bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of ethnic difference in the incidence of thrombocytopenia induced by trastuzumab emtansine (T-DM1): A meta-analysis.
Authors: Zhang Jingyi , Yang Yaning , Chen Ru , Chen Shanshan , Wang Jiayu , Luo Yang , Ma Fei , Xu Binghe , Fan Ying
Published: June 2021

e15096

Background: Trastuzumab emtansine (T-DM1) has been proved its value and efficacy in advanced metastatic cancer disease as well as in the adjuvant setting. However, there is an increasing concern in T-DM1-induced thrombocytopenia (TCP), which also showed difference of incidence in races. This meta-analysis, combining available data from all single-agent T-DM1 studies to date, aimed to evaluate the incidence of treatment-related thrombocytopenia of T-DM1 and the differences between Asian and non-Asian patients. Methods: We conducted a systematic search of the relevant published clinical studies of T-DM1 that reported safety profile including thrombocytopenia, from 1980 to March of 2020 using PubMed, Embase, and the Cochrane database. Screening and data extraction were conducted by two independent reviewers. Pooled-effect estimates calculated with fixed-effects or random-effects model were expressed as incidence with 95% CIs. Results: A total of 29 studies involving 6188 patients were included. The incidence of all-grade thrombocytopenia in Asian patients was 0.39 (95%CI 0.11-0.67) and 0.29 (95%CI 0.23-0.35) in non-Asian patients. And the incidence of the grade 3 or higher thrombocytopenia in Asians was 0.20 (95%CI 0.10-0.29), in non-Asians was 0.02 (95%CI 0.01-0.03). Gastrointestinal cancer type and the dose of 2.4 mg/kg Q3W T-DM1 treatment were both associated with the higher incidence of grade 3 or higher thrombocytopenia. Conclusions: Asian patients have the higher risk of thrombocytopenia induced by T-DM1. Clinicians should have an awareness of careful observation in platelet counts when patients receive T-DM1 therapy.
LincRNA-p21 as predictive response marker for preoperative chemoradiotherapy in rectal cancer.
Authors: Benitez Jose Carlos , Diaz Tania , Ferrer Carme , Acosta Melissa , Monzo Mariano , Cirera Luis , Besse Benjamin , Navarro Alfons , Campayo Marc
Published: June 2021

e15534

Background: Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients (pts). Despite the benefits of CRT, its use in non-responder pts can be associated with increased toxicities and resection delay. The identification of CRT response biomarkers, such as long non-coding RNAs (lncRNA), could improve the management of these pts. LincRNA-p21 is a lncRNA involved in the p53 pathway and angiogenesis regulation that acts as prognostic marker in several tumors. We aim to study lincRNA-p21 expression in pretreatment samples from RC pts treated with CRT to evaluate whether lincRNA-p21 can act as a predictive biomarker for CRT response. Methods: RNA from pretreatment endoscopy biopsies from 58 RC pts treated with preoperative CRT at Mutua Terrassa University Hospital were analyzed. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR and was correlated with CRT response and, time to relapse (TTR), disease-free survival (DFS) and overall survival (OS). Results: Samples from 58 pts were analyzed. Most of them males (n = 40, 69%). Median age at diagnosis of 67 (44-82) years. Fifty (86.2%) pts reported stage III and, 42 (72.4%) pts assessed TRG 0-3 with a 70.7% of downstaging reported. LincRNA-p21 was upregulated in stage III tumors (p < 0.0001) and also in tumors with worst response to CRT regarding TRG, TGR0-3 (TRG0-3, n = 42 vs TRG4, n = 16, p = 0.019). In this line, the ROC curve analysis showed that lincRNA-p21 expression had capacity to distinguish pts with maximum response (TRG4) from others (AUC:0.7; p = 0.02). The binary logistic regression analysis validated its independence as response biomarker. LincRNA-p21 levels correlated with pts relapse after surgery. When the pts were classified in 3 groups, high, medium and low, according to lincRNA-p21 levels, RC pts with highest lincRNA-p21 expression had the shortest TTR. TTR for pts with high levels was 74.5 months (m) (95% CI:31-117), while it was 114 m (95% CI:95-133) for those with Medium levels and 123 m (95% CI:111-134) for those with low levels (p = 0.047). Conclusions: LincRNA-p21 is a marker of advanced disease and worse response to CRT. LincRNA-p21 may add valuable information for individualizing pre-operative CRT in locally advanced RC pts.
The impact of myosteatosis on outcomes following surgery for gastro-intestinal malignancy: A systematic review and meta-analysis.
Authors: MacCormick Andrew , Puckett Mark , Streeter Adam , Aroori Somaiah
Published: June 2021

