tbuckley/cabot-search huggingface dataset:
Prognostic significance of sarcopenia in metastatic esophageal squamous cell carcinoma.
Authors: Kirsty Taylor, Osvaldo Espin-Garcia, Tina Romagnuolo, Frances Allison, Lucy Xiaolu Ma, Micheal McInnis, Aline Fusco Fares, Geoffrey Liu, Gail Elizabeth Darling, Rebecca Wong, Eric Xueyu Chen, Patrick Veit-Haibach, Raymond Woo-Jun Jang, Dmitry Rozenberg, Elena Elimova
Journal: Journal of Clinical Oncology (2019)

4068 Background: Sarcopenia is defined as low skeletal muscle mass and represents a quantifiable marker of frailty. Disease related symptoms of anorexia, nausea and dysphagia, in addition to reduced physical activity contribute to muscle wasting in metastatic esophageal squamous cell cancer (MESCC) patients. This study set out to evaluate the prognostic utility of sarcopenia and its association with nutritional indices. Methods: MESCC patients (pts) with available abdominal CT imaging, attending Princess Margaret Cancer Centre between 2011 and 2016, were identified from the institutional database. Skeletal muscle index (SMI), normalized by height, was calculated at the third lumbar (L3) vertebra using SliceOMatic software. SMI cutoffs for sarcopenia were 34.4cm 2 /m 2 in females and 45.4cm 2 /m 2 in males based on previously established consensus. Nutritional risk index (NRI) was calculated using weight and albumin with malnutrition defined as &lt; 97.5. Results: Of the 58 pts analyzed, 26 presented with de novo MESCC, median age was 64 (range 48-85), 30 pts were ECOG PS ≤1 and 45% received systemic therapy. 93% of pts experienced weight loss &gt; 5% in the 3 months preceding diagnosis and median BMI was 20.4 (range 16.3-34.9). Twenty-four (41%) pts were sarcopenic (SP) with differences in BMI and NRI (p &lt; 0.05) compared to non-sarcopenic (NSP) pts. Median BMI in SP pts was 18.9 (16.3-25.6), 46% had a BMI &lt; 18.5 and none were obese (BMI ≥ 30). By NRI, 58% of SP pts were malnourished. Males comprised 71% of SP pts (p = 0.03) but no difference from NSP MESCC pts was identified with age, race, ECOG PS or smoking status with univariate analysis. Median overall survival (OS) was 6 months; 4.2 in SP pts and 6.2 in NSP pts. Significant difference was identified with NRI (p = .0.009) but not sarcopenia (p = 0.247) or BMI (p = 0.393). With a multi-variate Cox model for NRI and sarcopenia, including age, sex, race, and ECOG PS, only ECOG PS was a significant predictor of mortality, HR for 2-3 vs 0-1 of 5.4 (2.5-11.9) p &lt; 0.001. Conclusions: Sarcopenia at diagnosis was not associated with OS. NRI was superior to BMI alone with respect to discriminating pt outcomes, however ECOG PS was the only measure significantly associated with survival.
Organ dysfunction (dys) and clinical outcomes in patients (pts) treated with immune checkpoint inhibitors (ICIs).
Authors: QI LIU, Elad Sharon, Issam Zineh, Diqiong (Joan) Xie, Shrujal S. Baxi, Chao Liu, Jizu Zhi, Aracelis Z. Torres, Anala Gossai, Rajeshwari Sridhara, Brian Booth, Gideon Michael Blumenthal, Shiew-Mei Huang, Sean Khozin
Journal: Journal of Clinical Oncology (2019)

