tbuckley/cabot-search huggingface dataset:
Can we satisfactorily measure the clinical value of new oncology agents with a single summary measure?
Authors: Clare Frances Jones, Giles Monnickendam, Mingshu Zhu, Jan McKendrick
Journal: Journal of Clinical Oncology (2017)

6606 Background: Current value frameworks (VFs) assess clinical value primarily through using clinical trial endpoints as survival metrics (e.g., median and hazard ratio (HR)). But, if key assumptions do not hold, the interpretation of these summary statistics can become problematic and fail to adequately capture the expected benefit to a patient. This has been observed with innovative oncology treatments. As a proof of concept analysis, we reviewed how two VFs (ASCO and ESMO) dealt with cases where the assumption of proportional hazards (PH) does not hold. Methods: Oncology agents approved by the FDA since 2011 were reviewed and three agents were identified with survival profiles where the assumption of PH was found not to hold because, on visual inspection, the survival curves displayed non-standard patterns: Divergence followed by convergence – panobinostat OS in RRMM; Curves initially track together then diverge – nivolumab OS in NSCLC; Curves diverge steadily then a plateau emerged in the active treatment curve – pembrolizumab PFS in refractory melanoma. We evaluated these agents to assess which measures of clinical benefit were most valued under each VF and how the issue of non-PH influenced the outcome. Results: Clinical benefit/value scores varied: ASCO: 14-27 (maximum 100), ESMO: grade 1-3. The ASCO VF uses a hierarchical approach (incorporating HR and median survival benefit, always prioritising the former) adding a bonus for survival benefit in the tail of the distribution. The combination of HR, median survival benefit 2 and 3 year survival rates in the ESMO non-curative VF can potentially capture aspects of clinical benefit in some cases of non-PH. Overall, the ASCO VF appears less flexible to accommodate non-PH than the ESMO VF. Conclusions: Despite VFs using summary statistics which cannot be easily interpreted under conditions of non-PH, the case of non-PH is not explicitly catered for. Additionally, both VFs may miss important interpretation where value is differentiated across patients groups with different response profiles which may underlie non-standard survival curves. In these situations, a more flexible approach to assessing clinical value may render VFs more relevant for clinical decision making.
Genome-wide screen of DNA methylation study in stage IIIa (N2) EGFR 19 deletion adenocarcinoma with erlotinib treatment.
Authors: Xiaomin Niu, Fatao Liu, Yi Zhou, Daizhan Zhou, Ziming Li, Xiangyun Ye, Yongfeng Yu, Yun Liu, Zhiwei Chen, Shun Lu
Journal: Journal of Clinical Oncology (2016)

e20067 Background: Lung cancer is the leading cause of cancer related death in the world. The challenge of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) will be an issue in EGFR directed targeted therapies in lung adenocarcinoma. Methods: Methyl-sensitive cut counting sequencing (MSCC), one of the most commonly used whole-genome DNA methylation sequencing technology, was applied to investigate the changes of paired tissue DNA methylation before and after TKI (erlotinib) treatment lasting two cycles with partial response (PR) for stage IIIa (N2) lung adenocarcinoma patients (N = 2) with activating EGFR 19 deletion. Sequenom EpiTYPER assay method was further analyzed to double confirm the changed methylated candidate genes through comparing the methylated changes in paired tissues before and after TKI treatment. Western blotting, cell cycle and apoptosis analysis by the candidate gene (GABBR2) knockout and overexpression using siRNA technology were performed in one EGFR wild type cell line (A549), and two EGFR 19 deletion cell lines (HCC4006 and HCC827) to elucidate the mechanism of GABBR2 gene in the regulation of EGFR-TKI treatment. Results: Sixty aberrant methylated genes were first screened using MSCC method. Two methylated genes, CBFA2T3 and GABBR2, were clearly validated by the Sequenom EpiTYPER assay, subsequently. GABBR2 was significantly down regulated in HCC4006 and HCC827 cells but remained conservative in A549 cells after erlotinib treatment by Western blotting. The phenomenon was in line with the obvious apoptosis of HCC4006 and HCC827 cell lines, but not in A549 cells, using cell cycles and apoptosis analysis. GABBR2 was further induced down regulation after erlotinib exposure through apoptosis method silenced by siRNA using RNAi technology. Meanwhile, GABBR2 gene was demonstrated up regulation rescued the apoptosis significantly, when overexpressing GABBR2 in HCC827 cell lines along with erlotinib treatment. Conclusions: Genome-wide screen of DNA methylation changes demonstrated that GABBR2 gene might be as a novel potential treatment target for stage IIIa (N2) EGFR 19 deletion adenocarcinoma with erlotinib treatment.
Predicting overall survival in patients (pts) with treatment-naive metastatic Merkel cell carcinoma (mMCC) treated with avelumab.
Authors: Ash Bullement, Sandra P. D'Angelo, Amerah Amin, Ceilidh Stapelkamp, Anna Willis, Cameron Lilley, Anthony Hatswell, Murtuza Bharmal
Journal: Journal of Clinical Oncology (2018)

