tbuckley/cabot-search huggingface dataset:
Change in CEA as an early predictor of progression to first-line systemic therapy in metastatic colorectal cancer.
Authors: Pat Gulhati, Jun Yin, Levi Pederson, Hans-Joachim Schmoll, Paulo Marcelo Hoff, Jean-Yves Douillard, J. Randolph Hecht, Christophe Tournigand, Niall Tebbut, Benoist Chibaudel, Aimery De Gramont, Qian Shi, Michael J. Overman
Journal: Journal of Clinical Oncology (2018)

3525 Background: Carcinoembryonic antigen (CEA) levels are used in conjunction with imaging to monitor response to systemic therapy in pts with metastatic colorectal cancer (mCRC). We sought to identify a threshold for change in CEA from baseline that can predict progressive disease (PD) at first restaging scan in mCRC pts receiving first-line therapy. Methods: Pts from trials collected in ARCAD database were included if baseline CEA was ≥10 ng/mL and repeat CEA was available within 14 days of first restaging scan. Optimal cutoffs for CEA change were identified by ROC analysis. Prediction performance of cutoffs was evaluated by sensitivity, specificity, and negative predictive value (NPV). Analyses were conducted by treatment class: chemotherapy alone (chemo) and chemotherapy plus anti-VEGF antibody (anti-VEGF). Results: 2828 pts from 7 trials [M/F: 60%/40%; median age: 61 yrs; ECOG PS 0-1: 97%] with mCRC [55% pts with ≥2 metastatic sites] treated with systemic therapy were included. In chemo group (n = 957), median percent change of CEA from baseline to first restaging was -53.1% and +23.6% for pts with CR/PR/SD and PD, respectively. In anti-VEGF group (n = 1355), median percent change of CEA was -71.7% and -45.3% for pts with CR/PR/SD and PD, respectively. Optimal cutoffs based on sensitivity and specificity (AUC cutoff) or 99% NPV are shown in the table. The optimal AUC cutoff for differentiating PD from CR/PR/SD on first restaging was -7.5% for chemotherapy and -62.0% for anti-VEGF group. A drop in CEA less than optimal AUC cutoff was significantly associated with higher risk of PD at 1st restaging; chemo, ORadj = 6.51; anti-VEGF, ORadj = 3.45. The use of a 99% NPV cutoff for prediction of CR/PR/SD would avoid a CT scan at first restaging in 21% of chemotherapy and 16% of anti-VEGF treated patients. Conclusions: Change in CEA from baseline to first restaging can accurately predict PD in pts receiving chemotherapy. PD Prediction by CEA Change in CEA AUC Sensitivity Specificity NPV CT scans avoided Cutoff by optimal AUC Chemo only -7.5% 0.79 71.6% 76.2% 97.3% 72.8% Chemo + Anti-VEGF -62.0% 0.72 66.7% 63.6% 97.9% 62.4% Cutoff by 99% NPV Chemo only -79.4% 0.79 97.0% 22.4% 99% 21.0% Chemo + Anti-VEGF -88.7% 0.72 96.3% 16.7% 99% 16.0%
Neutrophil-to-lymphocyte ratio (NLR) conversion during checkpoint inhibitors therapy as a early prognostic factor.
Authors: Jefferson Rios Pimenta, Tiago Felismino, Alexandre Andre B. A. Da Costa, Victor Hugo Fonseca Jesus, Daniel Vilarim Araujo, Jose A. Rinck
Journal: Journal of Clinical Oncology (2018)