2569 Background: ICIs (anti-PD-L1/PD-1/CTLA-4) are approved in multiple cancers. The impact of organ dys on the pharmacokinetics of ICIs is known, but associated clinical outcomes are not well characterized. We compared real-world (rw) clinical outcomes in ICI-treated pts by liver and renal function. Methods: This retrospective study used longitudinal, patient-level data from community practices in the Flatiron Health electronic-health record (EHR)-derived database. We included pts diagnosed with advanced cancers (NSCLC, renal cell, melanoma, gastric/esophageal, or head and neck) on or after 1/1/2011, treated with an ICI with follow-up through 12/31/2018 and with baseline liver or renal function results in the EHR ≤30 days prior to ICI start. Organ function was stratified as normal, mild, moderate, or severe dys based on NCI CTCAE. We computed unadjusted median estimates for rw time to treatment discontinuation (rwTTD) for any reason and overall survival (OS) across baseline groups using the Kaplan-Meier method. Results: Of 15,979 pts, we identified 12,978/12,840 pts with evaluable renal/liver function, respectively; median follow-up was 5.1 mos and median age was 69.0 yrs (IQR: 61.0, 76.0) for both. Most pts had NSCLC (69.4/69.0%), were men (60.1/60.0%), white (73.5/73.6%), and diagnosed at stage IV (58.7%/58.6%). Most ICI was given in 1st-line (42.3/42.1%) (outcomes in Table). Conclusions: Pts with categorically worse baseline liver function had progressively worse on-treatment outcomes, including shorter OS, which differed from trends in renal dys. Whether baseline dys is prognostic or predictive of ICI outcomes should be further investigated in addition to reasons for discontinuation. Clinical outcomes (unadjusted median times, mos [95% CI]) by organ function. [Table: see text]
Identifying and predicting the most costly patients in oncology.
Authors: Mark Raymond Waddle, William C Stross, Timothy D Malouff, Tasneem Kaleem, Daniel Michael Trifiletti, Laura Vallow, Launia White, Zhuo Li, James Naessens, Aaron Spaulding, Daniel Ma, Sameer R. Keole, Robert Clell Miller
Journal: Journal of Clinical Oncology (2019)

6633 Background: Quality based payment programs in medicine are currently being introduced nationally, aimed to improve care and reduce cost. This study aimed to evaluate the top spenders (TS) after cancer diagnosis and predict TS at two separate time points using predictive analytics. Methods: Patient characteristics, cancer details, treatments, adverse events, and outcomes were collected for patients treated for cancer at Mayo Clinic from 2007 - 2017. Standardized costs over a 2 year period after first treatment were obtained from the Mayo Clinic Cost Data Warehouse with Medicare reimbursements assigned to all services and adjusted to the 2017 GDP Implicit Price Deflator for inflation. TS were identified as those with greater than 93 rd percentile costs (≥$113,158) due to a sharp rise in cost at that level. Descriptive statistics and univariate analysis were used for comparison. A prediction model with a training (80%) and validation set (20%) using multivariate selection was used to predict TS and was repeated using information available at 1) the time of consultation and 2) at last follow-up. Results: A total of 80,385 patients were included and 5,626 TS were identified. Mean cost (25 th , 75 th percentile) overall was $44,953 ($16,776, $51,889). Prediction models at time 1 and 2 had ROC AUC statistics of 0.82 and 0.89 in training and 0.82 and 0.88 in the validation indicating good prediction of high costs. Factors most predictive of TS included need for blood transfusions within 90 days of treatment (OR 5.3), bone marrow transplant (OR 4.0), mild liver disease (OR 3.5), hemiplegia (OR 3.4), weight loss &gt; 10% within 90 days of treatment (OR 3.3), upper GI cancer (OR 3.0), ‘other’ cancer type (OR 2.8), immunotherapy use (OR 2.7), and hospitalizations within 90 days (OR 2.4), all p &lt; 0.001, among others. The largest costs were due to hospital services in the TS and non-TS groups, mean costs $114,258 and $13,185 respectively. Conclusions: This is the first study to predict with high accuracy the top spenders in Oncology. Patient comorbidities and toxicities were among the strongest predictors of high costs, along with certain treatments (bone marrow transplant and immunotherapy). Our findings suggest that quality payment programs should adjust for comorbidities, and that reducing toxicity may be an effective method at reducing costs.
Sustainable responses in metastatic melanoma patients with/without brain metastases after immunotherapy induced CR.
Authors: Florentia Dimitriou, Egle Ramelyte, Clara Allayous, Camille L. Gérard, Katharina C. Kähler, Frédéric Toussaint, Sarah Schäfer, Jessica Cecile Hassel, Lucie Heinzerling, Axel Hauschild, Olivier Michielin, Celeste Lebbe, Ralph P Braun, Reinhard Dummer, Joanna Mangana
Journal: Journal of Clinical Oncology (2019)