e21620 Background: Data from the JAVELIN Merkel 200 (JM 200) trial of avelumab in mMCC with a minimum follow-up of 18 mo for 88 pts who had received prior chemotherapy demonstrated robust survival estimates. Available data for treatment-naive pts are less mature due to partial enrolment (Mar 24, 2017 data cut: 6 wk min follow-up, 39 pts enrolled). To enable treatment reimbursement decisions, health technology assessment agencies require long-term survival data. To provide this, the current analysis used novel statistical extrapolation methods (based on JM 200 data) to predict overall survival for treatment-naive pts with mMCC treated with avelumab. Methods: Flexible parametric models using data from both the prior treatment and treatment-naive populations were fitted, and a stitching analysis was used to combine extrapolations. Resulting survival estimates were compared with observed survival data in both populations, and the extrapolated mean survival time was calculated. Results: Extrapolation using early data from the treatment-naive cohort demonstrated that the hazard of death was greater for prior treatment pts than for treatment-naive pts after 21 mo. Assuming the same extrapolation for treatment-naive pts as for prior treatment pts produced more realistic estimates of the hazard of death after 21 mo but underestimated survival for treatment-naive pts before this time. The stitching analysis avoided the aforementioned issues, although it may still underestimate survival given the reliance on longer-term prior treatment data. Survival estimates are in the table. Conclusions: The use of novel extrapolation methods quantifies the expected long-term survival associated with avelumab in treatment-naive pts, which is expected to be at least as good as the prior treatment population despite the lack of long-term data. While survival extrapolations are promising, maturing data from the ongoing JM 200 trial will aid validation of these estimates. Extrapolation Method Survival Estimate Mean (2.5th, 97.5th percentiles), mo 1-y, % 5-y, % Treatment-naive data 49.9 (6.3, 179.4) 66 23 Prior treatment data 42.3 (28.4, 77.4) 51 19 Stitching analysis 54.9 (27.4, 70.6) 66 25
Sorafenib plus 5-azacytidine (AZA) in older untreated <i>FLT3</i>-ITD mutated AML.
Authors: Maro Ohanian, Guillermo Garcia-Manero, Mark J. Levis, Elias Jabbour, Naval Guastad Daver, Gautam Borthakur, Tapan M. Kadia, Mark Brandt, Sherry Pierce, Jan Andreas Burger, Mary Ann Richie, Keyur Patel, Jorge E. Cortes, Hagop M. Kantarjian, Farhad Ravandi
Journal: Journal of Clinical Oncology (2017)

7029 Background: Sorafenib plus 5-azacytidine (AZA) is observed to be safe and effective in relapsed / refractory FLT3-ITD mutated acute myeloid leukemia (AML) patients (pts). Hypothesis: Combining sorafenib with AZA is safe and effective in older untreated FLT3-ITD mutated AML pts. Methods: Eligibility included: untreated FLT3-ITD mutated AML (≥10% mutation burden), age ≥60 yrs, adequate organ function, and ECOG performance status ≤ 2. The regimen was: AZA 75 mg/m 2 daily x 7 days and sorafenib 400 mg twice daily for 28 days. Results: 26 pts with untreated AML [median age 73 (61-86)] were enrolled: 16 (62%) pts had normal karyotype, 2 (8%) complex karyotype, 4 (15%) other miscellaneous abnormalities, and 4 (15%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all pts with a median allelic ratio of 0.3735 (0.009-0.885). The overall response rate (ORR) in 25 evaluable pts was (76%) [7 (28%) with CR, 10 (40%) CRi/CRp, and 2 (8%) PR]. Pts underwent a median of 3 (1-35) treatment cycles. The median number of cycles to response was 2 (1-4), and the median time to achieve response, 1.77 months (mos) (0.689-4.271 mos). The median duration of CR/CRp/CRi is 14.5 mos (1.18—28.74). Three (18%) responding pts (CR, CRp, CRi) have proceeded to allogeneic stem cell transplant. With a median follow-up of 6.8 mos (0.2-18.8), 6 pts are alive, 3 in remission (CR/CRP/CRi). The median overall survival (OS) for the entire group is 8.3 mos; 9.2 mos in 17 responders. Evaluable pts treated with AZA + sorafenib (n = 25) were compared to a matched cohort of historical FLT3-ITD mutated pts &gt; 60 yrs, but treated with hypomethylator-based (HMA) therapy without sorafenib (n = 20); the respective ORR (CR, CRp, CRi, PR) (76% vs. 70%, p = 0.653) and median OS (8.3 and 9.4 mos, p = 0.69) were similar. The remission duration for the responding pts treated with AZA+sorafenib was significantly longer (14.5 mos) than those on other HMA regimens without sorafenib (3.8 mos) (p = 0.01). Adverse events possibly attributable to the regimen included: grade (Gr) 1/2 nausea (n = 3), Gr 1/2 diarrhea (n = 2), Gr 1 dyspnea (n = 1), and Gr 1 breast pain (n = 1). Conclusions: The combination of AZA and Sorafenib is both well tolerated and effective in older untreated FLT3-ITD mutated AML. Clinical trial information: NCT02196857;NCT01254890.
Trends in Risks for Second Primary Cancers Associated With Index Human Papillomavirus–Associated Cancers
Authors: Ryan Suk, Parag Mahale, Kalyani Sonawane, Andrew G. Sikora, Jagpreet Chhatwal, Kathleen M. Schmeler, Keith Sigel, Scott B. Cantor, Elizabeth Y. Chiao, Ashish A. Deshmukh
Journal: JAMA Network Open (2018)

