Phase II Trial of Trifluridine/Tipiracil in Patients with Advanced, Refractory Biliary Tract Carcinoma

1 day 18 hours ago
AbstractLessons Learned.Trifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5‐fluorouracil refractory tumors.FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first‐line therapy.Background.Patients with advanced biliary tract carcinoma (BTC) refractory to first‐line therapy lack an established second‐line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine‐sensitive and ‐resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.Methods.Patients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression‐free survival (PFS), and toxicity.Results.Of 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.Conclusion.FTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.
Sakti Chakrabarti, Tyler J. Zemla, Daniel H. Ahn, Fang-Shu Ou, Briant Fruth, Mitesh J. Borad, Mindy L. Hartgers, Jaclynn Wessling, Rachel L. Walkes, Steven R. Alberts, Robert R. McWilliams, Minetta C. Liu, Lori M. Durgin, Tanios S. Bekaii-Saab, Amit…

Subtype‐Guided 18F‐FDG PET/CT in Tailoring Axillary Surgery Among Patients with Node‐Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: A Feasibility Study

1 day 18 hours ago
AbstractBackground.The purpose of this study was to investigate the value of 18[F]‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) in tailoring axillary surgery by predicting nodal response among patients with node‐positive breast cancer after neoadjuvant chemotherapy (NAC).Methods.One hundred thirty‐three patients with breast cancer with biopsy‐confirmed nodal metastasis were prospectively enrolled. 18F‐FDG PET/CT scan was performed before NAC (a second one after two cycles with baseline maximum standardized uptake value [SUVmax] ≥2.5), and a subset of patients underwent targeted axillary dissection (TAD). All the patients underwent axillary lymph node dissection (ALND). The accuracy was calculated by a comparison with the final pathologic results.Results.With the cutoff value of 2.5 for baseline SUVmax and 78.4% for change in SUVmax, sequential 18F‐FDG PET/CT scans demonstrated a sensitivity of 79.0% and specificity of 71.4% in predicting axillary pathologic complete response with an area under curve (AUC) of 0.75 (95% confidence interval, 0.65–0.84). Explorative subgroup analyses indicated little value for estrogen receptor (ER)‐negative, human epidermal growth factor receptor 2 (HER2)‐positive patients (AUC, 0.55; sensitivity, 56.5%; specificity, 50.0%). Application of 18F‐FDG PET/CT could spare 19 patients from supplementary ALNDs and reduce one of three false‐negative cases in TAD among the remaining patients without ER‐negative/HER2‐positive subtype.Conclusion.Application of the subtype‐guided 18F‐FDG PET/CT could accurately predict nodal response and aid in tailoring axillary surgery among patients with node‐positive breast cancer after NAC, which includes identifying candidates appropriate for TAD or directly proceeding to ALND. This approach might help to avoid false‐negative events in TAD.Implications for Practice.This feasibility study showed that 18[F]‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) could accurately predict nodal response after neoadjuvant chemotherapy (NAC) among patients with breast cancer with initial nodal metastasis except in estrogen receptor‐negative, human epidermal growth factor receptor 2‐positive subtype. Furthermore, the incorporation of 18F‐FDG PET/CT can tailor subsequent axillary surgery by identifying patients with residual nodal disease, thus sparing those patients supplementary axillary lymph node dissection. Finally, we have proposed a possibly feasible flowchart involving 18F‐FDG PET/CT that might be applied in post‐NAC axillary evaluation.
Siyu Wu, Yujie Wang, Jianwei Li, Na Zhang, Miao Mo, Suzanne Klimberg, Virginia Kaklamani, Alexandre Cochet, Zhiming Shao, Jingyi Cheng, Guangyu Liu

Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy

1 week ago
AbstractBackground.Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy.Methods.We performed a retrospective review of 90 patients enrolled on immunotherapy‐based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias‐adjusted log‐rank test. A four‐level risk stratification was used to create low‐risk (PLR <242 and nonsarcopenic), intermediate‐risk (PLR <242 and sarcopenic), high‐risk (PLR ≥242 and nonsarcopenic), and very‐high‐risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival.Results.Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high‐risk, high‐risk, and intermediate‐risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65–27.01; p < .001; HR, 5.32; CI, 1.96–14.43; p = .001; and HR, 4.01; CI, 1.66–9.68; p = .002, respectively) and progression‐free survival (HR, 12.29; CI, 5.15–29.32; p < .001; HR, 3.51; CI, 1.37–9.02; p = .009; and HR, 2.14; CI, 1.12–4.10; p = .022, respectively) compared with low‐risk patients.Conclusion.Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy‐treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents.Implications for Practice.Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk‐stratification system that combined sarcopenia and platelet‐to‐lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression‐free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk‐stratify patients who are beginning treatment with immunotherapy.
Mehmet Asim Bilen, Dylan J. Martini, Yuan Liu, Julie M. Shabto, Jacqueline T. Brown, Milton Williams, Amir I. Khan, Alexandra Speak, Colleen Lewis, Hannah Collins, Haydn T. Kissick, Bradley C. Carthon, Mehmet Akce, Walid L. Shaib, Olatun&#x0237;i B…

Novel Risk Scoring System for Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

1 week ago
AbstractBackground.The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the gold standard for risk‐stratifying patients with metastatic renal cell cancer (mRCC). We developed a novel risk scoring system for patients with mRCC treated with immune checkpoint inhibitors (ICIs).Methods.We performed a retrospective analysis of 100 ICI‐treated patients with mRCC at Winship Cancer Institute from 2015 to 2018. Several baseline variables were collected, including markers of inflammation, body mass index (BMI), and sites of metastatic disease, and all were considered for inclusion in our risk scoring system. Upon variable selection in multivariable model, monocyte‐to‐lymphocyte ratio (MLR), BMI, and number and sites of metastases at baseline were used for risk score calculation. Patients were categorized using four‐level risk groups as good (risk score = 0), intermediate (risk score = 1), poor (risk score = 2), or very poor (risk score = 3–4). Cox's proportional hazard model and the Kaplan‐Meier method were implemented for survival outcomes.Results.Most patients were male (66%) with clear cell renal cell carcinoma (72%). The majority (71%) received anti–programmed cell death protein‐1 monotherapy. Our risk scoring criteria had higher Uno's concordance statistics than IMDC in predicting overall survival (OS; 0.71 vs. 0.57) and progression‐free survival (0.61 vs. 0.58). Setting good risk (MLR <0.93, BMI ≥24, and D_Met = 0) as the reference, the OS hazard ratios were 29.5 (95% confidence interval [CI], 3.64–238.9), 6.58 (95% CI, 0.84–51.68), and 3.75 (95% CI, 0.49–28.57) for very poor, poor, and intermediate risk groups, respectively.Conclusion.Risk scoring using MLR, BMI, and number and sites of metastases may be an effective way to predict survival in patients with mRCC receiving ICI. These results should be validated in a larger, prospective study.Implications for Practice.A risk scoring system was created for patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. The results of this study have significant implications for practicing oncologists in the community and academic setting. Importantly, these results identify readily available risk factors that can be used clinically to risk‐stratify patients with metastatic renal cell carcinoma who are treated with immune checkpoint inhibitors.
Dylan J. Martini, Yuan Liu, Julie M. Shabto, Bradley C. Carthon, Emilie Elise Hitron, Greta Anne Russler, Sarah Caulfield, Haydn T. Kissick, Wayne B. Harris, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen

PD‐L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

1 week ago
AbstractBackground.PD‐1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD‐L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab.Methods.Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD‐L1.Results.CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD‐L1+ CTCs (14/25, 64%) had significantly longer progression‐free survival (PFS) compared with patients with PD‐L1− CTCs (26.6 months vs. 5.5 months; p = .018). The 12‐month PFS rates were 76% versus 22% in the PD‐L1+ versus PD‐L1− CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD‐L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052–1.012; p = .026).Conclusion.Our results reveal the potential of CTCs as a noninvasive real‐time biopsy to evaluate PD‐L1 expression in patients with melanoma. PD‐L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS.Implications for Practice.The present data suggest that PD‐L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.
Muhammad A. Khattak, Anna Reid, James Freeman, Michelle Pereira, Ashleigh McEvoy, Johnny Lo, Markus H. Frank, Tarek Meniawy, Ali Didan, Isaac Spencer, Benhur Amanuel, Michael Millward, Melanie Ziman, Elin Gray