e21042 Background: Immunotherapy (IT) has demonstrated an improved overall survival (OS) in advanced melanoma with 15% complete responses (CR) in treatment-naïve patients (pts) with brain metastases (met) in the anti-PD1/anti-CTLA4 combination. However, data on brain-met pts who discontinue treatment (EoT) after achieving a CR are lacking. Methods: Disease characteristics and clinical outcome were retrospectively collected from 6 centers on advanced melanoma pts treated with anti-PD1 or anti-PD1/anti-CTLA4. Pts were followed for at least 10 weeks (10.8 – 242). Off-treatment survival (OTS) was defined as time between last IT dose to disease progression or death. Results: Out of 890 pts, 62 achieved a CR; 40 pts stopped treatment due to CR, while 22 due to an adverse event (AE) (n = 19) or investigator decision (n = 3) with subsequent CR. 14 were treated with anti-PD1/anti-CTLA4 and 48 with anti-PD1. 24 had a BRAF mutation, of which 10 had previously received targeted therapy (TT). The median time to first CR was 31 weeks (6 – 138), median duration of response and OTS was 91.1 and 60.7 (10.6 – 242) weeks respectively. OTS was numerically longer for those pts with EoT after AE (85 weeks, 13-242) versus those with EoT due to CR (60 weeks, 11-130). Median OS was not reached. 6/62 (3%) progressed after EoT; 4 locoregionally while 2 were subsequently treated with IT. All pts were alive at last follow-up. 19 pts had brain mets. 8 were BRAF mutated. 10 were treatment naïve, 6 received previously anti-CTLA4, 1 chemotherapy and only 2 TT. Data on reasons for EoT and responses in brain mets are seen in the table. Conclusions: Early data suggest that OTS is numerically longer in patients with EoT due to AE with subsequent CR. EoT due to sustained CR is a feasible option also in brain mets. EoT due to AE with subsequent CR was a more frequent event in the combination treatment. [Table: see text]
ml-RECIST: Machine learning to estimate RECIST in patients with NSCLC treated with PD-(L)1 blockade.
Authors: Kathryn Cecilia Arbour, Luu Anh Tuan, Hira Rizvi, Adam Yala, Matthew David Hellmann, Regina Barzilay
Journal: Journal of Clinical Oncology (2019)

9052 Background: Real-world evidence (RWE) is increasingly important for discovery and may be an opportunity for regulatory approval. Effective use of RWE relies on determining treatment-specific outcomes, such as overall response rate (ORR) and progression-free survival (PFS), which are challenging to accurately evaluate retrospectively and at scale. We hypothesized the use of machine learning of text radiology reports from patients with NSCLC treated with PD-1 blockade could be used to train a model that estimates RECIST-defined outcomes. Methods: 2753 imaging reports from 453 patients with advanced NSCLC treated with PD-1 blockade were collected and separated into independent training (80%, n = 362) and validation (20%, n = 92) cohorts. Reports were limited to interval of PD-1 blockade. RECIST reads performed by thoracic radiologists on all patients served as “gold standard” to determine ORR, occurrence of, and date of progression. Baseline reports were compared to all follow up reports to determine machine-learning RECIST (ml-RECIST). A four layers neural-network model for classification was proposed to solve the three above tasks. Results: In the training cohort, ml-RECIST best estimated ORR by RECIST (accuracy CR/PR 84%, SD 82%, POD 91%). ml-RECIST estimated PFS by RECIST accurately predicting progression occurred at any time (86%) and exact progression date (65%). Date of progression was closely correlated (Pearson’s r coefficient = 0.91, 95% CI:0.89-0.94, p &lt; 0.001) in patients determined to have progressed by both methods. Similar accuracy of ml-RECIST was observed in the validation cohort (accuracy CR/PR 84%, SD 80%, POD 90%; progression occurred 86%, progression date 72%). Accuracy was consistent when RECIST reads were performed prospectively as part of clinical trials vs retrospectively for standard of care treatment (e.g. CR/PR 82% vs 88%, respectively). ml-RECIST-defined response similarly determined improvement in overall survival compared to RECIST (HR = 0.19, p &lt; 0.001 vs HR = 0.26, p &lt; 0.001 respectively). Conclusions: Machine learning-RECIST ("ml-RECIST") accurately estimates outcomes using imaging text reports. ml-RECIST may be tool to determine outcomes expeditiously and at scale for use in RWE studies, enabling more useful and reliable applications of large clinical databases.
Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.
Authors: Salah-Eddin Al-Batran, Claudia Pauligk, Ralf Hofheinz, Sylvie Lorenzen, Andreas Wicki, Alexander Rheinhard Siebenhuener, Michael Schenk, Manfred Welslau, Vera Heuer, Eray Goekkurt, Harald Schmalenberg, Peter C. Thuss-Patience, Lisa Waberer, Jonathan Talbot, Thorsten Oliver Goetze, Nils Homann
Journal: Journal of Clinical Oncology (2019)