e24038 Background: Immunotherapy is a standard treatment in metastatic cutaneous melanoma (mCM). Yet it still lacks adequate predictors of response. The NLR is a prognostic factor in mCM. We aim to evaluate the NLR dynamics during treatment with Ipilimumab and/or Nivolumab and its relation with Overall Survival (OS) and Clinical Benefit (CB), in patients (pts) with mCM. Methods: We retrospectively analyzed mCM pts treated with Nivolumab and/or Ipilimumab in our center from Jan/2010 to Aug/2016. NLR was collected at baseline and at week 6 (w6). We defined NLR cutoff of 3. We hypothesized 4 different clinical scenarios A: baseline NLR (bNRL) < 3 / w6 < 3; B: baseline NRL > 3 / w6 < 3; C: bNRL < 3 / w6 > 3; and D: bNRL > 3 / w6 > 3. Overall survival (OS) was estimated by Kaplan-Meier. Clinical benefit (CB) was defined as a composite of complete response, partial response and stable disease, using RECIST post week 12. Results: We analysed 133 pts, in two groups: G1 and G2. G1 with 116 pts used Ipilimumab as first line. G2 with 43 pts received Nivolumab as subsequent therapy. Median follow-up was 27,6 months in G1 and 18,6m in G2. In G1 mOS was 32,4m vs 17,9m for patients with baseline NLR < 3 vs ≥3 (p = 0,046) respectively. In G2 mOS was 28,4m vs 16,5m (p = 0,03) respectively. According to clinical scenarios, in G1 mOS was as follows: A: 36,5m, B: 22,8m, C: 13,2m and D: 10,4m (p < 0,0001). In G2 mOS was not reached for scenarios A and B, C: 15,8m and D: 3,5m (p = 0,01). In G1, CB was 48,2%vs18,1% for patients in scenarios A/B and C/D, respectively (p = 0,037). Conclusions: Our data suggests that an elevated NLR correlates with worse survival, as found by previous studies. Nevertheless we showed here that early changes in NRL (week 6) can guide clinicians on an early evaluation of prognosis particularly with ipilimumab therapy.
Morbidities and socioeconomic factors of uninsured patients with cancer in free clinics.
Authors: Katherine Robinson, Abu-Sayeef Mirza, Yuanyuan Lu, Noura Ayoubi, Aldenise Ewing, Rahul Suresh Mhaskar, Richard Roetzheim, Smitha Pabbathi
Journal: Journal of Clinical Oncology (2018)

e18681 Background: There are few studies documenting the prevalence of malignancies and associated chronic conditions in free clinics. Cancer patients become lost to follow-up after treatment and end up in free clinics for further management of chronic morbidities. Charlson Comorbidity Index (CCI) has been used to study the mortality risk of patients with comorbid conditions, with the intention of adding standardized, weighted value to the disease profile of cancer patients. Methods: Demographic data and chronic disease measures were extracted from medical charts of patients managed in eight free clinics between January to December 2016 in the Tampa Bay Area. Descriptive statistics as well as Pearson correlation coefficient were used to demonstrate relationships between socioeconomic factors, cancer diagnoses, and comorbidities. CCI was used to assess severity of disease and mortality risk. Results: In 2016, 4804 uninsured patients were evaluated. From manual chart review, 86 patients (1.7%) were diagnosed with cancer. They were predominantly female (65.1%) and had an average age of 54.37 years (SD 13.42), significantly greater than patients without cancer (p < 0.001). Most common malignancies included breast (19, 22.09%), prostate (8, 9.30%), melanoma (6, 6.97%), cervical (5, 5.81%), colon (5, 5.81%), squamous carcinoma (5, 5.81%), ovarian (4, 4.65%), and lung cancer (4, 4.65%). The average length of survival was approximately 8.53 years (SD 7.55). Overall, cancer patients had a higher CCI (3.04 (1.928)), compared to patients without cancer (.90 (1.209)), p < 0.001. Cancer patients had more CCI comorbidities compared to patients without cancer (p < 0.001). Other factors of chronic disease including obesity and substance abuse are reported as correlations with cancer history among the uninsured. Conclusions: Uninsured patients from free clinics are considered outside the health care system and represent a unique population that is understudied in the literature. The most common malignancies identified in free clinics correlate with national epidemiology. Cancer patients without insurance have greater burdens of diseases as evidenced by their calculated CCI compared to uninsured patients without cancer.
Autologous stem cell transplantation as a treatment modality for type 1 cryoglobulinemia in monoclonal gammopathy of renal significance.
Authors: Joshua Ryan Richter, Zhen Wang, David H. Vesole, Noa Biran, Michele Donato, Scott D. Rowley, Alan P. Skarbnik, Andrew Pecora, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2017)