e15540

Background: Recent research has demonstrated the impact that body composition parameters can have on the outcomes following cancer surgery. Adipose tissue deposition in muscle, known as myosteatosis, can be detected on pre-operative imaging. This systematic review aims to analyse the impact of pre-operative myosteatosis on long-term outcomes following surgery for gastro-intestinal malignancy. Methods: Using MeSH terms, a systematic search of the databases PubMed MEDLINE, EMBASE, Cochrane, CINAHL and AMED was performed. Studies were included if they reported hazard ratios (HR) analysing the impact of pre-operatively defined myosteatosis, or similar term, on the long-term outcomes following surgery for gastro-intestinal malignancy. A total of 39 full texts articles were reviewed for inclusion, with 19 being included after the inclusion criteria were applied. A sub-group analysis was performed for those studies reporting outcomes for colorectal cancer patients only. Results: The total number of included patients across all studies was 14,481. Patients with myosteatosis had a significantly poorer overall survival, according to univariate (HR 1.82, 95% CI 1.67 – 1.99) and multivariable (HR 1.66, 95% CI 1.49 – 1.86) analysis. This was also demonstrated with regards to cancer-specific survival (univariate HR 1.62, 95% CI 1.18 – 2.22, multivariable HR 1.73, 95% CI 1.48 – 2.03) and recurrence-free survival (univariate HR 1.28, 95% CI 1.10 – 1.48, multivariable HR 1.38, 95% CI 1.07 – 1.77). Conclusions: This review demonstrates that patients with pre-operative myosteatosis have poorer long-term outcomes following surgery for gastro-intestinal malignancy. Therefore, myosteatosis should be used for pre-operative optimisation and as a prognostic tool before surgery. More standardised definitions of myosteatosis and further cohort studies of patients with non-colorectal malignancies are required.
System inflammation markers of resectable colorectal cancer patients with different mismatch repair gene status.
Authors: Jingjing Li , Zhang Yiwen , Qi Xu , Wei Qing , Ying Jieer , Cong Luo
Published: June 2021

e15612

Background: Clinical trials suggested that solid tumors with MSI-high or dMMR are associated with responses to programmed cell death 1 inhibitors. Understanding the associations of MMR status with clinicopathological characteristics in CRC patients would help further guide clinical treatment and explore the pathogenetic mechanisms of this disease. Methods: Bioinformatics analysis was used to identify the differential expression genes between CRC patients with different MMR status. 208 resectable colorectal cancer patients, including 104 dMMR patients and 104 matched pMMR patients were retrospectively analyzed. Clinicopathological data, including age, gender, tumor location, histological subtype, tumor grade, tumor stage, regional lymph node (LNs) metastasis, American Joint Committee on Cancer (AJCC) 8th edition stage, perineural invasion, vascular invasion, number of retrieved LNs, number of metastatic LNs, systemic inflammation markers, including C-reactive protein (CRP), lactic dehydrogenase (LDH), albumin, neutrophil, monocyte, lymphocyte, platelet and survival were retrospectively reviewed. Results: Bioinformatics analysis shown chemokine-mediated signalling pathway and inflammatory response were the main differences in gene expression between dMMR and pMMR CRC patients. In all 208 CRC patients, those with dMMR were more frequently located in right side, with more mucinous adenocarcinoma, and with more grade 3 for tumor grade. Patients with dMMR had earlier AJCC stage than pMMR ones. Meanwhile, lymph nodes (LNs) metastasis was more frequently in dMMR patients compared with pMMR patients. Interestingly, CRC patients with dMMR were able to remove more regional lymph nodes during surgery, but with less metastati. Resectable CRC patients with dMMR were more likely to have higher level of neutrophil, monocyte, platelet, NLR, PLR, MLR, CAR, GPS and CRP. In CRC patients with dMMR, the patients with higher level of PLR, MLR, CAR and co-effect present had shorter OS significantly. It was interesting to note that the prognosis of high level of systemic inflammatory markers did not predict long OS in pMMR CRC patients. Conclusions: dMMR CRC has presented a comprehensively distinct systemic inflammatory microenvironment. The systemic inflammatory response can predict oncological outcomes in CRC patients with dMMR.
Phase-II study of toripalimab combined with neoadjuvant chemotherapy for the treatment of resectable esophageal squamous cell carcinoma.
Authors: Liu Delin , Zhang Qin , Zhu Jinghua , Qian Ting , Yin Rong , Fan Zhaohui , Jiang Feng , Li Houhuai , Lu Jianwei , Cao Guochun
Published: June 2021

