AbstractBackground.Research on cancer survivorship associated with nasopharyngeal carcinoma (NPC) is rare. We aimed to elucidate the risk of ischemic stroke in 5‐year survivors of NPC following radiotherapy (RT) or concurrent chemoradiation therapy (CCRT).Subjects, Materials, and Methods.NPC survivors, defined as those who survived longer than 5 years after diagnosis, were identified and matched at a 1:5 ratio with normal controls from the Longitudinal Health Insurance Database 2005 of Taiwan. The stratified Cox regression models were used to access the risk of ischemic stroke, with adjustment for age, treatment modality, comorbidities, and socioeconomic characteristics.Results.From 2000 to 2005, a total of 3,016 NPC survivors who had received RT (n = 959) or CCRT (n = 2,057) and 15,080 controls were matched for age, sex, income, and urbanization level. The risk of ischemic stroke was significantly higher in the NPC survivor cohort than in the control cohort. Stroke was positively related to death. Moreover, the age onset of stroke for NPC survivors was 10 years earlier than that for the general population.Conclusion.Not only was the stroke risk in NPC survivors higher than that in the general population, but the onset age was also 10 years earlier. Future survivorship care should include ischemic stroke as a late complication, for its proper prevention and management.Implications for Practice.Nasopharyngeal carcinoma (NPC) is endemic in Taiwan, and its 5‐year survival is 65.2%. With the increased 5‐year cancer survivors, survivorship has become an important issue. However, research on NPC survivorship is very rare. To the authors’ knowledge, this is the first population‐based study on long‐term NPC survivors. This study's results indicated that not only was the risk of ischemic stroke in NPC survivors at least triple that of the general population, but the onset age was also 10 years earlier. These results may provide solid evidence that survivorship care guidelines should include stroke as a late complication in 5‐year NPC survivors, for its proper prevention and management.
AbstractOn February 22, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product gemtuzumab ozogamicin (Mylotarg; Pfizer, New York City, NY), intended for the treatment of acute myeloid leukemia. Mylotarg was designated as an orphan medicinal product on October 18, 2000. The applicant for this medicinal product was Pfizer Limited (marketing authorization now held by Pfizer Europe MA EEIG).The demonstrated benefit with Mylotarg is improvement in event‐free survival. This has been shown in the pivotal ALFA‐0701 (MF‐3) study. In addition, an individual patient data meta‐analysis from five randomized controlled trials (3,325 patients) showed that the addition of Mylotarg significantly reduced the risk of relapse (odds ratio [OR] 0.81; 95% CI: 0.73–0.90; p = .0001), and improved overall survival at 5 years (OR 0.90; 95% CI: 0.82–0.98; p = .01) [Lancet Oncol 2014;15:986–996]. The most common (>30%) side effects of Mylotarg when used together with daunorubicin and cytarabine are hemorrhage and infection.The full indication is as follows: “Mylotarg is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33‐positive acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL).”The objective of this article is to summarize the scientific review done by the CHMP of the application leading to regulatory approval in the European Union. The full scientific assessment report and product information, including the Summary of Product Characteristics, are available on the European Medicines Agency website (www.ema.europa.eu).Implications for Practice.This article reflects the scientific assessment of Mylotarg (gemtuzumab ozogamicin; Pfizer, New York City, NY) use for the treatment of acute myeloid leukemia based on important contributions from the rapporteur and co‐rapporteur assessment teams, Committee for Medicinal Products for Human Use members, and additional experts following the application for a marketing authorization from the company. It's a unique opportunity to look at the data from a regulatory point of view and the importance of assessing the benefit‐risk.