e19500 Background: Type I cryoglobulinemia (CRYO) can be driven by disorders such as plasma cell dyscrasias. Monoclonal gammopathy of renal significance (MGRS) represents a group of kidney disorders characterized by the presence of a paraprotein; though not fitting the criteria for a hematologic malignancy. There exists no standard approach to manage these patients. Our patient is a 56-year-old man who was initially evaluated for edema. Workup revealed worsening renal function and proteinuria (Figure 1). Renal biopsy revealed abundant cryofibrinogen deposits and cryoglobulinemic glomerulonephritis with membranoproliferative pattern. Bloodwork showed type I (IgG Kappa) CRYO. Bone marrow evaluation revealed 7% clonal plasma cells. Further evaluation did not confirm a diagnosis of myeloma. Methods: Treatment was initiated with bortezomib, cyclophosphamide and dexamethasone. After 3 cycles of therapy the patient had normalization of his creatinine and marked improvement in edema. Peripheral blood stem cells were mobilized following the administration of high-dose cyclophosphamide (2gm/m2) plus filgrastim. He was subsequently conditioned for transplantation with high-dose melphalan (200mg/m2; HDM) followed by autologous stem cell rescue. He tolerated the procedure well without any unexpected toxicities; achieving prompt hematologic recovery Results: Evaluations post transplant revealed resolution of any circulating cryoglobulins and reduction in proteinuria. At 1 year post transplant, the patient has returned to his premorbid condition. Conclusions: Type 1 CRYO associated MGRS represents a complicated disorder for which there is no consensus treatment approach. As this process may be driven by clonal plasma cells, classical anti-myeloma therapy may provide a strategy for management. Given the typical low plasma cell burden in these patients, HDM has the potential to offer deep and durable remissions. Prospective studies are needed to validate this approach. [Table: see text]
Neurologic assessment in neuro-oncology (NANO) scale in a prospective phase II trial of anti-PD1 antibody, pembrolizumab with or without bevacizumab in patients with recurrent glioblastoma.
Authors: Lakshmi Nayak, Timothy Smith, Sarah C. Gaffey, Katherine B. Peters, Jennifer Leigh Clarke, Justin T Jordan, John Frederick De Groot, Phioanh Leia Nghiemphu, Thomas Joseph Kaley, Howard Colman, Terri Armstrong, Martin J. Taphoorn, Victoria Caruso, Myriam Bednarek Debruyne, Chinmay Bhavsar, Annette M Molinaro, Mariano Severgnini, Patrick Y. Wen, David A. Reardon
Journal: Journal of Clinical Oncology (2018)

2037 Background: The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients (pts) with brain tumors to complement radiographic assessment in defining overall outcome. The scale has been incorporated in various prospective studies to assess pts and to determine its utility. Methods: A multicenter, open label, phase II trial of pembrolizumab with and without bevacizumab in pts with recurrent glioblastoma (GBM) incorporated NANO scale as an exploratory endpoint. Neurologic examination by NANO was documented at baseline and each cycle until pts came off study. Statistical analyses including descriptive data analysis and generalized linear models were performed using R (version 3.4.3). Results: Eighty pts received treatment on study and underwent NANO evaluations. NANO compliance rate was 94%; of a total 388 expected NANO evaluations, 24 were missing. Of 80 pts, 7 missing NANO at baseline visit were excluded from analysis. Fifteen pts did not have end of treatment NANO evaluation. Of 73 pts, 35 (48%) had a normal neurologic examination at baseline by NANO. Two NANO domains (strength and language) accounted for the majority of variability in neurologic function over the course of study treatment. There was a significant correlation between NANO at each cycle and Karnofsky performance status score (p= 0.02). Nineteen pts were on dexamethasone at baseline; 42 required it during study. Corticosteroid requirement (OR = 1.9, p< 0.001) and an increase in corticosteroid dose (OR = 2.6, p< 0.001) were associated with higher risk of NANO progression (PD). Eighteen pts (25%) met NANO criteria for PD, including 2 without PD on MRI. Three pts (4%) had a neurologic response per NANO criteria associated with stability on MRI. Conclusions: Evaluation of neurologic function by NANO was feasible in a multicenter prospective study in GBM pts with a high compliance rate. NANO was able to objectively track neurologic function throughout the trial including preservation of baseline status in non-progressors. Clinical trial information: NCT02337491.
Multicenter case registry study on medication-related osteonecrosis of the jaw in advanced cancer patients.
Authors: Morten Schiodt, Saroj Vadhan-Raj, Mark Steven Chambers, Ourania Nicolatou-Galitis, Constantinus Politis, Ruxandra Coropciuc, Stefano Fedele, Danielle Jandial, Jeffrey Zhang, Haijun Ma, Deborah Saunders
Journal: Journal of Clinical Oncology (2016)