Opioid Prescribing Trends in Women Following Mastectomy or Breast‐Conserving Surgery Before and After the 2014 Federal Reclassification of Hydrocodone

1 week 1 day ago
AbstractBackground.Given concerns about suboptimal pain management for actively treated cancer patients following the 2014 federal reclassification of hydrocodone, we examined changes in patterns of opioid prescribing among surgical breast cancer patients.Materials and Methods.Data from a large nationally representative commercial health insurance program from 2009 to 2017 were used to identify women aged 18 years and older who were diagnosed with carcinoma in‐situ or malignant breast cancer and received breast‐conserving surgery or mastectomy from 2010 to 2016. Generalized linear mixed models were used to estimate the adjusted odds ratio (aOR) for receipt of ≥1‐day, >30‐day, or ≥ 90‐day supply of opioids in the 12 months following surgery adjusting for demographics, cancer treatment–related characteristics, and preoperative opioid use.Results.A total of 60,080 patients were included in the study. Surgically treated breast cancer patients in 2015 (aOR = 0.90, 0.84–0.97) and 2016 (aOR = 0.80, 0.74–0.86) were less likely to receive ≥1‐day supply of opioid prescriptions when compared with patients in 2013. Patients who had surgery in 2015 (aOR = 0.89, 0.81–0.98) and 2016 (aOR = 0.80, 0.73–0.87) were also less likely to receive >30‐day supply of prescription opioids in the 12 months following surgery. However, only surgical breast cancer patients in 2016 were less likely to receive ≥90‐day supply (aOR = 0.86, 0.76–0.98).Conclusion.Surgically treated breast cancer patients are less likely to receive short‐ and long‐term opioid prescriptions following the implementation of hydrocodone rescheduling. Further studies on the potential impact of federal policy on cancer patient pain management are needed.Implications for Practice.Clinicians and researchers with diverse perspectives should be included as stakeholders during policy development for restricting opioid prescriptions. Stakeholders can identify potential unintended consequences early and help identify methods to mitigate concerns, specifically as it relates to policy that influences how providers manage pain for actively treated cancer patients. This work shows how federal policy may have led to declines in opioid prescribing for breast cancer patients who underwent mastectomy or breast‐conserving surgery.
Derrick C. Gibson, Lin-Na Chou, Mukaila A. Ra&#x0237;i, Jacques G. Baillargeon, Yong-Fang Kuo

Phase IIIb Safety and Efficacy of Intravenous NEPA for Prevention of Chemotherapy‐Induced Nausea and Vomiting (CINV) in Patients with Breast Cancer Receiving Initial and Repeat Cycles of Anthracycline and Cyclophosphamide (AC) Chemotherapy

1 week 1 day ago
AbstractBackground.NEPA, a combination antiemetic of a neurokinin‐1 (NK1) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5‐HT3RA, palonosetron] offers 5‐day CINV prevention with a single dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase III study of patients receiving cisplatin found no infusion‐site or anaphylactic reactions related to IV NEPA. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, particularly fosaprepitant in patients receiving anthracycline‐cyclophosphamide (AC)‐based chemotherapy. This study evaluated the safety and efficacy of IV NEPA in the AC setting.Materials and Methods.This phase IIIb, multinational, randomized, double‐blind study enrolled females with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30‐minute infusion of IV NEPA or single oral NEPA capsule on day 1 prior to AC, in repeated (up to 4) cycles. Oral dexamethasone was given to all patients on day 1 only.Results.A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral NEPA and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment‐related AEs in both groups. There were no treatment‐related injection‐site AEs and no reports of hypersensitivity or anaphylaxis. The efficacy of IV and oral NEPA were similar, with high complete response (no emesis/no rescue) rates observed in cycle 1 (overall [0–120 hours] 73.0% IV NEPA, 77.3% oral NEPA) and maintained over subsequent cycles.Conclusion.IV NEPA was highly effective and safe with no associated hypersensitivity and injection‐site reactions in patients receiving AC.Implications for Practice.As a combination of a neurokinin‐1 (NK1) receptor antagonist (RA) and 5‐HT3RA, NEPA offers 5‐day chemotherapy‐induced nausea and vomiting prevention with a single dose and an opportunity to improve adherence to antiemetic guidelines. In this randomized multinational phase IIIb study, intravenous (IV) NEPA (fosnetupitant/palonosetron) was safe and highly effective in patients receiving multiple cycles of anthracycline‐cyclophosphamide (AC)‐based chemotherapy. Unlike other IV NK1RAs, the IV NEPA combination solution does not require any surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. Hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, most commonly with fosaprepitant in the AC setting. Importantly, there were no injection‐site or hypersensitivity reactions associated with IV NEPA.
Lee Schwartzberg, Rudolph Navari, Rebecca Clark-Snow, Ekaterine Arkania, Irena Radyukova, Kamal Patel, Daniel Voisin, Giada Rizzi, Rita Wickham, Richard J. Gralla, Matti Aapro, Eric Roeland