AbstractImmunotherapy has changed the field of oncology around the world with the approval of immune checkpoint inhibitors for a number of tumor types over the last 5 years. However, immune‐mediated adverse events can be challenging and difficult to treat, with one of the most dire consequences being immune‐mediated pneumonitis.Key Points. Rapid intervention and aggressive management for grade 3 or greater pneumonitisSlow taper of steroids and also recommend pneumocystis carinii pneumonia prophylaxisMonitor carefully for a pneumonitis flare with steroid taper, which can occur in the absence of resuming anti‐programmed cell death protein 1 (PD‐1) , and do not resume anti‐PD‐1 therapy until completely off steroids and no clinical or radiologic evidence of recurrenceConsider observation without anti‐PD‐1 resumption—in this case, durable response was maintained even without resuming anti‐PD‐1 therapy.
Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response
AbstractBackground.Microsatellite instability (MSI)‐high (MSI‐H) colorectal cancer is known to be associated with increased tumor‐infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response.Materials and Methods.We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti‐CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.Results.Of the 345 patients, 57 demonstrated MSI‐H tumors and 288 demonstrated non‐MSI‐H tumors. MSI‐H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI‐H tumors and those with non‐MSI‐H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence‐free survival (RFS) or overall survival (OS) in the MSI‐H tumor group. In the non‐MSI‐H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS.Conclusions.The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response.Implications for Practice.This study demonstrates that the density of each subset of tumor‐infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)‐high and non‐MSI‐high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI‐high (MSI‐H) and non‐MSI‐H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI‐high gastric cancer.
Adapalene Gel 0.1% Versus Placebo as Prophylaxis for Anti‐Epidermal Growth Factor Receptor‐Induced Acne‐Like Rash: A Randomized Left‐Right Comparative Evaluation (APPEARANCE)
AbstractLessons Learned. The results of the APPEARANCE trial indicate that adapalene does not prevent acne‐like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect. Therefore, adapalene is not recommended as prophylaxis against acne‐like rash induced by anti‐epidermal growth factor receptor therapies.Given that acne‐like rash was completely controlled with placebo in approximately half of patients, predictive measures to identify patients needing intensive prophylaxis are required.Background.Anti‐epidermal growth factor receptor (EGFR) therapies are frequently associated with acne‐like rash. To evaluate the prophylactic efficacy of adapalene, a topical retinoid used as first‐line therapy for acne vulgaris, we conducted a randomized, placebo‐controlled, evaluator‐blinded, left‐right comparative trial.Methods.Patients with non‐small cell lung, colorectal, or head and neck cancer scheduled to receive anti‐EGFR therapies were randomly assigned to once‐daily adapalene application on one side of the face, with placebo on the other side. All patients had topical moisturizer coapplied to both sides of the face, and received oral minocycline. The primary endpoint was the difference in total facial lesion count of acne‐like rash at 4 weeks. Secondary endpoints included complete control rate (CCR) of acne‐like rash (≤5 facial lesions) and global skin assessment (Investigator's Global Assessment [IGA] scale, grade 0–4) at 4 weeks. Two blinded dermatologists independently evaluated the endpoints from photographs.Results.A total of 36 patients were enrolled, of whom 26 were evaluable. Adapalene treatment was associated with a greater lesion count than placebo at 4 weeks, although the difference was not statistically significant (mean, 12.6 vs. 9.8, p = .12). All four patients with a difference >10 in lesion count between face sides had a greater count on the adapalene‐treated side. No significant differences were observed in CCR of acne‐like rash (54% vs. 50%) or IGA scale (mean grade, 1.9 vs. 1.7) between the adapalene and placebo sides.Conclusion.Adapalene is not recommended as prophylaxis against acne‐like rash induced by anti‐EGFR therapies.
Inequalities in Financial Distress, Symptoms, and Quality of Life Among Patients with Advanced Cancer in France and the U.S.