e16029

Background: Compared with neoadjuvant chemotherapy alone，Neoadjuvant radiochemotherapy can significantly increase pCR rate in esophageal squamous cell carcinoma and improve patient overall survival. However, the addition of radiotherapy increases the risk of adverse reactions and surgery. Neoadjuvant radiochemotherapy is currently used in < 5% of Chinese patients.The purpose of this phase II study is to assess the efficacy and safety of toripalimab combined with paclitaxel and cisplatin as neoadjuvant treatment for resectable locally advanced esophageal squamous cell carcinoma(clinical trial registration number: ChiCTR1900025318). Methods: Patients 18–75 years old with esophageal squamous cell carcinoma confirmed by endoscopic biopsy, assessed to be locally advanced esophageal squamous cell carcinoma (cT1–cT2, N+; cT3–cT4 a, any N), and expected to be resectable were given toripalimab (240 mg d1 + PTX 175 mg/m2 + PDD 75 mg/m2 q3w) before surgery for two treatment cycles, followed by efficacy assessment. A consultation meeting with thoracic surgeons was held to assess radical surgery for patients with resectable lesions 4–6 weeks after neoadjuvant therapy was completed. pCR and postoperative-stage statistical analysis were conducted based on postoperative pathology test results. These results were used to determine the efficacy and safety of PD-1 monoclonal antibody combined with chemotherapy as neoadjuvant therapy for locally advanced esophageal cancer. Results: By December 2020, 23 subjects were enrolled. Of the subjects, five withdrew without undergoing surgery (three subjects refused surgery and switched to radical radiochemotherapy, one subject progressed to PD after two cycles of neoadjuvant therapy and switched to palliative treatment, and one subject could not undergo surgery after neoadjuvant treatment and gave up the treatment) and 18 evaluable patients underwent surgery. The R0 resection rate was 100%, and T0–Tis 33.3% (6/18) achieved pCR. Among these patients, 61.1% (11/18) achieved T0–T1 after surgery, and 72.2% (13/18) achieved N0. Moreover, stage reduction effects were significant compared with preoperative TN staging. Common side-effects include nausea, vomiting, neutropenia, thrombocytopenia, rash, asthenia, constipation, and muscle soreness. Most adverse events were grades 1–2, and grades 3/4 adverse events include one case of grade 3 neutropenia and one case of grade 3 diarrhea (suspected immune-related colitis), which improved after symptomatic treatment. Conclusions: Toripalimab combined with the TP scheme showed preliminary efficacy and controllable safety in the treatment of resectable locally advanced esophageal squamous cell carcinoma and is worthy of further exploration. Clinical trial information: ChiCTR1900025318.
Risk of hepatocellular carcinoma after spontaneous and nucleos(t)ide analogue induced hepatitis B surface antigen seroclearance.
Authors: Yoo Sunghwan , Lee Hyun Woong
Published: June 2021

e16162

Background: Despite a favorable clinical course, the risk of hepatocellular carcinoma (HCC) still exists in patients achieving HBsAg seroclearance. Therefore, we investigated the incidence of HCC after spontaneous and nucleos(t)ide analogue (NA) induced HBsAg seroclearance in real-life clinical practice. Methods: A cohort study was conducted using data from Gangnam Severance Hospital. We identified all subjects with positive HBsAg between January 1, 2001 and March 21, 2018. NA use, liver biochemistries, serial HBsAg and anti-HBs results were retrieved. The primary endpoint was the incidence of HCC after naturally and NA induced HBsAg seroclearance. Results: Among the 5,609 HBsAg-positive patients, 83 chronic hepatitis B (CHB) patients achieved HBsAg seroclearance during 19 years. The cumulative incidence of HBsAg seroclearance was 0.024% at 2 years to 32.4% at 19 years. Of the 83 patients with HBsAg seroclearance, 52 patients achieved spontaneous HBsAg seroclearance and 31 patients achieved NA-induced HBsAg seroclearance. Of 52 patients with spontaneous HBsAg seroclearance, only one patient (2%) developed HCC 6 months after HBsAg seroclearance. On the other hands, there was no development of HCC in patients with NA-induced HBsAg seroclearance. No significant difference was observed in the cumulative incidence of HCC between two groups ( P=0.443). All patients had sustained HBsAg seroclearance and there was no HBsAg seroreversion. Conclusions: The incidence of HCC was extremely rare after spontaneous and NA induced HBsAg seroclearance in real-life clinical practice. NA-induced HBsAg seroclearance is also as durable as spontaenous HBsAg seroclearance.
The association between real-world CA19-9 level monitoring patterns and with clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the second- and third-line of therapy.
Authors: George Ben , Chudnovsky Aleksander , Cockrum Paul , Lamarre Neil , Kent Matthew , Surinach Andy
Published: June 2021

e16251

Background: Pancreatic cancer has an aggressive disease course, mandating close clinical monitoring while on treatment. Evaluation of treatment response in patients with mPDAC necessitates scheduled clinical and radiographic assessments along with monitoring serum CA 19-9 levels. We investigated the impact of serum CA 19-9 monitoring and its association with clinical outcomes in patients with mPDAC who received second- (2L) and third line (3L) in a population-based setting. Methods: Data were extracted from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database for patients diagnosed with mPDAC and subsequently treated in the 2L or 3L setting between January 1, 2014 and June 30, 2020. Serum CA 19-9 levels at baseline were extracted – defined as the values obtained ≤ 60 days of treatment initiation and during treatment. CA 19-9 levels > 40 IU/mL were considered elevated. Survival analysis was performed using Kaplan-Meier methods. Categorical measures were compared with a chi-square test and survival outcomes with a log-rank test. Results: There were 2,402 patients who received 2L and 790 patients who received 3L treatment included in the study. Among the 2L cohort, median age at treatment initiation was 67 years (IQR: 60 – 73), 54% were male, 57% had an ECOG score of 0-1, and 82% had a baseline serum CA 19-9 level available. Among the 3L cohort, median age at treatment initiation was 67 years (IQR: 60 – 73), 53% were male, 58% had an ECOG score of 0-1, and 84% had a baseline CA 19-9 level available. Most patients in the 2L and 3L cohorts had an elevated CA 19-9 at baseline, 85.2% and 82.0%, respectively. Among the 2L and 3L cohorts, 38.5% and 31.9% had CA 19-9 levels decrease/remain stable during treatment and 27.6% and 31.4% had levels increase during treatment, respectively. Patients with normal baseline CA 19-9 experienced longer survival than patients with elevated levels [2L: 7.2 months (95% CI: 6.1 – 9.2) vs 5.2 months (4.9 – 5.6), p < 0.001; 3L: 6.1 months (5.4 – 9.1) vs 3.9 months (3.4 – 4.3), p < 0.001]. Similarly, patients with decreasing/stable CA 19-9 during treatment had longer survival than patients who had their CA 19-9 levels increase [2L: 8.2 months (7.7 – 8.5) vs 4.3 months (4.1 – 4.7), p < 0.001; 3L: 7.5 months (6.6 – 9.2) vs 3.7 months (3.4 – 4.3), p < 0.001]. Conclusions: In this large, contemporary, real-world study of patients with mPDAC, CA 19-9 levels at treatment initiation had a prognostic value across later lines of therapy. Routine serial monitoring of CA 19-9 levels during treatment, in addition to clinical and radiographic assessment, may help with timely additional diagnostic testing and treatment intervention. Further validation studies are needed to understand the generalizability of these results.
An internal review of chemotherapy toxicities in patients with pancreatic cancer.
Authors: Shankar Karthik , Huffman Deanna , Peterson Chelsea , Alhamad Khaled , Jayakrishnan Thejus Thayyil , Attah Abraham Attah , Alrifai Nada , Onokwai Nkechi , Cherico Adriani , Asawa Palash , Kancharla Pragnan , Srinivasamaharaj Srividya , Samhouri Yazan , Rizwan Saleha , Monga Dulabh K.
Published: June 2021