Olanzapine Versus Haloperidol for Treatment of Delirium in Patients with Advanced Cancer: A Phase III Randomized Clinical Trial

1 week 1 day ago
AbstractBackground.Treatment of delirium often includes haloperidol. Second‐generation antipsychotics like olanzapine have emerged as an alternative with possibly fewer side effects. The aim of this multicenter, phase III, randomized clinical trial was to compare the efficacy and tolerability of olanzapine with haloperidol for the treatment of delirium in hospitalized patients with advanced cancer.Materials and Methods.Eligible adult patients (≥18 years) with advanced cancer and delirium (Delirium Rating Scale‐Revised‐98 [DRS‐R‐98] total score ≥17.75) were randomized 1:1 to receive either haloperidol or olanzapine (age‐adjusted, titratable doses). Primary endpoint was delirium response rate (DRR), defined as number of patients with DRS‐R‐98 severity score <15.25 and ≥4.5 points reduction. Secondary endpoints included time to response (TTR), tolerability, and delirium‐related distress.Results.Between January 2011 and June 2016, 98 patients were included in the intention‐to‐treat analysis. DRR was 45% (95% confidence interval [CI], 31–59) for olanzapine and 57% (95% CI, 43–71) for haloperidol (Δ DRR −12%; odds ratio [OR], 0.61; 95% CI, 0.2–1.4; p = .23). Mean TTR was 4.5 days (95% CI, 3.2–5.9 days) for olanzapine and 2.8 days (95% CI, 1.9–3.7 days; p = .18) for haloperidol. Grade ≥3 treatment‐related adverse events occurred in 5 patients (10.2%) and 10 patients (20.4%) in the olanzapine and haloperidol arm, respectively. Distress rates were similar in both groups. The study was terminated early because of futility.Conclusion.Delirium treatment with olanzapine in hospitalized patients with advanced cancer did not result in improvement of DRR or TTR compared with haloperidol. Clinical trial identification number. NCT01539733. Dutch Trial Register. NTR2559.Implications for Practice.Guidelines recommend that pharmacological interventions for delirium treatment in adults with cancer should be limited to patients who have distressing delirium symptoms. It was suggested that atypical antipsychotics, such as olanzapine, outperform haloperidol in efficacy and safety. However, collective data comparing the efficacy and safety of typical versus atypical antipsychotics in patients with cancer are limited. If targeted and judicious use of antipsychotics is considered for the treatment of delirium in patients with advanced cancer, this study demonstrated that there was no statistically significant difference in response to haloperidol or olanzapine. Olanzapine showed an overall better safety profile compared with haloperidol, although this difference was not statistically significant.
Maurice J.D.L. van der Vorst, Elisabeth C.W. Neefjes, Manon S.A. Boddaert, Bea A.T.T. Verdegaal, Aart Beeker, Saskia C.C. Teunissen, Aartjan T.F. Beekman, Janneke A. Wilschut, Johannes Berkhof, Wouter W.A. Zuurmond, Henk M.W. Verheul

Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs

1 week 1 day ago
AbstractA number of important drugs used to treat cancer—many of which serve as the backbone of modern chemotherapy regimens—have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice.
Erin P. Balogh, Andrew B. Bindman, S. Gail Eckhardt, Susan Halabi, R. Donald Harvey, Ishmael Jaiyesimi, Rebecca Miksad, Harold L. Moses, Sharyl J. Nass, Richard L. Schilsky, Steven Sun, Josephine M. Torrente, Katherine E. Warren