AbstractBackground.Financial distress (FD) is common among patients with advanced cancer. Our purpose was to compare the frequency and intensity of FD and its associations with symptom distress and quality of life (QOL) in these patients in France and the U.S.Materials and Methods.In this secondary analysis of two cross‐sectional studies, we assessed data on 292 patients who received cancer care at a public hospital or a comprehensive cancer center in France (143 patients) or the U.S. (149 patients). Outpatients and hospitalized patients over 18 years of age with advanced lung or breast or colorectal or prostate cancer were included. Diagnosed cognitive disorder was considered a noninclusion criterion. Advanced cancer included relapse or metastasis or locally advanced cancer or at least a second‐line chemotherapy regimen. Patients self‐rated FD and assessed symptoms, psychosocial distress, and QOL on validated questionnaires.Results.The average patient age was 59 years, and 144 (49%) were female. FD and high intensity were reported more frequently in U.S. patients than in French (respectively 129 [88%] vs. 74 [52%], p < .001; 100 [98%] vs. 48 [34%], p < .001,). QOL was rated higher by the U.S. patients than by the French (69 [SD, 18] vs. 63 [SD, 18], p = .003). French patients had more psychological symptoms such as anxiety (8 [SD, 4] vs. 6 [SD, 5], p = .008). Associations were found between FD and U.S. residence, FD and single status (0.907, p = .023), and FD and metastasis (1.538, p = .036). In contrast, negative associations were found between FD and older age (−0.052, p = .003) and FD and France residence (−3.376, p = .001).Conclusion.Regardless of health care system, FD is frequent in patients with advanced cancer. U.S. patients were more likely to have FD than French patients but reported better QOL. Further research should focus on factors contributing to FD and opportunities for remediation.Implications for Practice.Suffering is experienced in any component of the lives of patients with a life‐threatening illness. Financial distress (FD) is one of the least explored cancer‐related symptoms, and there are limited studies describing its impact on this frail population. This study highlights the high frequency and severity of FD in patients with advanced cancer in the U.S. and France as well as its impact on their physical and emotional symptoms and their quality of life in these different health care systems. It is necessary for all health care providers to explore and evaluate the presence of FD in patients living with life‐threatening illnesses.
AbstractLessons Learned.Patients with metastatic colorectal cancer with good performance status or no liver metastasis could benefit from apatinib.Circulating tumor DNA abundance may be a predictor in serial monitoring of tumor load.Background.Apatinib, an oral vascular endothelial growth factor (VEGF) receptor‐2 inhibitor, has been approved as third‐line treatment for metastatic gastric cancer in China. The aim of this study was to evaluate the efficacy and safety of apatinib, in the treatment of patients with refractory metastatic colorectal cancer after failure of two or more lines of chemotherapy.Methods.In this open‐label, single‐arm, phase II study, patients with histological documentation of adenocarcinoma of the colon or rectum were eligible if they had received at least two prior regimens of standard therapies including fluoropyrimidine, oxaliplatin, and irinotecan. These patients were treated with apatinib in a daily dose of 500 mg, p.o., in the third‐line or higher setting. Capture sequencing was dynamically performed to identify somatic variants in circulating tumor DNA (ctDNA) with a panel of 1,021 cancer‐related genes. The primary endpoint was progression‐free survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Interim analysis was applied as predefined.Results.From June 1, 2016 to December 31, 2017, 26 patients were enrolled. The median PFS of the whole group was 3.9 months (95% confidence interval [CI]: 2.1–5.9). The median overall survival (OS) was 7.9 months (95% CI: 4.6–10.1+). Patients with performance status (PS) 0–1 had longer PFS than those with PS 2 (4.17 months vs. 1.93 months, p = .0014). Patients without liver metastasis also had longer PFS than those who had live metastasis (5.87 months vs. 3.33 months, p = .0274). The common side effects of apatinib were hypertension, hand‐foot syndrome, proteinuria, and diarrhea. The incidence of grade 3–4 hypertension, hand‐foot syndrome, proteinuria, and diarrhea was 76.92%, 11.54%, 73.08%, and 23.08%, respectively. All of the patients received dose reduction because of adverse effect. Results of capture sequencing showed APC, TP53, and KRAS were most frequently mutant genes. ctDNA abundance increased before the radiographic assessment in ten patients.Conclusion.Apatinib monotherapy showed promising efficiency for patients with refractory colorectal cancer, especially in patients with PS 0–1 or no liver metastasis. ctDNA abundance may be a predictor in serial monitoring of tumor load.