e16258

Background: Cytotoxic chemotherapy remains the standard of care in the treatment of pancreatic ductal adenocarcinoma (PDAC). There is more excitement in the last few years regarding the use of neoadjuvant chemotherapy even when the disease is resectable. In this analysis, we sought to study the different regimens used in our institutions, in regards to setting and toxicity. Methods: We retrospectively reviewed all patients diagnosed with pancreatic adenocarcinoma at Allegheny General Hospital between 2009-2020. Data was extracted from electronic medical records and de-identified. Institutional Review Board approval was obtained. Descriptive analysis was undertaken and multivariate analysis was performed to compare differences in the prevalence of toxicity across the regimens and demographics using Stata version 16. The primary outcome was the rate of toxicity that prompted dose adjustment, stratified by the setting chemotherapy was administered (neoadjuvant, adjuvant, or palliative). Results: Of the 121 patients studied, 88 patients received chemotherapy. Median age was 69 years. 66 patients (55%) were females. 40 patients suffered from adverse effects requiring a dose adjustment. 85% of the adverse effects occurred in Caucasians. 15 out of 37 patients (42.9%) who received Folfirinox, 15 out of 31 patients (48.4%) who received gemcitabine and nab-paclitaxel, 6 out of 10 patients (60.0%) who received gemcitabine and capecitabine, 3 out of 4 patients (75.0%) who received gemcitabine monotherapy required dose adjustment (table). Folfirinox and gemcitabine with nab-paclitaxel were statistically compared and found to be not significant (p-value=0.12). No significant impacts of race, gender, or age were noted in a multivariate model. Conclusions: Approximately 42% of patients receiving chemotherapy suffered from toxicities that required dose adjustments. We found a trend toward more use of neoadjuvant chemotherapy in resectable PDAC with a similar toxicity rate compared with other settings.[Table: see text]
Clinical features and outcomes of colloid carcinoma of pancreas compared to pancreatic ductal adenocarcinoma.
Authors: Khalil Lana , Zakka Katerina Mary , Jiang Renjian , Penely Mckenna , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Diab Maria , Behera Madhusmita , Reid Michelle D. , El-Rayes Bassel F. , Akce Mehmet
Published: June 2021

e16259

Background: Colloid carcinoma (CC) of the pancreas is a rare histopathological subtype of ductal adenocarcinoma (PDAC), with poorly defined prognostic factors and therapeutic outcomes. The aim of this study is to characterize the clinicopathological features and evaluate the overall survival (OS) and prognostic factors of patients with pancreatic CC using National Cancer Database (NCDB). Methods: Patients diagnosed with CC of the pancreas and PDAC between 2004 and 2016 were identified from the NCDB using ICD-O-3 morphology (8480/3 for CC and 8140/3 for PDAC) and topography codes (C25). Univariate and multivariable analyses were conducted and Kaplan-Meier analysis and Cox proportional hazards models were used to perform OS analysis. Results: A total of 56,846 patients met the inclusion criteria for the final analysis. Of the total population included, 2,430 patients (4.3%) had CC and 54,416 patients (95.7%) had PDAC. For both, CC and PDAC, there was a male preponderance (52.0%, 52.5%), Caucasians (85.1%, 84%), occurrence above the age of 70 (39.2%, 38.2%), and the most common primary site was the head of the pancreas (50.5%, 53%). For CC, the percentage of pathologic stage III colloid pancreas cancer appeared the lowest (3.5%, 85 patients), compared to stage I (16.7%), stage II (37.8%), and stage IV (42.1%). While in PDAC, the percentage of pathologic stage I (5.94%) and stage III (4.44%) patients was lower than stage II (37.21%) and IV (52.41%). CC and PDAC more frequently presented with < 5cm tumor, at academic or research cancer centers, and diagnosed between 2009 and 2013 compared to 2004–2008 ( p< 0.001). For both CC and PDAC, the majority underwent surgical resection (58%, 53%), systemic chemotherapy (57.8%, 63%) and did not receive radiotherapy (78.8%, 77.6%). A positive surgical margin on pathologic evaluation was associated with worse outcomes for CC and PDAC in both univariate and multivariate analysis (HR 1.61; 1.56–1.66; p< 0.001 and HR 1.43; 1.38–1.48, p< 0.001). CC had a better 1-year overall survival (OS) in all stages compared to PDAC (p < 0.001). In multivariate analysis, mucinous carcinoma histology, female sex, diagnosis between 2004 and 2009, well/moderately differentiated histology, chemotherapy, age at diagnosis less than 60, radiation therapy after surgery, and local surgical procedure of primary site and pancreatectomy (p < 0.001) were associated with better OS compared to PDAC. Colloid histology was associated with better 1-year overall survival (OS) in all stages compared to PDAC (p < 0.001). Conclusions: Colloid carcinoma of pancreas is associated with a better overall survival as compared to pancreatic ductal adenocarcinoma. This is the largest study to address the clinical features and outcomes of colloid carcinoma of pancreas.
Efficacy and safety of MUC1 targeted CIK cells for the treatment of advanced liver cancer.
Authors: Lu Yin Ying , Yu Haoyang , Tang Yunxia
Published: June 2021

