Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, ...limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib, which was shown to be noninferior to sorafenib, excluded patients with main portal trunk invasion. Regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT.
The role of real‐world evidence (RWE) in regulatory, drug development, and healthcare decision‐making is rapidly expanding. Recent advances have increased the complexity of cancer care and widened ...the gap between randomized clinical trial (RCT) results and the evidence needed for real‐world clinical decisions. Instead of remaining invisible, data from the >95% of cancer patients treated outside of clinical trials can help fill this void.
The real-world incidence of chronic liver damage after transarterial chemoembolization (TACE) is unclear. LiverT, a retrospective, observational study, assessed liver function deterioration after a ...single TACE in real-world hepatocellular carcinoma (HCC) patients in US practice.
Eligible HCC patients identified from Optum's integrated database using standard codes as having had an index TACE between 2010 and 2016 with no additional oncologic therapy in the subsequent 3 months. At least one laboratory value (bilirubin, albumin, aspartate transaminase AST, alanine transaminase ALT, international normalized ratio INR) was required at baseline and the acute (≤29 days after TACE) and chronic (30-90 days after TACE) periods. Due to lack of universally accepted liver function deterioration criteria, clinically meaningful changes in laboratory parameters were pre-defined by authors (FP, RM, and SO).
Of the 3963 TACE patients, 572 were eligible for analyses. Deterioration of liver function from baseline occurred in the acute period and persisted in the chronic period (bilirubin 30 and 23%, albumin 52 and 31%, AST 44 and 25%, ALT 43 and 25%, INR 25 and 15%, respectively). In a subgroup analysis, a higher proportion of patients with diabetes had deterioration in AST and ALT.
A clinically meaningful proportion of real-world HCC patients had deterioration of liver function-related laboratory values 30-90 days after a single TACE in modern US practice. Future electronic health record research may help determine causality. The present findings highlight the need for the careful selection of patients for TACE, which is important to help optimize the benefit of the overall HCC treatment course.
A historically understudied group with increasing incidence, patients with early‐onset pancreatic cancer (EOPC) appear to have different treatment patterns than patients with average‐age‐onset ...pancreatic cancer (AOPC). Differences in the causal pathways of confounders and sources of bias common to all retrospective research suggest that future research is needed to confirm findings and that interventions to increase the receipt of appropriate treatment and to improve outcomes may differ between patients with EOPC and patients with AOPC.
Background
Despite the rapid adoption of immunotherapies in advanced non–small cell lung cancer (advNSCLC), knowledge gaps remain about their real‐world (rw) performance.
Methods
This retrospective, ...observational, multicenter analysis used the Flatiron Health deidentified electronic health record‐derived database of rw patients with advNSCLC who received treatment with PD‐1 and/or PD‐L1 (PD‐L1) inhibitors before July 1, 2017 (N = 5257) and had ≥6 months of follow‐up. The authors investigated PD‐(L)1 line of treatment and PD‐L1 testing rates and the relationship between overall survival (OS) and rw intermediate endpoints: progression‐free survival (rwPFS), rw time to progression (rwTTP), rw time to next treatment (rwTTNT), and rw time to discontinuation (rwTTD).
Results
First‐line PD‐(L)1 inhibitor use increased from 0% (in the third quarter of 2014 Q3 2014) to 42% (Q2 2017) over the study period. PD‐L1 testing also increased (from 3% in Q3 2015 to 70% in Q2 2017). The estimated median OS was 9.3 months (95% CI, 8.9‐9.8 months), and the estimated rwPFS was 3.2 months (95% CI, 3.1‐3.3 months). Longer OS and rwPFS were associated with ≥50% PD‐L1 percentage staining results. Correlations (⍴) between OS and intermediate endpoints were ⍴ = 0.75 (95% CI, 0.73‐0.76) for rwPFS and ⍴ = 0.60 (95% CI, 0.57‐0.63) for rwTTP, and, for treatment‐based intermediate endpoints, correlations were ⍴ = 0.60 (95% CI, 0.56‐0.64) for rwTTNT (N = 856) and ⍴ = 0.81 (95% CI, 0.80‐0.82) for rwTTD.
Conclusions
The use of first‐line PD‐(L)1 inhibitors and PD‐L1 testing has substantially increased, with better outcomes for patients who have ≥50% PD‐L1 percentage staining. Intermediate rw tumor‐dynamics estimates were moderately correlated with OS in patients with advNSCLC who received immunotherapy, highlighting the need for optimizing and standardizing rw endpoints to enhance the understanding of patient outcomes outside clinical trials.
Immunotherapy adoption in non–small cell lung cancer has been rapid. The evaluation of progression endpoints in large cohorts of real‐world patients is feasible and can assess real‐world immunotherapy performance.
Background & Aims The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies ...substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy. Methods A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174). Results The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK , which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort. Conclusions Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.