Inhibition of Serotonin Synthesis May Have Antitumor Activity? Long‐Term Efficacy in a Patient with Gastrointestinal Neuroendocrine Tumor
AbstractIn this article, we propose, based on a clinical case, the potential antitumor effect related to the inhibition of serotonin in neuroendocrine tumors (NETs). Currently, the only drug that exists for the symptomatic treatment of carcinoid syndrome refractory to somatostatin analogues is telotristat, based on its pivotal study, the TELESTAR trial. Based on the existing preclinical rationale, it seems that the inhibition of serotonin may have an antitumoral role in NETs. Briefly, serotonin may act as an autocrine growth factor of NETs, and it may also play an immunomodulatory role by enhancing macrophage polarization to an immunotolerant M2 phenotype. To our knowledge, this rationale for the possible antitumor effect of serotonin in NETs has not yet been published in the literature.
What Is Important When Making Treatment Decisions in Metastatic Breast Cancer? A Qualitative Analysis of Decision‐Making in Patients and Oncologists
AbstractBackground.Metastatic breast cancer (MBC) is an ideal environment for shared decision‐making because of the large number of guideline‐based treatment options with similar efficacy but different toxicity profiles. This qualitative analysis describes patient and provider factors that influence decision‐making in treatment of MBC.Materials and Methods.Patients and community oncologists completed in‐person interviews. Academic medical oncologists participated in focus groups. Interviews and focus groups were audio‐recorded, transcribed, and analyzed using NVivo. Using an a priori model based on the Ottawa Framework, two independent coders analyzed transcripts using a constant comparative method. Major themes and exemplary quotes were extracted.Results.Participants included 20 patients with MBC, 6 community oncologists, and 5 academic oncologists. Analysis of patient interviews revealed a decision‐making process characterized by the following themes: decision‐making style, contextual factors, and preferences. Patient preference subthemes include treatment efficacy, physical side effects of treatment, emotional side effects of treatment, cognitive side effects of treatment, cost and financial toxicity, salience of cutting‐edge treatment options (clinical trial or newly approved medication), treatment logistics and convenience, personal and family responsibilities, treatment impact on daily activities, participation in self‐defining endeavors, attending important events, and pursuing important goals. Physician decisions emphasized drug‐specific characteristics (treatment efficacy, side effects, cost) rather than patient preferences, which might impact treatment choice.Conclusion.Although both patients with MBC and oncologists considered treatment characteristics when making decisions, patients’ considerations were broader than oncologists’, incorporating contextual factors such as the innovative value of the treatment and life responsibilities. Differences in perspectives between patients and oncologists suggests the value of tools to facilitate systematic communication of preferences in the setting of MBC.Implications for Practice.Both patients with metastatic breast cancer (MBC) and oncologists emphasized importance of efficacy and physical side effects when making treatment decisions. However, other patient considerations for making treatment decisions were broader, incorporating contextual factors such as the logistics of treatments, personal and family responsibilities, and ability to attend important events. Furthermore, individual patients varied substantially in priorities that they want considered in treatment decisions. Differences in perspectives between patients and oncologists suggest the value of tools to facilitate systematic elicitation of preferences and communication of those preferences to oncologists for integration into decision‐making in MBC.
AbstractBackground.The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co‐mutations in resected epidermal growth factor receptor (EGFR)‐mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment.Materials and Methods.Mutation profiling of 416 cancer‐relevant genes was conducted for 139 resected stage I–IIIa lung ADCs with EGFR mutations using targeted next‐generation sequencing. Co‐mutation profiles were systematically analyzed.Results.Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first‐generation TKIs. Ninety‐one percent of patients harbored at least one co‐mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II–III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty‐four percent of patients with EGFR TKI‐sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1.Conclusion.Operable lung ADCs with EGFR TKI‐sensitizing mutations are associated with a high proportion of co‐mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy.Implications for Practice.The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next‐generation sequencing of 416 cancer‐relevant genes in 139 resected lung cancers revealed the co‐mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI‐resistant mutations in 34.71% of patients with a drug‐sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.