TPS4142 Background: Perioperative FLOT chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient outcomes are still unsatisfactory and 5-year survival in T3-4 or nodal positive disease is still around 50%. Targeting the PD-1/PD-L1 pathway has proven active in different cancers, including esophagogastric cancer, and was associated with response rates in the 10-15% range in unselected, heavily pre-treated gastric cancer patients. Atezolizumab is a PD-L1 inhibitor with established efficacy and tolerability profiles. This study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with FLOT. Methods: This is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Eligibility status is centrally evaluated. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS) as assessed by the Kaplan-Meier-Method. The statistical design is based on a target HR of 0.68, a power of 0.8, and a significance level of p&lt; 0.05 (1-sided log rank test). A total of 295 patients will be randomized. Main secondary endpoints are rates of centrally assessed pathological regression (rates of complete and nearly complete pathological regression), overall survival, R0 resection, and safety. Recruitment started in Sept 2018; by February 2019, a total of 27 patients have been randomized. Clinical trial information: NCT03421288.
Ibrutinib and Venetoclax for First-Line Treatment of CLL
Authors: Nitin Jain, Michael Keating, Philip Thompson, Alessandra Ferrajoli, Jan Burger, Gautam Borthakur, Koichi Takahashi, Zeev Estrov, Nathan Fowler, Tapan Kadia, Marina Konopleva, Yesid Alvarado, Musa Yilmaz, Courtney DiNardo, Prithviraj Bose, Maro Ohanian, Naveen Pemmaraju, Elias Jabbour, Koji Sasaki, Rashmi Kanagal-Shamanna, Keyur Patel, Jeffrey Jorgensen, Naveen Garg, Xuemei Wang, Katrina Sondermann, Nichole Cruz, Chongjuan Wei, Ana Ayala, William Plunkett, Hagop Kantarjian, Varsha Gandhi, William Wierda
Journal: New England Journal of Medicine (2019)

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.
Patients’ understanding and adherence to oral anti-cancer medication (OAM): Results of an institutional pilot study.
Authors: Angie Mae Rodday, Douglas W Hackenyos, Raisa Masood, Nicole Savidge, Mingqian Lin, Daqin Mao, Feng Qing Wang, Rachel Murphy-Banks, Ruth Ann Weidner, Rachel J. Buchsbaum, John Kalil Erban, Susan K. Parsons
Journal: Journal of Clinical Oncology (2019)

e18280 Background: Advancements in biopharmaceuticals have led to increasing availability and use of OAM. While oral medications allow patients (pts) to receive treatment at home, OAM use introduces new challenges related to prescription filling, monitoring for and reporting of side effects, safe medication handling, and adherence. We assessed understanding of and adherence to OAM in pts vulnerable to these home-based challenges. Methods: This 2018 pilot study defined vulnerable pts based on spoken language (Chinese), older age (≥65 yrs), and public insurance ( &lt; 65 yrs). All pts had a cancer diagnosis, had been taking an OAM, and received prescriptions through the hospital’s specialty pharmacy. Prior to a clinic visit, pts completed patient-reported measures about OAM taking and handling. Clinical characteristics were extracted from medical records; medication information was extracted from pharmacy records. The study team’s specialty pharmacist (DH) classified patient-reported responses about OAM taking (days per week, times per day, special instructions) and handing (handling, storage, disposal) as adequate or inadequate. OAM regimens were classified by complexity based on number of drugs and schedule. Results: Of 61 eligible pts, 55 participated (90%). Mean age was 68 yrs (SD 12) and 53% were female. Pt subgroups were: 27% Chinese, 64% ≥65 yrs, and 9% &lt; 65 yrs with public insurance. 33% had solid tumor and 67% had hematologic malignancy; tyrosine kinase inhibitor was the most OAM type (42%). 49% of pts were on front-line therapy and overall median time on OAM was 1 year (Q1 0.4, Q3 1.7). Adequacy of OAM taking (30%) and handling (15%) were low; only 15% had adequacy in both. Pt subgroup and regimen complexity did not vary by adequacy of OAM taking or handling. Patient-reported adherence was high 5.4 (SD 1) (possible range 1-6) and did not vary by adequacy of OAM taking or handling. Conclusions: Understanding of how OAM should be taken and handled in a group of vulnerable pts was strikingly low and did not align with pts’ self-reports of adherence. Future interventions are needed to ensure that pts understand how to safely take and handle OAM, thereby optimizing their therapeutic potential.
DPP4 inhibitors as novel agents in improving survival in patients with prostate cancer: A SEER-Medicare study.
Authors: Chintan Shah, Young-Rock Hong, Rohit Bishnoi, azka ali, William Paul Skelton, Long H. Dang, Jinhai Huo, Nam H. Dang
Journal: Journal of Clinical Oncology (2019)