e16278

Background: To assess the efficacy and safety of CIK treatment with MUC1/CD3 bis-Ab for patients with advanced liver cancer. Methods: A total of 11 patients were enroll from when in which hospitals, including 5 male and 6 female patients with a median age of 59 years old. Trial Design and Treatment: All participants provided written informed consent before enrollment. The study protocol was approved by the institutional review board at each participating center. All methods and procedures associated with this study were conducted in accordance with the Good Clinical Practice guidelines and accorded ethically with the principles of the Declaration of Helsinki and local laws. This phase I clinical study was a single-armed open-labeled trial. All patients received targeted activated CIK cell treatment of 6x109 cells/month until the disease progressed, the patient could not tolerate the treatment, or the study endpoint had reached. PBMC were collected from each patient on D0. After PBMC collection, patients received 10 mg/day decitabine for 5 consecutive days (D0–D4). On D14 the first batch of CIK cells were harvested and the infusion of cells was performed in two consecutive days (total cells ≥ 6x109). The bispecific antibody was infused together with CIK cells. After cell infusion, the bispecific antibody was infused alone for another 3 days. Each treatment course lasted for 4 weeks, with a total of 4 courses. Results: Efficacy: 9 patients completed 4 or fewer courses of CIK bispecific antibody treatment, and 2 patients completed 9 courses of treatment. Till the data cut-off date of Dec. 31, 2020, 9 patients died, of whom 5 patients achieved SD and 4 patients had PD. Two patients (case 1 & 2) are still alive, of whom one achieved PR and one achieved SD during CIK treatment, and both achieved CR after subsequent PD-1 inhibitor treatment when the disease progressed. The PFS ranged from 1-16.7 months with a median PFS of 4 months, and the OS ranged from 3.9-32.7 months with a median OS of 13.2 months. The DCR of CIK treatment reached 63.6%. Safety: All 11 patients developed fever after cell infusion, which subsided after a few hours by oral administration of Xinhuangpian. 2 patients developed anorexia. Other AEs included debilitation, drowsiness, nausea, hepatotoxicity and dizziness. Five patients discontinued treatment due to serious AEs. Conclusions: This study showed that adjuvant CIK cell immunotherapy prolongs the survival time of patients with advanced liver cancer, which is mainly due to the local tumor chemotaxis of CIK cells via the MUC1/CD3 bispecific antibody and the decitabine pretreatment. Clinical trial information: NCT03146637.
Exploring the synergistic effects of cabozantinib (cabo) and a programmed cell death protein 1 (PD1) inhibitor in metastatic renal cell carcinoma (mRCC) with artificial intelligence (AI).
Authors: Duran Ignacio , Costa Luis , Puente Javier , Anido Urbano , Martin Lidia , Gómez Jessica , Castellano Daniel
Published: June 2021

e16555

Background: Nonclinical and clinical data suggest that cabo with a PD1 inhibitor provides synergistic antitumor activity in patients with mRCC, possibly by a cabo-induced switch to an immunopermissive tumor microenvironment. We used a complementary, unbiased, AI approach to gain a holistic view of the complex interplay between multiple pathways, cells and molecules and identify the mechanisms that may underpin this synergism. Methods: Biological targets associated with mRCC pathophysiology or drug actions were identified from proteomic, genomic and transcriptomic databases and literature. Using systems- and AI-based technology, the data were integrated using machine learning into mathematical models of the human mRCC protein network topology. The combined effects of cabo and a PD1 inhibitor on biological targets were simulated assuming target receptors were fully activated or fully inhibited. Relevant effects on known cancer processes (e.g. angiogenesis, metastasis, cell proliferation, immune evasion) were identified using artificial neural networks. Biologically plausible synergistic mechanisms were described with sampling methods. Results: Inhibition of VEGF/VEGFR and GAS6/TAMR axes by cabo enhanced the known effects of PD1 inhibitors on immune evasion mechanisms by modulating multiple humoral and cellular components of the innate and adaptive immune responses (Table). PD1 inhibitors further enhanced the anti-angiogenic and tumor pro-apoptotic effects of cabo by modulating pro- and anti-angiogenic factors and T cell cytotoxicity. Conclusions: These data provide a mechanistic rationale and further support for the beneficial combination of cabo and a PD1 inhibitor and may guide future nonclinical and clinical research.[Table: see text]
Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC).
Authors: Parikh Anish B. , Psutka Sarah P. , Yang Yuanquan , Collier Katharine , Miah Abdul , Li Mingjia , Mori-Vogt Sherry , Hinkley Megan , Orcutt Delaney , Trott Elliott , Gross Evan , Hussey Duncan , Kramer Joel , Oliva Kaylee , Mortazavi Amir , Monk Paul , Folefac Edmund , Clinton Steven K. , Yin Ming
Published: June 2021

