Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS: A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).

Land management explains major trends in forest structure and composition over the last millennium in California's Klamath Mountains.

SignificanceWe provide the first assessment of aboveground live tree biomass in a mixed conifer forest over the late Holocene. The biomass record, coupled with local Native oral history and fire scar records, shows that Native burning practices, along with a natural lightning-based fire regime, promoted long-term stability of the forest structure and composition for at least 1 millennium in a California forest. This record demonstrates that climate alone cannot account for observed forest conditions. Instead, forests were also shaped by a regime of frequent fire, including intentional ignitions by Native people. This work suggests a large-scale intervention could be required to achieve the historical conditions that supported forest resiliency and reflected Indigenous influence.

The impact of myelosuppression on quality of life of patients treated with chemotherapy.

Side effects from chemotherapy-induced myelosuppression can negatively affect patients' quality of life (QoL). Neutropenia increases infection risk, and anemia frequently results in debilitating fatigue. Additionally, the bleeding risk associated with thrombocytopenia can lead to fear and anxiety. However, traditional interventions for myelosuppression fall short of the ideal. Granulocyte colony-stimulating factors reduce the risk of severe neutropenia but commonly lead to bone pain. Erythropoiesis-stimulating agents are not always effective and may cause thromboembolic events, while transfusions to correct anemia/thrombocytopenia are associated with transfusion reactions and volume overload. Trilaciclib, which is approved for reducing myelosuppression in patients with extensive-stage small cell lung cancer, together with several investigational agents in development for managing myelosuppression have the potential to improve QoL for patients on chemotherapy.

Chemotherapy can cause side effects by killing blood-forming cells in the bone marrow. This is known as myelosuppression and leads to neutropenia (decreased neutrophils [white blood cells]), anemia (decreased red blood cells) and thrombocytopenia (decreased platelets). Neutropenia can increase the risk of getting an infection, and severe cases might result in patients being hospitalized. Both neutropenia and anemia can cause fatigue, which is often reported by patients as being the most draining symptom of chemotherapy. Thrombocytopenia increases the risk of bleeding and can cause patients with cancer to become even more scared and anxious. Myelosuppression due to chemotherapy is usually managed with delays or reductions in the amount of chemotherapy that patients receive, but this may worsen the disease. Other treatments, known as supportive care interventions, include growth factors, which stimulate the production of blood cells and red blood cell or platelet transfusions. However, having these treatments in addition to chemotherapy can be a burden to patients, and they can cause side effects such as bone pain and blood clots. A treatment called trilaciclib is approved by the US Food and Drug Administration for patients receiving certain types of chemotherapy for advanced small-cell lung cancer. Trilaciclib has been shown to reduce neutropenia, anemia and thrombocytopenia in these patients and improve their quality of life. Other drugs are also being assessed in clinical trials for preventing or treating myelosuppression in patients with different cancer types. In the future, these drugs may improve quality of life for patients on chemotherapy.

The impact of new and emerging agents on outcomes for febrile neutropenia: addressing clinical gaps.

PURPOSE OF REVIEW: While chemotherapy treatment options for patients with solid and hematologic malignancies have dramatically improved over recent years, chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) remain major barriers to delivering treatment at full doses and optimal timing. Despite concurrent advances in granulocyte colony-stimulating factor (G-CSF) administration, multiple barriers to the administration of and disparities in the access to these agents remain. The introduction of new, emerging agents, including biosimilars and novel therapies show promise in improving outcomes for CIN. RECENT FINDINGS: The introduction of biosimilar filgrastim products has improved access to G-CSF administration by driving marketplace competition and has reduced costs for both patients and healthcare systems without sacrificing efficacy. Emerging therapies to address similar issues include long-acting G-CSF products, efbemalenograstim alfa and eflapegrastin-xnst, as well as agents with novel mechanisms of action, plinabulin and trilaciclib. These agents have shown efficacy and cost-saving benefits in certain populations and disease groups. SUMMARY: Multiple emerging agents show promise in decreasing the burden of CIN. Use of these therapies will reduce access disparities and will improve outcomes for patients with cancer receiving cytotoxic chemotherapy. Many ongoing trials are underway to evaluate the roles of these agents for more widespread use.

Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

Chemotherapy-Induced Neutropenia and Febrile Neutropenia in the US: A Beast of Burden That Needs to Be Tamed?

Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost burden of chemotherapy-induced neutropenia/FN in the US, and summarizes recommendations for FN prophylaxis, including the interim guidance that was recommended during the coronavirus disease 2019 (COVID-19) pandemic. This review indicates that neutropenia/FN place a significant burden on patients in terms of hospitalizations and mortality. Most patients with neutropenia/FN presenting to the emergency department will be hospitalized, with an average length of stay of 6, 8, and 10 days for elderly, pediatric, and adult patients, respectively. Reported in-hospital mortality rates for neutropenia/FN range from 0.4% to 3.0% for pediatric patients with cancer, 2.6% to 7.0% for adults with solid tumors, and 7.4% for adults with hematologic malignancies. Neutropenia/FN also place a significant cost burden on US healthcare systems, with average costs per neutropenia/FN hospitalization estimated to be up to $40 000 for adult patients and $65 000 for pediatric patients. Evidence-based guidelines recommend prophylactic granulocyte colony-stimulating factors (G-CSFs), which have been shown to reduce FN incidence while improving chemotherapy dose delivery. Availability of biosimilars may improve costs of care. Efforts to decrease hospitalizations by optimizing outpatient care could reduce the burden of neutropenia/FN; this was particularly pertinent during the COVID-19 pandemic since avoidance of hospitalization was needed to reduce exposure to the virus, and resulted in the adaptation of recommendations to prevent FN, which expanded the indications for G-CSF and/or lowered the threshold of use to >10% risk of FN.