e21663 Background: Medication-related osteonecrosis of the jaw (MRONJ) is defined as exposed jawbone or bone that can be probed through a fistula, persisting for 8 or more weeks. MRONJ occurs in the absence of radiation or metastatic disease to the jaws, and in the presence of current or previous antiresorptive or antiangiogenic treatment (Ruggiero et al, 2014). This multicenter observational case registry of advanced cancer patients (pts) with MRONJ reports on the natural history of ONJ and describes the estimated rate and time course of MRONJ resolution. Methods: Cancer pts with positively-adjudicated, newly diagnosed MRONJ were enrolled in the registry. Baseline cancer and dental histories were collected. Follow-up visits were conducted every 3 months for 2 years then every 6 months for 3 years, for a total of 5 years or until death, withdrawal, or loss to follow-up. Results: For this interim analysis, 225 pts enrolled and 170 (75.6%) were continuing on study and observed for a median of 6.3 month (range 0.1-31.0). The most common cancers were breast (33.3%), myeloma (24.4%), and prostate (23.6%). Most pts with solid tumors had stage IV disease (56%). At baseline, most pts had stage II ONJ (n = 139, 62%; AAOMS criteria) and had associated oral risk factors (73%) including tooth extraction (54%). Two hundred and eighteen pts (97%) received antiresorptive therapies for a median duration of 23.3 months (0.0, 124.9) prior to MRONJ diagnosis. Of the pts who received prior cancer therapy (60%), 118 pts (52%) received antiangiogenic agents or immunosuppressants. MRONJ treatment was largely conservative, with 92% of pts receiving medications (eg, oral rinses, antibiotics). Fifty-four pts (24%) required limited surgical procedures (eg, debridement, curettage). Forty-seven pts (21%) achieved ONJ resolution (defined as of complete mucosal coverage of exposed bone) with a median time of 8.2 (2.8, 33.7) months. Conclusions: At baseline,most pts had stage II MRONJ and were conservatively managed. Most pts had additional risk factors, including prior tooth extractions and cancer therapies involving antiangiogenic or immunosuppressant agents. Of the evaluable pts, the majority had stable, improved or resolved ONJ outcomes. Clinical trial information: NCT01666106.
FACTS: Factors affecting combination trial success.
Authors: Channing Judith Paller, Erich Huang, Thomas Luechtefeld, Holly A. Massett, Christopher Williams, Jinxiu Zhao, Amy Gravell, Steven A. Reeves, Gary L. Rosner, Michael Anthony Carducci, Larry Rubinstein, S. Percy Ivy
Journal: Journal of Clinical Oncology (2018)

2544 Background: Experimental therapeutic oncology agents are often combined in an effort to circumvent tumor resistance to individual agents; most combination trials, however, fail to demonstrate sufficient safety and efficacy to advance to a later phase. The FACTS study collected survey data on phase 1 combination therapies to: 1) assess rates of advancement and regulatory approval, 2) identify factors associated with these rates, and 3) assess the degree that phase 1 trials were concordant with Clinical Trial Design Task Force (CTD-TF) Guidelines. Methods: A 13-question survey collected data on phase 1 trial design, predefined expectations and criteria to assess success, biomarker information, and questions about the trials’ results and progress. Online surveys (N = 289, July-Dec. 2017) were emailed to PIs of early-phase NCI and/or industry trials; 263 emails (91%) were received and 114 surveys completed (43%). Two independent coders validated 10% of survey responses (N = 12) against manuscript publications (intercoder Reliability = 99%). Results: Phase 1 results indicated further investigation was warranted for 39.8% of combinations (95% CI: 30.8%, 48.8%). 24.9% of combination trials (95% CI: 15.3%, 34.4%) progressed to phase 2 or further. 18.7% (95% CI: 5.90%, 31.4%) progressed to phase 3 or FDA approval. 12.4% (95% CI: 0.00%, 25.5%) achieved regulatory approval. Trial results where “clinical promise was observed” in phase 1 of the combination study were associated with higher rates of progression past each milestone toward regulatory approval (cumulative OR = 11.9; p = 0.0002). The phase 1 study designs were concordant with CTD-TF Guidelines for 79.6% of the combinations (95% CI: 72.2%, 87.1%); most discordances occurred where no plausible pharmacokinetic or pharmacodynamic interactions were expected. Conclusions: “Clinical promise” of a combination may predict progress toward regulatory approval. Although concordance between study designs of phase 1 trials of combination therapies and CTD-TF Guidelines was relatively high, raising more awareness of the best study design to use when no plausible pharmacokinetic or pharmacodynamic interactions are expected may be beneficial.
Impact of tyrosine kinase inhibitor (TKI) dose on outcomes of patients with lung cancer.
Authors: Emily Miao, Stephen Eng, Chung-Shien Lee, Nagashree Seetharamu, Kevin M. Sullivan, Myriam Kline
Journal: Journal of Clinical Oncology (2018)