e16567

Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]
Association of elevated serum CEA with visceral metastasis and distinctive circulating tumor DNA alterations in castrate-resistant prostate cancer.
Authors: Bray Alexander , Malalur Pannaga G. , Drusbosky Leylah , Gourdin Theodore Stewart , Lilly Michael B.
Published: June 2021

e17023

Background: Serum carcinoembryonic antigen (CEA) is elevated in certain subtypes of castrate resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). Independent association of CEA expression with clinical stage and specific tumor gene variants could enable its use as a prognostic indicator and non-invasive biomarker of therapeutic response. Methods: Circulating tumor DNA (ctDNA) alterations in a commercially available panel of genes (Guardant Health) and serum CEA from 178 CRPC patients were retrospectively analyzed. These patients were defined as AVPC or non-AVPC based on the presence of 1 or more of the published Aparicio criteria (Aparicio et al, 2013). Clinical characteristics and ctDNA alterations were compared in patients with elevated and normal CEA. AVPC and non-AVPC patients were then compared to evaluate the uniqueness of CEA associated findings. Results: Patients with CRPC and elevated serum CEA were more likely to have liver (36.1% vs 12.0%, p = 0.002) and lung metastasis (19.4% vs 6.4%, p = 0.0441) compared to patients with normal CEA. When ctDNA profiles were analyzed there were no significant differences in rates of single nucleotide variants (SNVs) between patients with elevated and normal CEA. In contrast, patients with elevated CEA were significantly more likely to harbor copy number amplifications (CNAs) in BRAF, CDK6, FGR1, MET, CCNE1, MYC, KIT, CCND2, PIK3CA, RAF1, and KRAS. Of these, only PIK3CA and KRAS were significantly elevated in AVPC patients compared to non-AVPC patients. Relative to non-AVPC CRPC, patients with AVPC were significantly more likely to have clonal SNVs in TP53, PTEN, or RB (p = 0.0131). They were also more likely to have clonal SNVs in TP53 (p = 0.06). Conclusions: 1.) Elevated serum CEA is independently associated with visceral metastases in patients with CRPC. 2.) Elevated serum CEA in CRPC is associated with specific gene amplifications which are detectable by ctDNA analysis and not associated with AVPC as a whole. 3.) The ctDNA findings in patients with AVPC mirror previous tissue-based studies which documented recurrent genetic variations in TP53, PTEN, and RB (Aparicio et al, 2016). Together these findings outline a potential role for ctDNA profiling and serum CEA as non-invasive biomarkers in CRPC. They also suggest that elevated serum CEA may be associated with a genetically distinct subtype of AVPC.
Comparative efficacy of docetaxel versus novel hormonal agent in de novo metastatic hormone-sensitive prostate cancer: Real-world data curated by deidentified chart abstraction.
Authors: Liaw Bobby Chi-Hung , Guin Sunny , Jun Tomi , Ayers Kristin , Patel Bonny , O'Connell Timmy , Dietz Matthew , Klein Michael , Prentice Tony , Newman Scott , Fink Marc , Zhou Xiang , Schadt Eric , Chen Rong , Oh William K.
Published: June 2021

e17047

Background: The addition of docetaxel or a novel hormonal agent (NHA), such as abiraterone acetate or enzalutamide, has become standard of care for mHSPC, but prospective data for comparative efficacy remains limited. Clinical variables abstracted through natural language processing of free text from patient charts can provide real-world data to answer important clinical questions. Methods: Using an innovative data abstraction process, we retrospectively identified men with de novo mHSPC within deidentified charts from the Mount Sinai Health System treated with either docetaxel or a NHA between January 1, 2014 and April 30, 2019. Dates were chosen to reflect the timeline for which these therapeutic agents received regulatory approval for mHSPC, but also to allow sufficient clinical follow up after treatment initiation. Primary outcome of failure-free survival (FFS), defined as the time to next treatment, was assessed using the Kaplan-Meier method and multivariable Cox proportional hazards models. We additionally performed multivariable analysis to evaluate the prognostic significance of post-treatment PSA nadir on FFS. Results: A total of 94 de novo mHSPC patients that received either docetaxel or an NHA were identified using proprietary Sema4 data abstraction process: 52 received docetaxel, 42 received an NHA. Use of an upfront NHA in mHSPC was associated with a significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p = 0.023). While NHAs were associated with a significantly longer FFS than docetaxel in patients with high metastatic burden of disease (25.12 vs. 9.63 months, p = 0.014), this was not observed in low-volume disease (20.71 vs. 26.5 months, p = 0.9). In multivariable model analysis adjusting for age, baseline PSA, and metastasis burden, docetaxel remains independently associated with worse FFS compared to NHA (HR 1.96, 95% CI 1.12−3.45, p = 0.019). Irrespective of docetaxel or NHA use, lower post-treatment PSA nadir levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, > 0.4ng/ml, respectively; p < 0.001). Conclusions: Clinical variables abstracted from deidentified clinical documentation can efficiently provide relevant and reliable data upon which clinical research can be based. Comparative analysis of real-world data demonstrates superior FFS in de novo mHSPC treated with a NHA as compared to docetaxel. The depth of PSA response holds prognostic value for mHSPC outcomes, regardless of treatment used.
Phoenix Cancer Support Network provides non-medical assistance to reduce disparities among cancer patients.
Authors: Weiss Glen J. , Thompson Adam R. , Pastuszak Kathryn M. , Torre Samantha R. , Martin Jeanette S.
Published: June 2021

