and Survivor Care Plan within 180 days of completing treatment (QOPI 18, 20, CoC 3.3) 2 (9/391) 19 (33/172)
Interim data analysis of the ADAPT trial using the modified intent to treat (mITT) population re-evaluates Rocapuldencel-T for clinical benefit over standard of care.
Authors: Robert A. Figlin, Christopher G. Wood, Alicia H. Gamble, Ana Plachco, Marcus S. Norris, Joe M. Horvatinovich, Irina Y. Tcherepanova, Charles A. Nicolette, Mark A. DeBenedette
Journal: Journal of Clinical Oncology (2018)

4557 Background: The Phase 3 ADAPT trial evaluates overall survival (OS) of Rocapuldencel-T (Roca) in combination (combo) with standard-of-care (SoC) for the treatment of newly diagnosed mRCC compared to SoC alone. At a February 2017 interim analysis, the study was judged unlikely to demonstrate statistically significant improvement in OS. However, the ITT patients included 39 patients (combo) that did not receive Roca and 14 SoC patients not treated. Therefore, additional analyses for the modified ITT (mITT) was evaluated for OS and immune response (IR) in patients receiving therapy. Methods: The mITT includes 268 combo patients who received ≥1 dose of Roca + sunitinib and 141 SoC patients that received ≥1 cycle of sunitinib. Median OS was calculated by log-rank analysis and correlated with IR measured over 1 year Roca dosing. Also, the potency of Roca product administered (measured by level of IL-12 secretion) was correlated with OS. IR and IL-12 levels were assayed by flow cytometry and correlations were analyzed by the Spearman’s rank correlation coefficient method. Results: The mITT combo arm had a median OS of 30.4 months (mo) vs. 32.4 mo in the SoC arm (HR 0.97 95%Cl 0.72, 1.33), however, > 50% of patients were censored at the time of analysis. To test for delayed effects of Roca, we stratified patients based on follow-up time from randomization. For patients in the 1st quartile (longest follow-up time), OS was 35.5 mo for the combo arm (n = 66, 32% censored) and 22.5 mo for SoC (n = 35, 15% censored). As the percentage of censored subjects increased and follow-up time decreased, the OS advantage in the combo arm diminished (3.5 months, 1st 50% randomized and 3.1 months, 1st 75% randomized). Also, the magnitude of anti-tumor IR after 7 doses of Roca correlated with OS (r = 0.4, p < 0.0001) and IL-12 levels correlated with both IR (r = 0.4, p < 0.0001) and OS (r = 0.27, p < 0.0002). Conclusions: The mITT combo subjects, all of whom received Roca therapy, are anticipated to be the population that could benefit from this treatment. This analysis demonstrated correlations between Roca mechanism of action and OS and longer follow-up time is warranted to assess potential efficacy of Roca. Clinical trial information: NCT01582672.
Frequency of target attainment and toxicity with reduced PEG-asparaginase (PEG) dosing in acute lymphoblastic leukemia (ALL).
Authors: Mitchell Streck, Trevor Christ, Wendy Stock, Randall Knoebel
Journal: Journal of Clinical Oncology (2017)

e18501 Background: Asparaginase (ASN) is a critical part of ALL therapy; however, in adults, a higher incidence of toxicities results in treatment delays and suboptimal exposure. We have reported a higher rate of PEG toxicity in pts &gt; 50 yrs of age, baseline liver dysfunction, diabetes, and obesity (BMI ≥ 30). Thus, we hypothesized that reducing the PEG dose from 2500 units/m 2 to 1000 units/m 2 with further reduction to 500 units/m 2 if any of those co-morbidities were present would reduce toxicities and still achieve therapeutic ASN levels. Methods: This is a single-center, retrospective study that included adult pts with ALL. Pts must have received at least one dose of PEG using a pediatric inspired regimen that includes 7 doses of PEG. The primary objective was to determine the rate of target ASN activity (≥ 0.1 IU/mL) one week after administration of reduced PEG during induction. Secondary objectives included the incidence of grade 3/4 toxicity based upon CTACE 4 criteria (hepatotoxicity, pancreatitis, hypertriglyceridemia, and VTE) between standard (SD) &gt; 1000 units/m 2 and reduced (RED) ≤1000 units/m 2 PEG dosing. Results: 41 consecutive pts with ALL were included. Median age was 43 years (range 18-76). Median WBC upon admission was 7.6. At baseline, 25 pts (61%) had at least one comorbidity. 26 pts (63%) received SD PEG and 15 pts (37%) received RED PEG with median dose 1000 units/m 2 . 80% of pts achieved target ASN activity following administration of a RED PEG induction dose, median level of 0.1 IU/mL (IQR 0.1-0.24 IU/mL). 30 pts (73%) experienced grade 3/4 toxicity during induction, 81% in the SD group vs 60% in the RED group (p = 0.3). During induction, grade 3/4 hepatotoxicity was seen in 16 SD pts (62%) vs 6 RED pts (40%) (p = 0.211). Grade 3/4 hyperbilirubinemia was seen in 12 SD pts (46%) vs 1 RED pt (7%) (p = 0.014). Conclusions: The majority of pts attained a therapeutic ASN activity level with RED PEG. This resulted in a trend towards lower incidence of overall toxicity and a significant decrease in hyperbilirubinemia. A larger prospective study will be needed to determine whether decreased toxicity during induction correlates with fewer treatment delays, improved drug delivery, and better treatment outcome.
A new prediction model for prognosis of patients with intermediate HCC after conventional transarterial chemoembolization.
Authors: Rong-xin Chen, Yu-Hong Gan, Ning-lin Ge, Yi Chen, Boheng Zhang, Yan-hong Wang, Zhenggang Ren
Journal: Journal of Clinical Oncology (2018)