e16532 Background: Dipeptidyl peptidase-4 (DPP4) is a cell surface protein expressed in variable amounts on different tissues and plays a vital role in tumor biology as well as regulation of the immune system. In-vitro studies have shown that the DPP4 biochemical activity is twice as high in prostate cancer cells compared to benign prostate tissues. Furthermore, blocking of DPP4 activity in-vitro was demonstrated to inhibit tumor angiogenesis and tumor invasiveness through a number of cellular mechanisms. Meanwhile, DPP4 expression is modest in normal as well as cancerous pancreatic cells. Methods: Using linked SEER and MEDICARE database, we identified patients with prostate cancer (PRC) or pancreatic cancer (PC) with coexisting type II diabetes mellitus. Furthermore, we analyzed the impact of DPP4 inhibition in the overall survival (OS) in these patients between 2001 and 2013. Analyses were performed using SAS, version 9.4. We excluded patients taking metformin. Results: We identified 7229 patients with PRC and 2401 patients with PC. OS was significantly better in PRC patients taking DPP4 inhibitors (262 patients) with HR 0.75 (95% CI: 0.59-0.97; P = 0.02) compared to those not on DPP4 inhibitors. Meanwhile, for patients with PC, OS was not significantly different between patients taking DPP4 inhibitors (177 patients) compared to those who were not (HR 1.03; 95% CI: 0.88-1.21; P = 0.7). Subgroup analyses of PRC patients demonstrated a trend toward a beneficial effect of DPP4 inhibitors, irrespective of stage (stage I, NR; stage II, HR 0.81; stage III, NR; stage IV, 0.76),use of chemotherapy (HR 0.83 with chemotherapy and HR 0.70 without chemotherapy) or hormonal use (ADT) (HR 0.87 with ADT and HR 0.71 without ADT), prostatectomy (HR 0.50 with prostatectomy and HR 0.77 with no prostatectomy) or radiation (HR 0.89 with radiation and HR 0.64 without radiation). Conclusions: This is the first population-based analysis showing the OS benefit of DPP4 inhibitors in PRC patients. On the other hand, OS was not improved in PC patients taking DPP4 inhibitors likely due to low levels of expression of DPP4 cell surface protein on pancreatic tissues. A prospective trial would help confirm our findings.
The continued osimertinib plus chemotherapy overcoming resistance after histologic transformation in <i>EGFR</i>-mutant lung adenocarcinoma treated with osimertinib.
Authors: Jin Kang, Xiang-Meng Li, Jia-Tao Cheng, Huajun Chen, Xuchao Zhang, Hai-Yan Tu, Qing Zhou, Yi-Long Wu, Jin-Ji Yang
Journal: Journal of Clinical Oncology (2019)

e20615 Background: Although the third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is more potent, histologic transformation from lung adenocarcinoma to other histological types is still a mechanism of resistance in EGFR-mutant adenocarcinoma. Those with histologic transformation usually have poor prognosis. Hence, we focused on the unique molecular mechanism of histologic transformation after osimertinib and explore the strategy of treatment. Methods: Pathology was confirmed in 55 EGFR-mutant patients treated with osimertinib at baseline and disease progression. They were all lung adenocarcinoma at baseline. We established the patient-derived xenograft (PDX) mouse model from an EGFR-mutant adenocarcinoma transforming to neuroendocrine carcinoma. Preclinical efficacy of erlotinib versus osimertinib was evaluated in vivo. All the clinical data of these patients were analyzed. Results: The frequency of histologic transformation after resistance to osimertinib was 14.5% (8/55). Three of them were transformed to small-cell lung cancer totally, two transformed to complex small-cell lung cancer, two transformed to adenosquamous cell carcinoma and one transformed to neuroendocrine carcinoma without T790M mutation in which an PDX mouse model was successfully established. The genetic profiles of those transformed to small-cell lung cancer were characterized by Rb1, TP53 mutations, and PI3K/AKT/MTOR aberrances. Those transformed to adenosquamous carcinoma were characterized by KRAS amplification and EGFR amplification. The median progression-free survival (PFS) was not significantly different between the patients with histologic transformation and those without during the treatment of osimertinib (7.7 VS. 5.7 months, P = 0.763). One went on first-line osimertinib, added etoposide/ cisplatin (EP) chemotherapy meanwhile after progressive disease, and achieved minor response after 2 cycles. The other one received the treatment of EP + osimertinib + erlotinib, and acheived partial response with a PFS of 7 months without obvious toxicities. The PDX model showed more sensitivity to erlotinib than osimertinib. Conclusions: Continued osimertinib plus chemotherapy might be effective in overcoming the resistance. Particularly, the first-generation EGFR-TKI seems to be efficacious in histologically-transformed EGFR-mutant patients without T790M mutation. Further investigations of these patients and PDXs are warranted.