Prognostic Values of Long Noncoding RNA linc00152 in Various Carcinomas: An Updated Systematic Review and Meta‐Analysis

1 week 1 day ago
AbstractDysregulation of the long noncoding RNA linc00152 has been reported in various solid tumors. Here, we performed a synthetic analysis to clarify the clinical value of linc00152 as a prognostic indicator in malignant tumors. Article collection was conducted using several electronic databases, including PubMed, Web of Science, Medline, OVID, and Embase (up to February 13, 2018). The meta‐analysis comprised nine original studies and 808 total patients. The application of a random‐effects model revealed significant positive association between high expression level of linc00152 and lymph node metastasis (odds ratio [OR] = 2.93, 95% confidence interval [CI]: 1.88–4.57, p < .0001; I2 = 48.8, p = .119) and negative association with low‐grade cancer (OR = 2.43, 95% CI: 1.51–3.92; I2 = 61.7, p = .033), while with tumor recurrence (hazard ratio [HR] = 3.32, 95% CI: 1.98–5.57, p < .0001; I2 = 0, p = .451) by fixed‐effects model as the low heterogeneity. As demonstrated via the application of the fixed‐effects model, Linc00152 overexpression is positively related to poor overall survival (pooled HR = 1.98, 95% CI: 1.70–2.31, p < .0001; I2 = 0%, p = .756) and poor disease‐free survival (HR = 1.66, 95% CI: 1.20–2.29, p < .0001; I2 = 75.8%, p = .042) in human solid cancers. Statistically significant associations were additionally found with cancer type, sample size, and follow‐up time. In conclusion, linc00152 is of potential value as a novel biomarker of lymph node metastasis and prognosis in human cancer.Implications for Practice.linc00152 is of potential value as a novel biomarker of lymph node metastasis and prognosis in human cancer.
Han Wang, Yang Liu, Aifa Tang

Access to Novel Drugs for Non‐Small Cell Lung Cancer in Central and Southeastern Europe: A Central European Cooperative Oncology Group Analysis

1 week 6 days ago
AbstractBackground.Treatment of non‐small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune‐oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries.Material and Methods.The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries.Results.Although first‐generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies—even for ALK inhibitors and checkpoint inhibitors in first‐line—there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries.Conclusion.The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.
Tanja Cufer, Tudor E. Ciuleanu, Peter Berzinec, Gabriela Galffy, Marko Jakopovic, Jacek Jassem, Dragana Jovanovic, Zhasmina Mihaylova, Gyula Ostoros, Christiane Thallinger, Milada Zemanova, Christoph Zielinski

Blood‐Based Next‐Generation Sequencing Analysis of Appendiceal Cancers

1 week 6 days ago
AbstractBackground.Appendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next‐generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations.Materials and Methods.Molecular alterations in 372 plasma samples from 303 patients with AC using clinical‐grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54–73 genes, copy number amplifications, fusions, and indels in selected genes.Results.A total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25–83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n = 207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53‐associated genes (n = 71, 38.6%), KRAS (n = 33, 17.9%), APC (n = 14, 7.6%), EGFR (n = 12, 6.5%), BRAF (n = 11, 5.9%), NF1 (n = 10, 5.4%), MYC (n = 9, 4.9%), GNAS (n = 8, 4.3%), MET (n = 6, 3.3%), PIK3CA (n = 5, 2.7%), and ATM (n = 5, 2.7%). Other low‐frequency but clinically relevant genomic alterations were as follows: AR (n = 4, 2.2%), TERT (n = 4, 2.2%), ERBB2 (n = 4, 2.2%), SMAD4 (n = 3, 1.6%), CDK4 (n = 2, 1.1%), NRAS (n = 2, 1.1%), FGFR1 (n = 2, 1.1%), FGFR2 (n = 2, 1.1%), PTEN (n = 2, 1.1%), RB1 (n = 2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n = 1, 0.5%).Conclusion.Evaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC.Implications for Practice.The complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost‐effective, and promising methods that provide patients with access to personalized treatment.
Walid L. Shaib, Katerina Zakka, Charles Staley III, Ali Roberts, Mehmet Akce, Christina Wu, Olatun&#x0237;i B. Alese, Bassel F. El-Rayes