IMPORTANCEIn the last 4 decades, survival among patients with human papillomavirus (HPV)associated cancers has improved, while the incidence of these cancers has increased among younger cohorts.Among survivors of HPV-associated cancers, persistent HPV infection may remain a risk factor for preventable HPV-associated second primary cancers (HPV-SPCs).OBJECTIVES To investigate the risk of HPV-SPCs among survivors of HPV-associated index cancers and to test the hypothesis that the HPV-SPC risk among these persons has increased over the last 4 decades. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study of 9 cancer registries of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to identify patients with HPV-associated (cervical, vaginal, vulvar, oropharyngeal, anal, and penile) cancers diagnosed from January 1, 1973, through December 31, 2014.The dates of analysis were July 1, 2017, to January 31, 2018. MAIN OUTCOMES AND MEASURESThe HPV-SPC risk was quantified by calculating standard incidence ratios (SIRs) and excess absolute risks (EARs) per 10 000 person-years at risk (PYR).The HPV-SPC risk by time was estimated using Poisson regression. RESULTSFrom 113 272 (73 085 female and 40 187 male) survivors of HPV-associated cancers, 1397 women and 1098 men developed HPV-SPCs.The SIRs for HPV-SPCs were 6.2 (95% CI, 5.9-6.6)among women and 15.8 (95% CI, 14.9-16.8)among men.The EARs were 18.2 per 10 000 PYR for women and 53.5 per 10 000 PYR for men.Among both women and men, those who had index oropharyngeal cancers had the highest HPV-SPC risk (SIR, 19.8 [95% CI, 18.4-21.4]and EAR, 80.6 per 10 000 PYR among women; SIR, 18.0 [95% CI, 16.9-19.1]and EAR, 61.5 per 10 000 PYR among men).Women who had index cervical cancers and men who had index anal cancers had the lowest HPV-SPC risk (SIR, 2.4 [95% CI, 2.2-2.7] and EAR, 4.5 per 10 000 PYR among women; SIR, 6.5 [95% CI, 4.7-8.8]and EAR, 18.5 per 10 000 PYR among men).Both women and men who had index HPV-associated cancers of any kind had a significantly higher risk of oropharyngeal HPV-SPCs.Over the last 4 decades, the risk of developing most types of HPV-SPCs after index cervical, vaginal, and vulvar cancers increased. CONCLUSIONS AND RELEVANCEAccording to this study, the HPV-SPC risk among survivors of HPV-associated cancers is significant, implying that persistent HPV infection at multiple sites may be associated with HPV-SPCs.These findings have the potential to inform surveillance recommendations for survivors of HPV-associated cancers.
Phase 1b extension study of cancer stemness inhibitor BB608 (napabucasin) administered in combination with FOLFIRI +/- bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC).
Authors: Bert H. O'Neil, Joleen Marie Hubbard, Alexander Starodub, Derek J. Jonker, William Jeffery Edenfield, Bassel F. El-Rayes, Thorvardur Ragnar Halfdanarson, Ramesh K. Ramanathan, Henry C. Pitot, Carolyn D. Britten, Bamidele Adesunloye, Axel Grothey, Laura Borodyansky, Chiang Li
Journal: Journal of Clinical Oncology (2016)