e16128 Background: The prognosis of patients with intermediate hepatocellular carcinoma (HCC) treated by conventional TACE (cTACE) varies greatly. This study aimed to develop a new survival prediction model to help select patients who would benefit better from cTACE treatment. Methods: We collected data of 848 treatment-naïve patients with BCLC stage B HCC who received cTACE as first-line therapy. The prognostic model’s variables were derived from univariate and multivariate Cox regression analyses of patient, tumor, liver function and treatment-related factors. The concordance index (C-statistic) calculated through cross-validation and bootstrap resampling was used for the model selection. The calibration of our final prediction model was also assessed. Results: The model showed a slightly better discrimination ability than BCLC B1-B4 subclassification to predict the prognosis (C-statistic, 0.66 vs. 0.60; difference, 0.05, 95% CI, 0.03-0.07). In cross-validation, bootstrap resampling demonstrated that the model maintained sufficient discriminant (an average of C-statistic, 0.66; 95% CI, 0.65-0.68). The model calibration was accurate in predicting survival of patients matched well with the observed outcomes. On the basis of the improved survival of 18 months or more as the responding patient, the observations of patients in each response category (responder and non-responder) were fair-moderately matched with those predicted by the model (κ = 0.40, P< 0.001). Conclusions: Utilizing clinically available information of patient, tumor and liver function, we developed an applicable prediction model for estimating the survival of intermediate HCC patients after cTACE, which could help define the distinct subgroup of BCLC stage B patients who are suitable for cTACE treatment.
Phase 1/2 trial evaluating intratumoral administration of INT230-6 alone and in combination with an anti-PD1 antibody for advanced malignancies.
Authors: Yada Kanjanapan, Nilofer Saba Azad, Lillian L. Siu, Anthony J. Olszanski, Ian B Walters, Lisa Kamen, Lewis H. Bender, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2018)

TPS2609 Background: INT230-6 is a supermolecular complex of cisplatin, vinblastine, and an amphiphilic penetration enhancer, formulated for intratumoral injection. This agent utilizes technology that facilitates drug dispersion throughout the tumor and enhances receptor independent transport into cancer cells. INT230-6 preferentially saturates cancer cells, due to their greater membrane fluidity over normal cells. In Colon26 mouse models, intratumoral injections of INT230-6 resulted in up to 80% complete responses(CRs) with generation of antigen specific CD8 T-cells. Responses were seen in both injected tumors as well as bystander lesions. Animals maintained lifelong protection from tumor rechallenge, and partial protection from 4T1 (a different tumor type) which was dependent on CD4 and CD8 T-cells. Clear benefit with anti-PD1 was shown preclinically (increased CR and OS). Methods: This adaptive Phase 1/2 trial evaluates intratumoral INT230-6 in advanced malignancies (NCT03058289). The first cohort examines injection into superficially palpable tumors, dosed at 1ml:4cc drug:tumor concentration and administered monthly for 5 cycles. Intrapatient dose escalation is allowed. Additional cohorts include deep tumor injection, more frequent administration every 2 weeks, increased proportion of drug to tumor (1ml:2cc), and combination with an anti-PD1 antibody. Eligible patients (pts) have metastatic cancer and progressed on or are not candidates for approved therapies, or non-resectable locally advanced disease recurring within 6 months post radiation, with tumors suitable for injection. The primary objective is assessment of safety, with secondary objectives of PK and preliminary analysis of response in injected and bystander tumors. Correlative endpoints include tumor infiltrating lymphocytes in pre and on-study biopsies of injected and bystander lesions, peripheral blood for flow cytometry and circulating cytokine analyses. The superficial cohort has been completed with no DLTs in 6 treated pts. The deep tumor and every 2 week dosing cohorts are ongoing with tumor type specific expansion cohorts as guided by the Study Steering Committee. Clinical trial information: NCT03058289.
A comparison of measured and estimated glomerular filtration rate (GFR) for carboplatin dose calculation in women with ovarian cancer (OC).
Authors: Joanita Ocen, Ricky Dylan Frazer, Sarah Wright, Paul D Lewis, Gianfilippo Bertelli
Journal: Journal of Clinical Oncology (2017)