The Impact of Nonsteroidal Anti‐Inflammatory Drugs, Beta Blockers, and Metformin on the Efficacy of Anti‐PD‐1 Therapy in Advanced Melanoma

1 week 6 days ago
AbstractAnti–programmed cell death protein‐1 (anti‐PD‐1) therapy has greatly improved outcomes of patients with melanoma; however, many fail to respond. Although preclinical studies suggest a potentially synergistic relationship with anti‐PD‐1 therapy and certain concurrent medications, their clinical role remains unclear. Here, we retrospectively evaluated the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) and other drugs in 330 patients with melanoma treated with anti‐PD‐1 therapy from four academic centers. In the cohort, 37% of patients used NSAIDs including aspirin (acetylsalicylic acid; ASA; 47%), cyclooxygenase (COX)‐2 inhibitors (2%), and non‐ASA/nonselective COX inhibitor NSAIDs (59%). The objective response rates (ORRs) were similar in patients with NSAID (43.4%) and no NSAID (41.3%) use with no significant difference in overall suvival (OS). There was a trend toward improved progression‐free survival (PFS) in patients who took NSAIDs (median PFS: 8.5 vs. 5.2 months; p = .054). Most patients (71.3%) took NSAIDs once daily or as needed. Multivariate analysis did not reveal an association with NSAID use with ORR, PFS, or OS. Concurrent use of metformin or beta blockers did not affect ORR, PFS, or OS. Our study found no conclusive association of concurrent NSAID or other medication use with improved outcomes in patients with melanoma treated with anti‐PD‐1 therapy. Larger and more systematic analysis is required to confirm these findings.
Daniel Y. Wang, Jennifer L. McQuade, Rajat R. Rai, John J. Park, Shilin Zhao, Fei Ye, Kathryn E. Beckermann, Samuel M. Rubinstein, Romany Johnpulle, Georgina V. Long, Matteo S. Carlino, Alexander M. Menzies, Michael A. Davies, Douglas B. Johnson

Extended Survival After Surgical Resection for Pituitary Metastases: Clinical Features, Management, and Outcomes of Metastatic Disease to the Sella

1 week 6 days ago
AbstractBackground.Patients with pituitary metastasis (PM) have a relatively poor prognosis. We describe the presentation, management, and outcomes of patients with PM.Subjects, Materials, and Methods.We performed a retrospective review of patients diagnosed with PM at a single institution from 1996 to 2015. Eighty‐five patients diagnosed with metastasis to the pituitary or sella turcica by pathology or based on a combination of neuroimaging and clinical findings were included. Univariate and multivariable Cox regressions evaluated associations between clinical factors and overall survival.Results.The most frequent sites of primary malignancies resulting in PM were lung (26%) and breast (26%). Median age at diagnosis was 60 years (range, 18–95). The most common complaints at diagnosis included visual deficits (62%), headache (47%), and cranial nerve palsy (31%). Seventy percent of patients had pituitary insufficiency—adrenal insufficiency (59%), hypothyroidism (59%), or diabetes insipidus (28%). Management of PM included radiation therapy (76%), chemotherapy (68%), surgical resection (21%), or combination therapy (71%). Fifty percent and 52% of patients who received surgical treatment and irradiation, respectively, reported symptomatic improvement. Median overall survival (OS) was 16.5 months (95% confidence interval: 10.7–25.4). On multivariable analysis, a primary cancer site other than lung or breast (p = .020), age <60 years (p = .030), and surgical resection (p = .016) were associated with longer OS.Conclusion.Patients <60 years of age, those with primary tumor sites other than lung or breast, and those who undergo surgical resection of the pituitary lesion may have prolonged survival. Surgical resection and radiation treatment resulted in symptomatic improvement in ~50% of patients.Implications for Practice.This study is the largest original series of patients with metastatic disease to the sella. In patients with pituitary metastasis, younger age, primary site other than lung or breast, and metastatic resection may prolong survival. Resection and radiation led to symptomatic improvement in ∼50% of patients. Seventy percent of patients had hypopituitarism. These hormonal deficiencies can be life threatening and can result in substantial morbidity if left untreated. Patients should be treated using a multimodality approach—including a potential role for surgery, radiation, chemotherapy, and hormone replacement—with the goal of improving survival and quality of life.
Krupa R. Patel, Junting Zheng, Viviane Tabar, Marc A. Cohen, Monica Girotra