3564 Background: BB608 (aka Napabucasin, BBI-608) is an oral first-in-class cancer stemness inhibitor targeting Stat3-driven gene transcription. Anti-tumor activity was observed in vitro and in vivo. BB608 showed safety and encouraging signs of anti-cancer activity in phase I/II studies. Methods: A phase Ib extension multi-center study in pts with advanced CRC was undertaken to confirm the RP2D and signs of anti-cancer activity of BB608 in combination with FOLFIRI +/- Bev. BB608 was administered continuously at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2 infusion) +/- Bev 5 mg/kg, administered bi-weekly until disease progression, unacceptable toxicity, or other discontinuation criterion. Results: 46 pretreated CRC pts who had failed an average of > 2 prior lines of therapy were enrolled; including 20 pts (43.5%) previously progressed on FOLFIRI +/- Bev. Of the 46 pts, 14 received FOLFIRI and 32 FOLFIRI with Bev in combination with BB608. There was no dose-limiting or unexpected toxicity or significant pharmacokinetic interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. Grade 3 AEs observed in 15 pts included diarrhea (9), fatigue (3), dehydration/hyponatremia (1), hypokalemia (1) and burning in rectum (1) resolved with dose reduction and/or supportive care. Disease control (PR+SD) was observed in 37 of 40 evaluable pts (93%), with partial response (PR) in 11 pts (28%) (RECIST 1.1 30-65% regression), and stable disease with tumor regression in 21 pts (53%). Among 19 pts who had progressed on FOLFIRI +/- Bev previously and were evaluable for tumor assessment, disease control (PR+SD) was observed in 17 pts (90%), tumor regression was observed in 15 pts (80%) of which 6 pts achieved PR (32%). Conclusions: This phase Ib extension study confirmed that BB608 can be safely combined with FOLFIRI +/- Bev, and shows encouraging signs of anti-tumor activity in CRC pts, including pts who had previously progressed on FOLFIRI +/- Bev. Clinical trial information: NCT02024607.
Phase II feasibility study of rekindle: An online psychosexual intervention for cancer survivors and/or their partners.
Authors: Catalina Rosario Lawsin, Kevin McGeechan, Douglas O Williams, Phyllis Butow, Ilona Juraskova, Kim Hobbs, Frances M. Boyle, Judy Kay, Annie Miller, Haryana M. Dhillon
Journal: Journal of Clinical Oncology (2017)

e21597 Background: Changes to sexual wellbeing can negatively impact long-term quality of life for cancer patients and their partners. Rekindle is an online intervention aimed to provide accessible and tailored psychosexual support to cancer survivors. This study aimed to assessed the feasibility of delivering psychosexual support via Rekindleto cancer survivors and partners who self-report unmet sexual concerns. Methods: This phase II feasibility study, recruited Australian adult cancer survivors who had completed primary therapy &gt; 6 months earlier and/or their partners. Participants were randomized 1:2:1 ratio to either: i) wait list control (WC); ii) Rekindle (10-week online intervention addressing psychoeducational sexual communication and function) (Int); iii) Rekindle Plus ( Rekindleintervention plus three support telephone calls) (Int+). Intervention ran for 10 weeks, after which WC group had access to Int. Participants completed assessments at baseline (T1), intervention end/10 weeks (T2), and six months (T3). The primary feasibility endpoint was the proportion of participants completing prescribed intervention modules. Results: Nov 2015-Dec 2016, 100 participants were randomized: WC: 19, Int: 54, Int+: 27. Baseline characteristics were matched across groups. 57% were male and 91% cancer survivors; 46% had prostate and 23% breast cancer. Participants were prescribed a mean of 6.5 out of 7 modules based on self-reported unmet sexual needs. They completed mean of 1.9 (Int) and 2.5 (Int+) modules with 30% (Int) and 38% (Int+) completed within 10 weeks. A high proportion of users (94%, 100%) commenced Module 1 (Foundations). The largest drop-out between occurred between Modules 1 and 2. Once started, the majority of participants completed each module (76-100%). The mean number of days taken to complete each module varied (4-14 days). Factors impacting engagement with the intervention will also be reported. Conclusions: This phase II study has demonstrated: a need for psychosexual support amongst cancer survivors, that it is feasible to recruit them into an online sexual support study, and to deliver online psychoeducational content for sexual concerns. Clinical trial information: ACTRN12614001245684.
Application of multi-agent CT among patients with leg-type primary cutaneous B-cell lymphoma.
Authors: Sarah Swati Pai, Beant Singh Gill, Stanley M. Marks, John Austin Vargo, Goundappa K Balasubramani, David Andrew Clump, Sushil Beriwal
Journal: Journal of Clinical Oncology (2016)

