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.

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.

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.

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.

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.

AbstractExtramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required.In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane‐ and/or platinum‐based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability.This is the first regimen to combine taxane and anthracycline. When treating breast cancer, anthracycline is regarded as the key cytotoxic agent, and anthracycline in combination with taxane constitutes a key chemotherapeutic regimen. Given our results, we speculate both drugs are critical chemotherapeutic agents for the treatment of metastatic EMPD.

AbstractLeptomeningeal disease is a rare complication of chronic lymphocytic leukemia (CLL). We report a case of leptomeningeal disease in CLL with a complete clinical response and clearance of cerebral spinal fluid (CSF) after treatment with ibrutinib and intrathecal rituximab. In a comprehensive review of the published literature since 1976, we found 136 cases of CLL with leptomeningeal spread. We found that leptomeningeal disease in patients with CLL responds favorably to treatment in most cases and is associated with longer overall survival than is expected for other cancers. Clearance of CSF is associated with improved survival. Treatment with rituximab and ibrutinib is more frequently associated with complete response compared with older agents.Implications for Practice.The incidence of leptomeningeal CLL is more common than previously described and can be recognized by attention to certain symptoms and signs. This case presentation and literature review reveals that, in many cases, leptomeningeal lymphomatosis is reversible with the use of rituximab and ibrutinib. The authors show a survival benefit associated with treating to cerebral spinal fluid (CSF) clearance by cytology and compare outcomes with various treatment strategies, focusing on novel agents. Now that there is effective therapy for leptomeningeal lymphoma in CLL, the importance for oncologists to recognize this neurologic complication has become clear.

AbstractBiosimilar filgrastims are primarily indicated for chemotherapy‐induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%–40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital‐only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the “rebate trap” with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered.Implications for Practice.We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing “rebate traps” where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

AbstractBackground.Juvenile‐onset recurrent respiratory papillomatosis (JO‐RRP) is a human papilloma virus‐mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO‐RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth.Materials and Methods.We treated two patients with refractory JO‐RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling.Results.Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on‐treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma.Conclusion.Nivolumab appears to have promising activity in JO‐RRP, and further clinical investigation with more patients in clinical trials is warranted.Implications for Practice.To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death‐1 (PD‐1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD‐1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.

AbstractBackground.The benefit of repeat lumpectomy for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery is currently inconclusive.Materials and Methods.Patients with IBTR with definitive surgery were identified in the Surveillance, Epidemiology, and End Results registry between 1973 and 2013. The effect of different IBTR surgeries on overall and cancer‐specific mortality was assessed using risk‐adjusted Cox proportional hazard regression modeling and stratified propensity score‐matching analysis (PSMA).Results.Of the 5,098 patients with IBTR, 4,048 (79.4%) women underwent mastectomy and 1,050 (20.1%) underwent repeat lumpectomy. In multivariable Cox regression analysis, repeat lumpectomy was associated with increased overall mortality (hazard ratio for death [HR], 1.522; 95% confidence interval [CI], 1.317–1.759; p < .001) and cancer‐specific mortality (HR, 1.666; 95% CI, 1.319–2.105; p < .001). Similar HRs were derived from the PSMA cohort. However, we found no significant difference in overall mortality for women who underwent repeat lumpectomy followed by radiation therapy (RT) compared with that for those who underwent mastectomy. Moreover, patients with IBTR with small tumors (≤1 cm) who underwent repeat lumpectomy with RT rather than without had similar overall and cancer‐specific survival rates to those who underwent mastectomy.Conclusion.Our investigation suggests that compared with mastectomy, repeat lumpectomy for IBTR is associated with higher overall and cancer‐specific mortality under real‐world observational conditions. Furthermore, repeat lumpectomy with RT is equivalent to mastectomy with respect to overall mortality and may influence treatment decision making for patients with small IBTR.Implications for Practice.Although mastectomy has been regarded as the standard treatment for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery, many patients diagnosed with small and early‐detected recurrent tumor might be technically suitable for a less invasive surgical procedure. However, different studies have drawn inconsistent conclusions. The present study is a population‐based analysis, which demonstrated the overall unfavorable impact of repeat lumpectomy over mastectomy on survival outcomes for patients with IBTR. However, patients with small IBTR (≤1 cm) that can tolerate radiation therapy may be the optimal candidates for repeat lumpectomy.