Pretreatment Hemoglobin as an Independent Prognostic Factor in Primary Central Nervous System Lymphomas
AbstractBackground.Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal lymphoma. Despite established clinical prognostic scoring such as that of the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Extranodal Lymphoma Study Group, outcome prediction needs to be improved. Several studies have indicated an association between changes in hematologic laboratory parameters with patient outcomes in PCNSL. We sought to assess the association between hematological parameters and overall survival (OS) in patients with PCNSL.Methods.Pretreatment blood tests were analyzed in patients with newly diagnosed PCNSL (n = 182), and we divided the analysis into two cohorts (A and B, both n = 91). OS was evaluated using the Cox proportional hazards models and log‐rank test. Furthermore, the accuracy of the different multivariate models was assessed by Harrell's concordance index (C‐index).Results.Using prechemotherapy blood tests, anemia was found in 38 patients (41.8%) in cohort A and 34 patients (37.4%) in cohort B. In univariate analysis, anemia (<12 g/dL in women and <13 g/dL in men) was significantly associated with OS. None of the other blood tests parameters (neutrophils, lymphocyte, or platelets counts) or their ratios (neutrophil‐to‐lymphocyte ratio and neutrophil‐to‐platelets ratio) were associated with OS. In multivariate analysis, after adjusting by MSKCC score, anemia remained an independent prognostic factor. Interestingly, the prediction accuracy of OS using Harrell's C‐index was similar using anemia or MSKCC (mean C‐index, 0.6) and was increased to 0.67 when combining anemia and MSKCC.Conclusion.The presence of anemia was associated with poor prognosis in both cohorts of PCNSL. Validation of these results and biologic role of hemoglobin levels in PCNSL requires further investigation.Implications for Practice.The prediction of the outcome of primary central nervous system lymphoma (PCNSL) using the most frequently used scores (i.e., Memorial Sloan Kettering Cancer Center [MSKCC] or International Extranodal Lymphoma Study Group) needs to be improved. We analyzed a large cohort of PCNSL to dissect the potential prognostic value of blood tests in this rare entity. We found anemia as an independent predictor for overall survival in PCNSL. Interestingly, the accuracy to predict PCNSL outcome was improved using hemoglobin level. This improvement was additional to the currently used clinical score (i.e., MSKCC). Finally, none of the other blood tests parameters or their ratios had a prognostic impact in this study.
Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non‐Small Cell Lung Cancer
AbstractBackground.Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti‐programmed cell death‐1 protein receptor (PD‐1)/programmed cell death‐1 protein ligand (PD‐L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non‐small cell lung cancer (NSCLC).Materials and Methods.A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length.Results.Higher ctDNA TMB was significantly correlated with smoking history (p < .05, chi‐squared test). Among patients treated with immune checkpoint inhibitors (n = 20), higher ctDNA TMB was significantly correlated with shorter progressive free survival (PFS) and overall survival (OS; 45 vs. 355 days; hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.3–24.6; p < .01, and OS 106 days vs. not reached; HR, 6.0; 95% CI, 1.3–27.1; p < .01, respectively). In a small independent validation cohort (n = 12), there was a nonsignificant numerical difference for higher ctDNA TMB predicting shorter OS but not PFS. ctDNA TMB was not correlated with RECIST tumor burden estimation in the subset of patients treated with immune checkpoint blockade.Conclusion.The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes.Implications for Practice.Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti‐PD‐1/PD‐L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood‐based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
From Diagnostic‐Therapeutic Pathways to Real‐World Data: A Multicenter Prospective Study on Upfront Treatment for EGFR‐Positive Non‐Small Cell Lung Cancer (MOST Study)
AbstractIntroduction.Gefitinib, erlotinib, and afatinib represent the approved first‐line options for epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real‐world data may help to depict the diagnostic‐therapeutic pathway and treatment outcome in clinical practice.Methods.MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic‐therapeutic pathway of patients with nonsquamous EGFR‐mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials.Results.An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first‐line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression‐free survival from pivotal phase III trials was €1,813,557.88.Conclusion.Good regional adherence and compliance to the diagnostic‐therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real‐world data in the process of drug price negotiation.Implications for Practice.The MOST study is a real‐world data collection reporting a multicenter adherence and compliance to diagnostic‐therapeutic pathways defined for patients with epidermal growth factor receptor‐mutant non‐small cell lung cancer. This represents an essential element of evidence‐based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn‐around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging‐to‐treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.