Introduction
Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, ...tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are standard clinical trial metrics. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches.
Methods
In this retrospective study, cohorts were randomly selected from Flatiron Health’s database of de-identified patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach tested for feasibility (
N
= 26). Three non-RECIST approaches were tested for feasibility, reliability, and validity (
N
= 200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. Qualitative and quantitative methods were used.
Results
A RECIST-based approach was not feasible: cancer progression could be ascertained for 23% (6/26 patients). Radiology- and clinician-anchored approaches identified at least one rwP event for 87% (173/200 patients). rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months 95% confidence interval (CI) 14, 19. Median real-world progression-free survival (rwPFS) was 5.5 months (95% CI 4.6, 6.3) and 4.9 months (95% CI 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman’s rho 0.65–0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context.
Conclusions
RECIST cannot adequately assess cancer progression in EHR-derived data because of missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data.
Funding
Flatiron Health Inc., which is an independent subsidiary of the Roche group.
Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC).
In 600 ...patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy.
Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all P
<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both P
<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence.
American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.
Background
Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real‐world patient populations. Here we analyzed real‐world outcomes of patients ...with metastatic non‐small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD‐1) inhibitors in the first year following U.S. regulatory approval.
Materials and Methods
This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR‐documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90‐day gap between advanced disease diagnosis and first EHR structured data entry were excluded.
Results
Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4–9.0 months). Estimated median OS was 4.7 months (3.4–6.6) for patients with anaplastic lymphoma kinase rearrangement‐ and epidermal growth factor receptor mutation‐positive tumors, and 8.6 months (7.7–10.6) for patients without such mutations. Age at PD‐1 inhibitor initiation or line of therapy did not impact OS.
Conclusion
This analysis suggests OS in real‐world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD‐1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies.
Implications for Practice
This study evaluated data derived from electronic health records of patients with metastatic non‐small cell lung cancer treated with programmed cell death protein 1 (PD‐1) inhibitors in the year following regulatory approval. This real‐world cohort had shorter overall survival (OS) indexed to PD‐1 inhibitor initiation than reported in clinical trials. Late‐line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real‐world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.
摘要
背景。虽然来自癌症临床试验的证据具有很强的内部效度，但是，人们可能很难将其推广到真实世界的患者群体中。在本研究中，我们对在美国监管机构批准后第一年将程序性细胞死亡蛋白 1 (PD‐1) 抑制剂用于治疗转移性非小细胞肺癌 (mNSCLC) 患者的真实世界结果进行分析。
材料和方法。本回顾性研究利用在社区癌症治疗诊所的常规患者治疗期间收集的电子病历 (EHR) 数据。队列包含曾接受针对转移性疾病的纳武单抗和帕博利珠单抗治疗的 mNSCLC 患者 (n = 1 344)，他们在 2011 年 1 月 1 日至 2016 年 3 月 31 日期间已完成 >1 次 EHR 记录的看诊。我们已排除晚期疾病诊断与首次 EHR 结构化数据录入之间的时间跨度 > 90 天的患者。
结果。预估的中位总生存期 (OS) 为 8.0 个月(95% 置信区间 7.4–9.0 个月)。在出现间变性淋巴瘤激酶重排阳性和表皮生长因子受体突变阳性的患者中，预估的中位 OS 为 4.7 个月 (3.4–6.6)；在未出现此类突变的患者中，预估的中位 OS 为 8.6 个月 (7.7–10.6)。开始 PD‐1 抑制剂治疗的年龄或治疗线数不会影响 OS。
结论。本分析表明，真实患者的 OS 可能比传统临床试验患者队列的 OS 短，这可能是因为试验资格标准范围受限。按治疗线数或开始免疫治疗的年龄划分的 OS 之间没有差异，这表明 PD‐1 抑制剂可令经过多次治疗的 mNSCLC 患者持续获益，而且，年龄不是预后的预测因子。我们正在对既往曾经过多次治疗且患有并存病和器官功能障碍的患者实施进一步研究。
实践意义:本研究评估了在监管机构批准后第一年接受程序性细胞死亡蛋白 1 (PD‐1) 抑制剂治疗的转移性非小细胞肺癌患者的电子病历的数据。与临床试验报告的数据相比，此真实队列中与开始 PD‐1 抑制剂治疗相关的总生存期 (OS) 更短。后线治疗不会影响 OS；在开始免疫治疗时，年龄 >75 岁的患者不会比年轻患者取得更差的结果。
随着各种新的疗法加入临床实践，真实数据可以为临床试验证据提供补充，从而提供关于普遍适用性的信息并协助传达临床治疗决策。
This article reports on overall survival outcomes in a real‐world cohort of patients with metastatic non‐small cell lung cancer treated with PD‐1 inhibitors post‐approval. Understanding the differences between these real‐world data and those reported from clinical trials may provide insights on the generalizability of clinical trial data and optimize clinical treatment decisions in practice.
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