e18502

Background: Social determinants of health (SDOH) can lead to gaps in supportive care resources and services available to cancer patients. Established in 2017, Phoenix Cancer Support Network (PCSN) is a non-profit that endeavors to empower cancer patients (clients) throughout their cancer journey by providing support, guidance, and direction while promoting and protecting the unique needs, lifestyle, and abilities of each client and their caregivers. In this study, we investigate the non-medical needs of patients that engaged with PCSN for assistance and the increases in services provided over time. Methods: All patients that applied for and were eligible to receive assistance from PCSN were included. Eligibility requirements include patients primarily residing in Arizona and are receiving cancer therapy. Non-medical services offered included transportation, groceries and meals, housecleaning, other domestic services (e.g., child care or dog walking), financial support, and household goods. Summary statistics were conducted. Results: Between December 2017 and November 2020, 188 clients (117 were female) were offered assistance by PCSN. The median age was 58 (range 23-92). The number of clients assisted was 2 in 2017, 81 in 2018, 58 in 2019, and 38 in 2020. 145 clients had a solid tumor and 131 were actively undergoing cancer treatment when seeking PCSN assistance. Of 67 clients with available income data, 55 clients earned less than $25,000/year including 41 clients that were unemployed and 21 clients without insurance coverage. Most frequently requested services were transportation (49%), groceries and meals (41%), financial support (34%), housecleaning (26%), and other domestic services (10%). Of those requested services, PCSN was able to provide assistance for 76% of transportation, 62% of meal services, 79% of financial assistance, 50% of housecleaning, and 100% of other domestic services requested. Details of total expenditures for these services by year are depicted in the Table.Transportation service has been the largest expenditure overall, followed by other domestic services and groceries and meals. Conclusions: PCSN clients have needs that span multiple non-medical resources, reflecting potential sources of improvement in reducing disparities in the cancer community. At least 25% of clients requesting non-medical assistance reported annual income below $25,000/year. The amount of services provided has increased yearly, particularly transportation services. Additional study and follow-up to understand these service gaps and the impact of SDOH is warranted.[Table: see text]
Expanded access and early access provision: Awareness, educational needs and opportunities to improve access to care.
Authors: Krendyukov Andriy , Singhvi Sanjay , Green-Morrison Yianick , Zabransky Markus
Published: June 2021

e18507

Background: An unmet medical need exists for many oncology patients who cannot be treated satisfactorily by available therapeutics. Despite notable efforts made by FDA and EMA to expedite development, review and approval of Innovative Medicinal Products (InMPs), there may still be a lengthy delay before oncology patients can gain access to new therapies. Expanded access (EA) in the USA and compassionate use (CU) in the European Union are pathways endorsed to improve patient access to InMPs. Recently reported data from CDER and CBER revealed that applications for EA pathways dealing with patient cohorts remain low, despite high approval rates. The challenges that practicing oncologists may face when dealing with EA or other early access provision (EAP), together with limited education, may influence the access of oncology patients to care. Methods: An on-line, fully anonymous survey reaching out to more than 3,258 practicing physicians was initiated between November 2020- January 2021. Participants were asked questions about their knowledge and understanding of EA/EAP, level of experience, decision process, interest for further educational activities and opportunities to improve process, both in general and specifically during COVID 19 pandemic. Attributes were rated on a 5-point scale. Results: Analysis of first respondents showed that 70% of practicing physicians rated their own understanding and knowledge about EA/EAP as above average (good or very good). However, only 60% of responders answered specific knowledge-based question correctly. At the same time, only 44% of practicing oncologists reported notable experience with EA/EAP in daily practice. The majority of respondents (90%) felt that availability of clinical efficacy data from comparative phase III RCTs would be considered of high importance; other evidence and study types (e.g. clinical safety, PK/PD, preclinical data) were rated substantially lower. The need for further education around better understanding of the processes and regulatory requirements, roles and responsibilities, and data collection was emphasized by 61%, 36% and 30% of respondents, respectively. During current COVID 19 pandemic, majority of respondents highlighted the need to improve and substantially adapt EA with regard to application process and documentation, InMP supply and logistics, and safety reporting process. Conclusions: Results from this survey suggest that challenges posed by the EA process, together with a lack of education, might contribute to the under-utilization of EA/EAP for oncology patients. Continuous educational efforts are required to better inform and support practicing oncologists during the EA application process and regulatory framework. Competent authorities should consider optimization and implementation of digital tools to facilitate EA applications and follow up during the COVID 19 pandemic.
Cancer treatment among the elderly in the United States: Examining the interplay of race/ethnicity and comorbidities.
Authors: Pham Tung , Connor Avonne , Suneja Gita , Rositch Anne
Published: June 2021