Endostatin and Oxaliplatin‐Based Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma: Results of a Phase II Study
AbstractLessons Learned. Definitive concurrent chemoradiotherapy based on oxaliplatin and endostatin was effective with the objective response rate exceeding 80%, and the treatment‐related toxicities were acceptable.The treatment compliance of the current combination was much higher, without significant reduction in survival outcomes, than historical reports.Background.This phase II trial aimed at assessing the efficiency and safety of definitive concurrent chemoradiotherapy (dCRT) using oxaliplatin (OHP) and endostatin in patients with inoperable esophageal squamous cell carcinoma (ESCC).Methods.Radiotherapy was delivered with a daily fraction of 2.0 Gy to a total dose of 60.0 Gy over 6 weeks. Endostatin and OHP were both intravenously administered at doses of 7.5 mg/m2 daily for 2 weeks and 135 mg/m2 on day 1, respectively, every 3 weeks. The primary endpoint was the objective response rate (ORR).Results.The analysis included 37 patients. The median age was 63 years (range: 49–71 years), and all patients were stage III–IVA. Of these patients, 97.3% (36/37) completed the dCRT course with an ORR of 83.8%, including 10 (27.0%) patients with complete response and 21 (56.8%) patients with partial response. The median overall survival (OS) time was 18.5 months (95% confidence interval [CI]: 10.6–26.4) with a 2‐year OS rate of 39.6% (95% CI: 0.202–0.590). The median progression‐free survival (PFS) time was 11.5 months (95% CI: 7.6–15.4) with a 2‐year PFS rate of 20.2% (95% CI: 0.049–0.355). Grade 3 toxicities included esophagitis (five patients) and leukocytopenia (three patients). Grade 4 leukopenia was observed in one patient. Late toxicity was infrequent, and no treatment‐related death occurred. Posttreatment dysphagia scores were significantly improved when compared with baseline (p < .001).Conclusion.dCRT based on OHP and endostatin resulted in high treatment compliance with manageable toxicities. This combination resulted in encouraging ORR without compromising survival outcomes. It should be validated in future clinical studies.