Intratumoral Immunotherapy—Update 2019

1 week 6 days ago
AbstractIntratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications.Implications for Practice.This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.
Omid Hamid, Rubina Ismail, Igor Puzanov

Development and Validation of a Prognostic Nomogram to Guide Decision‐Making for High‐Grade Digestive Neuroendocrine Neoplasms

1 week 6 days ago
AbstractBackground.The objective of this study was to develop and validate a nomogram to predict 1‐year overall survival (OS) and 2‐year OS in patients with high‐grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy.Subjects, Materials, and Methods.We performed a retrospective analysis of 223 patients with NENs of the gut and hepato‐biliary‐pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one.Results.The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C‐index was 0.761 for OS, and the bias‐corrected C‐index was 0.744. Predictions correlated well with observed 1‐year and 2‐year outcomes (judged by eye). The area under the time‐dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log‐rank p < .001).Conclusion.The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials.Implications for Practice.The high‐grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum‐based chemotherapy may not bring clinical benefit for the low‐risk patients.
Zhenyu Lin, Haihong Wang, Yixuan Zhang, Guiling Li, Guoliang Pi, Xianjun Yu, Yaobing Chen, Kaizhou Jin, Liangkai Chen, Shengli Yang, Ying Zhu, Gang Wu, Jie Chen, Tao Zhang

Polypharmacy, Inappropriate Medication Use, and Drug Interactions in Older Korean Patients with Cancer Receiving First‐Line Palliative Chemotherapy

2 weeks 1 day ago
AbstractBackground.Polypharmacy is an important issue in the care of older patients with cancer, as it increases the risk of unfavorable outcomes. We estimated the prevalence of polypharmacy, potentially inappropriate medication (PIM) use, and drug–drug interactions (DDIs) in older patients with cancer in Korea and their associations with clinical outcomes.Subjects, Materials, and Methods.This was a secondary analysis of a prospective observational study of geriatric patients with cancer undergoing first‐line palliative chemotherapy. Eligible patients were older adults (≥70 years) with histologically diagnosed solid cancer who were candidates for first‐line palliative chemotherapy. All patients enrolled in this study received a geriatric assessment (GA) at baseline. We reviewed the daily medications taken by patients at the time of GA before starting chemotherapy. PIMs were assessed according to the 2015 Beers criteria, and DDIs were assessed by a clinical pharmacist using Lexi‐comp Drug Interactions. We evaluated the association between polypharmacy and clinical outcomes including treatment‐related toxicity, and hospitalization using logistic regression and Cox regression analyses.Results.In total, 301 patients (median age 75 years; range, 70–93) were enrolled; the most common cancer types were colorectal cancer (28.9%) and lung cancer (24.6%). Mean number of daily medications was 4.7 (±3.1; range, 0–14). The prevalence of polypharmacy (≥5 medications) was 45.2% and that of excessive polypharmacy (≥10 medications) was 8.6%. PIM use was detected in 137 (45.5%) patients. Clinically significant DDIs were detected in 92 (30.6%) patients. Polypharmacy was significantly associated with hospitalization or emergency room (ER) visits (odds ratio: 1.73 [1.18–2.55], p < .01). Neither polypharmacy nor PIM use showed association with treatment‐related toxicity.Conclusion.Polypharmacy, PIM use, and potential major DDIs were prevalent in Korean geriatric patients with cancer. Polypharmacy was associated with a higher risk of hospitalization or ER visits during the chemotherapy period.Implications for Practice.This study, which included 301 older Korean patients with cancer, highlights the increased prevalence of polypharmacy in this population planning to receive palliative chemotherapy. The prevalence of polypharmacy and excessive polypharmacy was 45.2% and 8.6%, respectively. The prescription of potentially inappropriate medications (PIMs) was detected in 45.5% and clinically significant drug–drug interaction in 30.6% of patients. Given the association of polypharmacy with increased hospitalization or emergency room visits, this study points to the need for increased awareness and intervention to minimize polypharmacy in the geriatric cancer population undergoing chemotherapy. Moreover, specific criteria for establishing PIMs should be adopted for the treatment of older adults with cancer.
Soo&#x0237;ung Hong, Ju Hyun Lee, Eun Kyeong Chun, Kwang-Il Kim, Jin Won Kim, Se Hyun Kim, Yun-Gyoo Lee, In Gyu Hwang, Jin Young Kim, Su-Jin Koh, Yoon Ho Ko, Seong Hoon Shin, In Sook Woo, Tae-Yong Kim, Ji Yeon Baek, Hyun Jung Kim, Hyo Jung Kim, Myung Ah…