e21081 Background: FDA approved starting doses of TKis are based on maximum tolerated dose (MTD) in clinical trials. In practice however, patients are started on lower doses due to tolerability concerns or dose-reduced subsequently for toxicity. Very few studies have addressed the impact of dose on clinical outcomes Methods: An IRB approved chart review of lung cancer patients receiving oral TKI therapy between 1/2014 and 6/2017 at our institution was conducted. Patients who were started on TKIs at the FDA dose (Group A) dose were compared to those started on a lower dose (Group B) for progression free survival (PFS), overall survival (OS), and time-to-discontinuation. Fisher’s exact test was used to compare groups on categorical variables and the Mann-Whitney test was used for continuous variables. The Kaplan-Meier method was used to estimate time-to-event stratified by group, and Cox regression models were used to adjust for potential confounders. Results: Seventy-nine patients were treated with an EGFR inhibitor and 11 patients were treated an ALK inhibitor. The Kaplan-Meier estimates of the median time-to-progression for Group A (n = 67) and Group B (n = 23) were 13.4 months (95% CI: 8.88, 15.55) and 15.1 months (95% CI: 5.56, 21.5), respectively; and for time-to-discontinuation, the estimates were 13.5 months (95% CI: 11, 20.15) for Group A and 21.5 months (95% CI: 6.44, ) for Group B. Median time to death was not estimable for OS. The predicted OS probability at approximately 15 months post treatment initiation for Group A was 81.8% (95% CI: 0.69, 0.90) vs. 80.5% (95% CI: 0.55, 0.92) for Group B. No statistically significant differences resulted from the Cox regression models. Conclusions: We found no evidence to support that patients who initiated therapy at full dose have different outcomes with respect to OS and PFS compared to those who initiated at a lower starting dose. Future prospective studies are needed to further evaluate this finding. Future clinical trials should report minimal effective dose in addition to MTD.
Physiologically based pharmacokinetic modelling to guide drug delivery in older people
Authors: Manoranjenni Chetty, Trevor N. Johnson, Sebastian Polak, Farzaneh Salem, Kosuke Doki, Amin Rostami-Hodjegan
Journal: Advanced Drug Delivery Reviews (2018)

Older patients are generally not included in Phase 1 clinical trials despite being the population group who use the largest number of prescription medicines. Physiologically based pharmacokinetic (PBPK) modelling provides an understanding of the absorption and disposition of drugs in older patients. In this review, PBPK models used for the prediction of absorption and exposure of drugs after parenteral, oral and transdermal administration are discussed. Comparisons between predicted drug pharmacokinetics (PK) and observed PK are presented to illustrate the accuracy of the predictions by the PBPK models and their potential use in informing clinical trial design and dosage adjustments in older patients. In addition, a case of PBPK modelling of a bioequivalence study on two controlled release products is described, where PBPK predictions reproduced the study showing bioequivalence in healthy volunteers but not in older subjects with achlorhydria, indicating further utility in prospectively identifying challenges in bioequivalence studies.
Utilization of consultative molecular tumor board in community setting.
Authors: Carol J. Farhangfar, Oshuna Morgan, Charlene Concepcion, Jimmy J. Hwang, Kathryn Finch Mileham, Daniel R. Carrizosa, Beth Dellinger, Farhang Farhangfar, Edward S. Kim
Journal: Journal of Clinical Oncology (2017)

6508 Background: Physicians in the community have a broad range of experience using genomics data to inform treatment decisions. They typically have a heavier patient load than found in academic centers and treat a variety of tumor types. Genomic data has been reportedly used less than anticipated, even when results were actionable. Monthly didactic molecular tumor boards have been implemented in a number of cancer centers to try to fill gaps in knowledge. Methods: A weekly virtual consultative molecular tumor board (MTB) was implemented (Mar 2016) at an academic hybrid, multi-site community-based cancer institute to provide rapid molecularly-driven treatment guidance to physicians, augment genomics education, provide supporting documents for off-label use and clinical trials. A baseline survey was performed prior to first MTB. MTB assessments were summarized and provided to treating physician. Data was abstracted from the electronic medical records and clinical trials management system. Descriptive statistics were utilized to summarize utilization of MTB and treatment recommendations. Results: Genomics testing with a large panel (~600 genes) was requested for 809 patients (Jun 2015-Feb 2017). The MTB received 81 requests for review from 32 physicians from 14 locations. Most commonly reviewed disease sites were lung, ovary, pancreatic, colon, breast and head and neck cancers; 37% of reviews requested were for rare tumors. Median time to review request was 15 days from receipt of results. MTB recommendations were followed in 70% of cases, 16% continued current/other therapy, 11% declined rapidly (hospice/died), and 3% of patients decided against recommendations. Forty-four (44) percent were screened for recommended clinical trials; 26% went on study. Conclusions: Implementation of a weekly virtual consultative MTB facilitates molecularly-driven treatment decisions in community setting, especially in rare tumor types and enhances clinical trial accruals.