AbstractBackground.About one third of patients with diffuse large B‐cell lymphoma (DLBCL) relapse after receiving first‐line (1L) treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). Relapsed patients may then be eligible for second‐line (2L) therapy. The study's objective was to examine health care use and costs among treated patients with DLBCL receiving 2L therapy versus those without relapse.Materials and Methods.We analyzed Truven Health MarketScan® claims data between 2006 and 2015. Patients (≥18 years of age) had ≥1 DLBCL claim from 1 year before to 90 days after beginning 1L therapy, and comprised those without 2L treatment for ≥2 years (cured controls) versus those who initiated non‐R‐CHOP chemotherapy after discontinuing 1L therapy (2L cohort). 2L patients were further subgrouped: hematopoietic stem cell transplant (HSCT [yes/no]) and time of relapse (months between 1L and 2L): early (≤3), mid (4–12), and late (>12) relapse. The primary outcome was 1‐ and 2‐year health care costs. Hospitalization rate and length of stay were also measured.Results.A total of 1,374 patients with DLBCL received R‐CHOP and fulfilled all criteria: 1,157 cured controls and 217 2L patients (87 early‐relapse, 66 mid‐relapse, 64 late‐relapse). Twenty‐eight percent of 2L patients received HSCT. Charlson Comorbidity Index/mortality risk was higher for 2L patients (4.2 [SD: 3.0]) versus controls (3.8 [2.6]; p = .039), as were yearly costs (Year 1: $210,488 [$172,851] vs. $25,044 [$32,441]; p < .001 and Year 2: $267,770 [$266,536] vs. $42,272 [$49,281]; p < .001). HSCT and chemotherapy were each significant contributors of cost among 2L patients.Conclusion.DLBCL is resource intensive, particularly for 2L patients. Great need exists for newer, effective therapies for DLBCL that may save lives and reduce costs.Implications for Practice.This study identified multiple important drivers of cost in the understudied population of patients with diffuse large B‐cell lymphoma (DLBCL) receiving second‐line (2L) treatment. Such drivers included hematopoietic stem cell transplant (HSCT) and chemotherapy. Even though HSCT is currently the only curative therapy for DLBCL, less than one third of patients receiving 2L and subsequent treatment underwent transplant, which indicates potential underuse. The variation in chemotherapy regimens suggested a lack of consensus for best practices. Further research focusing on newer and more effective treatment options for DLBCL has the potential to decrease mortality, in addition to reducing the extensive costs related to therapy options such as transplant.
Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series
AbstractBackground.Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce.Patients and Methods.Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT‐2000 trial and the HIT‐2000 Interim Registry, were analyzed.Results.Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA‐fused ependymoma [ST‐EPN‐RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF‐EPN‐A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST‐EPN‐RELA were alive in first or second complete remission (CR) 7.5–12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST‐EPN‐RELA, n = 1; PF‐EPN‐A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0–9.7 years after diagnosis. Progression‐free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively.Conclusion.Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified.Implications for Practice.Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population‐based, well‐characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA‐fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.
The Potential Clinical Implications of Circulating Tumor Cells and Circulating Tumor Microemboli in Gastric Cancer
AbstractBackground.Gastric adenocarcinoma (GAC) is the third deadliest malignant neoplasm worldwide, mostly because of late disease diagnosis, low chemotherapy response rates, and an overall lack of tumor biology understanding. Therefore, tools for prognosis and prediction of treatment response are needed. Quantification of circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) and their expression of biomarkers has potential clinical relevance. Our aim was to evaluate CTCs and CTM and their expression of HER2 and plakoglobin in patients with nonmetastatic GAC, correlating the findings to clinicopathological data.Materials and Methods.CTC enrichment was performed with isolation by size of epithelial tumor cells, and the analysis was performed with immunocytochemistry and microscopy. Two collections were made: one at diagnosis (55 samples before neoadjuvant treatment) and one after surgery and before adjuvant therapy (33 samples).Results.A high detection rate of CTCs (90%) was observed at baseline. We evaluated HER2 expression in 45/55 biopsy samples and in 42/55 CTC samples, with an overlap of 36 subjects. Besides the good agreement observed for HER2 expression in primary tumors and paired CTCs for 36 cases (69.4%; κ = 0.272), the analysis of HER2 in CTCs showed higher positivity (43%) compared with primary tumors (11%); 3/5 patients with disease progression had HER2‐negative primary tumors but HER2‐positive CTCs. A significant CTC count drop in follow‐up was seen for CTC‐HER2‐positive cases (4.45 to 1.0 CTCs per mL) compared with CTC‐HER2‐negative cases (2.6 to 1.0 CTCs per mL). The same was observed for CTC‐plakoglobin‐positive cases (2.9 to 1.25 CTCs per mL).Conclusion.CTC analysis, including their levels, plakoglobin, and HER2 expression, appears to be a promising tool in the understanding the biology and prognosis of GAC.Implications for Practice.The analysis of circulating tumor cell levels from the blood of patients with gastric adenocarcinoma, before and after neoadjuvant treatment, is useful to better understand the behavior of the disease as well as the patients more likely to respond to treatment.
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