e17051 Background:Carboplatin based chemotherapy is widely used to treat women with Ovarian cancer (OC) in the adjuvant, neoadjuvant and palliative settings. Carboplatin is normally dosed by the Calvert formula: [GRF+25] x AUC, with a target AUC (area under the plasma concentration curve) of 5-6 mg/ml/min. GFR (glomerular filtration rate) can be precisely measured with radionuclide based ligands such as 51Cr-ethylenediamine tetraacetic acid (51Cr-EDTA), but in clinical practice is often estimated using formulae incorporating serum creatinine, weight and age, such as the Cockcroft–Gault (CG) or Wright (WR) formulae. It is unknown, however, if these formulae allow a sufficiently accurate dosing of carboplatin in OC patients. Methods:We retrospectively compared measured (EDTA-based) and estimated (CG and WR formulae) GFR and the resulting carboplatin doses, in women with stage 1c to IV OC treated with carboplatin AUC 6 at our centre between 2015 and 2016. All patients (pts) had concurrent 51Cr-EDTA GFR and serum creatinine measurement before starting carboplatin. Accuracy and bias of The WR and CG formulae were analysed using mean absolute percentage error (MAPE) and mean percentage error (MPE). Results:92 pts were included in the study (median age = 69 years (r. 25 -89), median serum creatinine 63.5 umol/L (r. 38 – 168)). MPE was -37.3 and -26.0 and MAPE was 38.0 and 32.2 for the WR and CG formulae, respectively. If the WR or CG formulae had been used instead of EDTA to calculate the dose of carboplatin, the discrepancy would have been at least 10% in 77.1% and 69.8% of pts, respectively; a discrepancy of 50% or more would have occurred in 10% and 13% of pts. Conclusions:Neither the WR nor CG formulae precisely predict renal function in ovarian cancer pts. They often overestimate GFR, meaning that if these formulae are used instead of isotope-based measurement of GFR, most pts will receive a higher dose of carboplatin. Our findings are relevant for clinical practice and for the design and interpretation of clinical trials, where the choice between EDTA- or formulae- based calculations of carboplatin dose are often left to investigators’ preference.
Liposomal cisplatin response prediction in heavily pretreated breast cancer patients: A multigene biomarker in a prospective phase 2 study.
Authors: Erik Hugger Jakobsen, Dorte Nielsen, Hella Danoe, Soeren Linnet, Joergen Hansen, Ulrik Niels Lassen, Eva Balslev, Vesna Glavicic, Jurij Bogovic, Steen Knudsen, Bent Ejlertsen, Ann Søegaard Knoop, Ulla Hald Buhl, Mogens Winkel Madsen, Ida Kappel Buhl, Anker Hansen, Thomas Jensen, Annie Rasmussen, Peter Buhl Jensen, Sven Tyge Langkjer
Journal: Journal of Clinical Oncology (2018)

e13077 Background: In an ongoing, open-label Phase 2 study liposomal cisplatin (LiPlaCis) was evaluated in metastatic breast cancer (mBC) patients selected by a cisplatin-specific mRNA-based drug response predictor (DRP). The DRP was part of a Phase 2 trial screening program with > 1400 mBC patients using archival tumor tissue to classify the patients as DRP high (top 2/3) or low (bottom 1/3). Methods: Eligible were DRP high mBC patients after at least 2 prior treatment lines for advanced disease. 75 mg LiPlaCis was administered on days 1 and 8 every 3 weeks (wks) with efficacy evaluation every 6 wks. Efficacy was measured as progression-free survival (PFS) and objective response rate (ORR) against outcome of latest prior treatment. Top 1/3 in DRP level was compared with middle 1/3. Results: In all 12 patients have been included with a planned enrollment of 20 evaluable patients. Two patients did not receive a full cycle due to early death, deemed unrelated to LiPlaCis by a safety committee. ORR in the intention to treat group (n = 12) was 17%. Ten patients are evaluable for response 6 had a DRP score in the top 1/3 and 4 in the middle 1/3. LiPlaCis was the 8th line of treatment for advanced disease (median). Two had partial remissions (PR), 5 had stable disease (SD) and three had progressive disease (PD). Five of the 6 patients in the top 1/3 DRP level were platin-naïve and all 5 had clinical benefit with a median PFS of 25 wks vs 17 wks in latest prior treatment (hazard ratio (HR) 0.19, p = 0.04). Three out of the 5 had a better efficacy or longer response than with any previous medical treatment for advanced disease and ORR was 40% as both patients with PR were in top 1/3 score. Two patients in the middle 1/3 DRP level were platin naïve and they had a significant shorter PFS compared to the 5 of platin-naïve in top 1/3 DRP (25 wks vs. 8 wks; HR of 4e-10, p = 0.008). LiPlaCis has been well tolerated, with 4 grade 3 events and 2 grade 4 events being related to study drug in 43 given cycles in the presented 12 patients. Conclusions: LiPlaCis shows efficacy in mBC patients. DRP selection by top 1/3 identifies responders to treatment. A randomized Phase 2 study is planned. Clinical trial information: NCT01861496.