Initial Results from Mobile Low‐Dose Computerized Tomographic Lung Cancer Screening Unit: Improved Outcomes for Underserved Populations

2 weeks 2 days ago
AbstractIntroduction.The National Lung Screening Trial (NLST) demonstrated that screening high‐risk patients with low‐dose computed tomography (CT) of the chest reduces lung cancer mortality compared with screening with chest x‐ray. Uninsured and Medicaid patients usually lack access to this hospital‐based screening test because of geographic and socioeconomic factors. We hypothesized that a mobile screening unit would improve access and confer the benefits demonstrated by the NLST to this underserved group, which is most at risk of lung cancer deaths.Patients and Methods.We created a mobile unit by building a Samsung BodyTom portable 32‐slice low‐dose CT scanner into a 35‐foot coach; it delivers high‐quality images for both soft tissue and bone and includes a waiting area and high‐speed wireless internet connection for fast image transfer. The unit was extensively tested to show robustness and stability of mobile equipment. This project was designed to screen uninsured and underinsured patients, otherwise with eligibility criteria identical to that of the National Lung Screening Trial, with the only difference being exclusion of patients eligible for Medicare (which provides financial coverage for CT‐based lung cancer screening).Results.We screened 550 patients (20% black, 3% Hispanic, 70% rural) with a male‐to‐female ratio of 1.1:1, median age 61 years (range, 55–64), and found 12 lung cancers at initial screen (2.2%), including 6 at stage I–II (58% of total lung cancers early stage) and 38 Lung‐RADS 4 (highly suspicious) lesions that are being followed closely. Incidental findings included nonlung cancers and coronary artery disease.Discussion.In this initial pilot study, using the first mobile low‐dose whole body CT screening unit in the U.S., the initial cancer detection rate is comparable to that reported in the NLST, despite excluding patients over the age of 64 years who have Medicare coverage, but with marked improvement of screening rates specifically in underserved sociodemographic, racial, and ethnic groups and with better outcomes than conventionally found in the underserved and at lower cost per case.Implications for Practice.This study shows clearly that a mobile low‐dose CT scanning unit allows effective lung cancer screening for underserved populations, such as impoverished African Americans, Hispanics, Native Americans, or isolated rural groups, and has a pick‐up rate of 1% for early stage disease. If confirmed in a planned randomized trial, this will be policy changing, as these groups usually present with advanced disease; this approach will produce better survival data at lower cost per case.
Derek Raghavan, Mellisa Wheeler, Darcy Doege, John D. Doty II, Henri Levy, Kia A. Dungan, Lauren M. Davis, James M. Robinson, Edward S. Kim, Kathryn F. Mileham, James Oliver, Daniel Carrizosa

Clinical Outcomes of Second‐Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study

2 weeks 2 days ago
AbstractBackground.Owing to the rarity of this tumor, there is limited information about second‐line chemotherapy for patients with previously treated advanced thymic carcinoma.Material and Methods.We performed a multi‐institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second‐line chemotherapy were obtained from medical records.Results.In total, 191 patients were enrolled in this study. Second‐line chemotherapy included platinum‐based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow‐up time was 50.5 months, and the median overall survival (OS) from the start of second‐line chemotherapy was 22.4 (95% confidence interval, 17.5‐26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum‐based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum‐based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively).Conclusion.The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second‐line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study.Implications for Practice.Owing to the rarity of this tumor, there is limited information about second‐line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second‐line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.
Kazunari Tateishi, Ryo Ko, Takehito Shukuya, Yusuke Okuma, Satoshi Watanabe, Shoichi Kuyama, Kyoko Murase, Yoko Tsukita, Hironori Ashinuma, Taku Nakagawa, Kazutsugu Uematsu, Mika Nakao, Yoshiaki Mori, Kyoichi Kaira, Atsuto Mouri, Takao Miyabayashi,…
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