e18547

Background: As the life expectancy of Americans continues to increase, so does the number of individuals who are diagnosed with cancer and other comorbidities. Management of these patients can become increasingly complicated as physicians administer multiple combinations of interventions and drug therapies. To further complicate this issue, the average number of comorbidities among racial/ethnic minority patients is higher than non-Hispanic (NH) white patients, and this disparity could adversely affect receipt of curative cancer treatment among these minority groups. Therefore, we explored the association between race/ethnicity, comorbidities, and curative cancer treatment among elderly Americans diagnosed with the four most common cancer types. Methods: SEER-Medicare linked data was used to identify 727,136 individuals over 65 years old diagnosed with breast, colorectal, lung, or prostate cancer from 1992-2011. Comorbidity burden was measured using the Charlson Comorbidity Index (CCI) and analyzed as tertiles (T1: lowest CCI score to T3: highest CCI score). Treatment with curative intent was defined as receipt of any cancer-type-specific surgery, chemotherapy, radiation, hormone, or immune therapy within 6 months of cancer diagnosis. Modified Poisson regression models were used to assess the joint association between comorbidities and race/ethnicity on cancer treatment. Results: For all cancers, the percentage of patients receiving treatment declined rapidly with increasing age, CCI scores, number of comorbidities, and advanced cancer stage. In addition, variability in receipt of treatment by race/ethnicity was observed: 76% for NH-White patients, 75% for Hispanic patients, and 68% for NH-Black patients. Taking into account age, genders (for colorectal, lung cancer), year of diagnosis, stage at diagnosis, and socioeconomic status, we found that treatment proportions among NH-Black and Hispanic patients with low CCI score (T1) were 2%-15% lower than NH-White patients with the same CCI score (all p < 0.001). Although treatment proportions decreased with increasing CCI among NH White patients (ranging from 2.5-11.3%; p < 0.01), there was little difference in treatment by CCI among NH Black and Hispanic patients (ranging from 0.5%-2%; p > 0.05). Conclusions: Our findings suggested that racial disparities may exist in cancer treatment among patients with low comorbidities. This finding was unexpected as these patients are less likely than highly comorbid patients to experience drug interactions and other complications due to concurrent disease management therapies.
Evaluation of emergency department (ED) visits by oncology patients: A running comparison to admissions and ED visits under the CMS OP-35 ruling.
Authors: Alsuhebany Nada , Brown Jamie , Echave Jacquelyne , Elquza Emad , Babiker Hani M. , Abraham Ivo , McBride Ali
Published: June 2021

e18683

Background: The incidence of emergency department (ED) visits by oncology patients has grown in recent years. Some visits are medically unnecessary or could be prevented with improved prophylactic measures. Centers for Medicare & Medicaid Services (CMS) implemented the Hospital Outpatient Quality Reporting (OQR) Program, to which hospitals must report data on quality measures of care furnished in the outpatient setting. One of the proposed measures, OP-35, evaluates admissions and ED visits by patients receiving outpatient chemotherapy, assessing for ten potentially preventable visits. These ten visit reasons included are: anemia, nausea, vomiting, dehydration, neutropenia, diarrhea, pain, pneumonia, fever, and sepsis. This study evaluated the incidence and reasons for ED visits by patients receiving outpatient chemotherapy, as well as outcomes following these visits in order to assess appropriate prophylactic treatment related to outpatient chemotherapy at our institution. Methods: This single-center, retrospective chart review was conducted at The University of Arizona Cancer Center. We collected data using an electronic medical record and included oncology patients with active cancer who had ED visits from January 1, 2018, to December 31, 2018. Data points included baseline demographics; malignancy; ED visit reason; clinic visit history; past ED visits; treatment and supportive care data; and outcome of the ED visit. Results: Study authors included 205 of the 1,659 screened encounters. Approximately 70% of the encounters involved patients with solid tumors and 30% with hematologic malignancies. Nearly 50% of hematologic malignancy patients presented to the ED for potentially preventable reasons, while 32.8% of solid tumor patients had potentially preventable visits. The most common preventable ED visit reasons in both groups were pain, fever, nausea, vomiting, and dehydration. In our analysis, over 90% of patients presenting for neutropenia and fever had received appropriate growth factor prophylaxis when indicated based on their chemotherapy regimen. Of the patients presenting for nausea or vomiting, it was determined 95.3% had received appropriate antiemetic prophylaxis. Conclusions: This study showed that the incidence of potentially preventable visits was numerically higher in the hematologic cancer group compared with the solid tumor group. In addition, this study showed that a number of patients who were admitted to the ED with nausea/vomiting or neutropenia/fever received appropriate guideline-recommended prophylactic or supportive care therapy, regardless of the OP-35 proposed CMS core measure determination that these visit reasons should be considered preventable. These findings highlight the need for CMS to further review OP-35 to include information addressing the use of appropriate supportive care in the future.