7560 Background: Although most primary cutaneous B-cell lymphomas (PCBCL) are highly curable, leg-type PCBCL (PCBCL-LT) is a rare variant with high rates of extracutaneous relapse. Using the National Cancer Data Base (NCDB), cases of PCBCL-LT were evaluated to determine practice patterns and outcomes with the addition of chemotherapy (CT). Methods: Cases diagnosed from 1998-2012 with PCBCL-LT were identified. Information abstracted included age, Charlson-Deyo comorbidity score, disease status (AJCC stage, B symptoms) and treatment characteristics (CT use, type: single vs. multi-agent, surgical procedure and radiotherapy). Bivariate logistic regression was utilized to determine factors associated with CT use. Univariate and multivariable survival analyses were conducted using log-rank test and Cox proportional hazards modeling. Results: In total, 529 patients were identified with a median age of 77 years. Over half (54.6%) received CT, of which 85.5% received multi-agent regimens. CT use increased over time (52.5% 1998-2004 vs. 67.4% 2009-2012, p= 0.003). Older patients ( > 80 years) or those receiving radiotherapy were less likely to receive CT while patients with higher disease stage or B symptoms were more likely to receive CT. With 31.9-month median follow-up, the 3- and 5-year overall survival (OS) estimates were 56.0 and 39.9%, respectively. Receipt of CT resulted in a trend towards improved overall survival on univariate analysis (3-year OS 49.2 vs. 61.1%, p= 0.058). Highest survival rates were seen in those receiving CT-containing treatment regimens and with multi-agent CT. On multivariable analysis, along with lower age, lower stage and radiotherapy, multi-agent CT reduced the risk of overall mortality (HR 0.58, 95% confidence interval [CI] 0.39-0.85, p= 0.006) while single-agent CT trended towards a higher risk (HR 1.16, 95% CI 0.71-1.89, p= 0.546). Using a 4-month conditional landmark, multi-agent CT maintained a trend towards overall mortality risk reduction (HR 0.86, p= 0.323). Conclusions: Through use of a national hospital-based registry, this represents the largest published cohort of PCBCL-LT, confirming poor survival rates and a potential benefit to the use of multi-agent CT.
Risk stratification and predictive value of the HOSPITAL score for oncology patient readmissions.
Authors: Anu Radha Neerukonda, Blase N. Polite, Mark Connolly
Journal: Journal of Clinical Oncology (2018)

6548 Background: Hospital readmissions are costly, frequent and harmful. Prediction models such as the HOSPITAL scoring system are reasonably accurate and efficient in predicting the readmission risk after hospital discharge in a general medicine population. However, their utility remains unknown for cancer patients. HOSPITAL is the acronym for 7 variables included in the score: Hemoglobin before discharge (positive if < 12 g/dl), discharge from an Oncology service, Sodium level before discharge (positive if < 135 mmol/L), Procedure performed during hospitalization, Index admission Type, number of Admissions in the previous 12 months, and Length of stay (positive if ≥ 5 days). Methods: We retrospectively calculated HOSPITAL scores at the time of discharge for all oncology discharges at the University of Chicago Medical Center between November 2016 and November 2017 (N=2957). We used SQL, our internal data warehouse and electronic medical records database for data collection. The HOSPITAL score was calculated for each discharge, with each categorized into 1 of 3 risk groups based on number of points: low risk (0-4), intermediate risk (5-6), and high risk (≥7). Results: Table 1 reflects number of patients in each readmission risk category. Based on the HOSPITAL point scoring allotment described, 88% of oncology admissions were identified as intermediate or high risk, with very few patients in low risk category. This is in stark contrast to 38% of all general medicine patients who were identified as intermediate or high risk in the original publication externally validating the HOSPITAL score. Conclusions: Findings from this study indicate that HOSPITAL score may not be effective in differentiating readmission risk within an oncology specific patient population, and that other variables such as performance status need to be incorporated. Further research needs to be done for developing and validating specific readmission risk prediction models in the oncology population. Readmission rate by hospital risk group. Readmission Risk Group Number of medical oncology discharges Percentage of all medical oncology discharges Readmission Rate Low 352 11.9% 17% Intermediate 1058 35.8% 15% High 1547 52.3% 18%