A prospective study to evaluate febrile neutropenia incidence in patients receiving pegfilgrastim on-body injector vs other choices.

PURPOSE: We evaluated the incidence of febrile neutropenia (FN) and related clinical outcomes among patients treated with myelosuppressive chemotherapy for nonmyeloid malignancies who received pegfilgrastim on-body injector (OBI) or other options (Other) for FN prophylaxis. METHODS: In this prospective observational study, adult patients with breast, prostate, or lung cancer, or non-Hodgkin lymphoma at risk for FN were stratified into subgroups based on FN prophylaxis used in the first chemotherapy cycle: pegfilgrastim OBI vs Other (pegfilgrastim or biosimilar pegfilgrastim prefilled syringe, daily filgrastim, or no granulocyte colony-stimulating factor [G-CSF]) for up to 4 planned chemotherapy cycles. RESULTS: This US study enrolled 2575 eligible patients (OBI, 1624; Other, 951). FN incidence was lower in the OBI group (6.4% [95% CI, 5.2-7.6%]) than in the Other group (9.4% [7.5-11.2%]), with a relative risk (RR) of 0.66 (0.47-0.91; p = .006). A decreased risk of dose delays among patients receiving pegfilgrastim OBI vs Other was observed (RR for ≥ 5 days: 0.64 [0.42-0.96], p = .023; RR for ≥ 7 days: 0.62 [0.40-0.91], p = .016). Adherence, defined as G-CSF support for all chemotherapy cycles, was 94.0% (92.9-95.2%) in the OBI group compared with 58.4% (55.2-61.5%) in the Other group. Compliance with pegfilgrastim, defined as administration the day after chemotherapy, was 88.3% in the OBI group and 48.8% in the prefilled syringe group. CONCLUSION: Patients receiving pegfilgrastim OBI had a lower incidence of FN compared with those receiving alternatives. The OBI was associated with improved adherence to and compliance with clinically recommended G-CSF prophylaxis.

A prospective cohort study to evaluate the incidence of febrile neutropenia in patients receiving pegfilgrastim on-body injector versus other options for prophylaxis of febrile neutropenia: breast cancer subgroup analysis.

BACKGROUND: Breast cancer chemotherapy often carries a high risk of febrile neutropenia (FN); guidelines recommend prophylaxis with granulocyte colony-stimulating factor (G-CSF), such as pegfilgrastim. Neulasta® Onpro® on-body injector (OBI) is a delivery device administering pegfilgrastim approximately 27 h after application. METHODS: This prospective study examined patients with breast cancer who received chemotherapy with a high risk of FN, receiving OBI ("OBI") or other options (other G-CSF or none; "other"). The primary endpoint was FN incidence; secondary endpoints included chemotherapy delivery, adherence (G-CSF in all cycles), compliance (G-CSF day after chemotherapy), and FN incidence in patients receiving curative or palliative treatment. RESULTS: A total of 1776 patients with breast cancer were enrolled (OBI, n = 1196; other, n = 580). Across all cycles, FN incidence was lower for OBI (4.4% [95% CI, 3.3-5.6%]) than other (7.4% [5.3-9.6%]). For curative treatment, the FN incidence across all cycles was lower for OBI (4.6% [3.4-5.8%]) than for other (7.1% [5.0-9.3%]). For palliative treatment (OBI, n = 33; other, n = 20), 3 patients (15%) in the other and none in the OBI group had FN. After adjusting for baseline covariates, FN incidence remained lower for OBI (4.6% [3.5-6.1%]) versus other (7.8% [5.7-10.5%]). Adherence was higher for OBI (93.8%) than for other G-CSF (69.8%), as was compliance (90.5 and 53.2%, respectively). Chemotherapy dose delays/reductions were similar for OBI (4.7%/32.3%, respectively) and other (4.7%/30.0%) groups. CONCLUSION: Pegfilgrastim OBI was associated with a lower FN incidence in patients with breast cancer compared to other options for FN prophylaxis. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02178475, registered 30 June, 2014.

Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Chemotherapy-induced toxicities lead to therapy dose reduction or delay, affecting patient outcomes. This systematic review and meta-analysis evaluated the impact of relative dose intensity (RDI) on survival in adult patients with solid tumor cancer on nonadjuvant-based chemotherapy regimens. METHODS: PubMed, Embase, and Web of Science databases were searched for peer-reviewed English journal articles or congress abstracts evaluating association between RDI and survival; observational studies, case series of ≥20 patients, and clinical trials published between 2013 and 2020 were eligible. Meta-analyses were conducted to quantify the association between RDI levels and overall survival (OS) among studies reporting a hazard ratio (HR) for OS by similar tumor types, regimens, and RDI. Forest plots represented summary HR and 95% confidence interval (CI); Cochran's Q and I2 tests evaluated study heterogeneity. RESULTS: Overall, 919 articles were reviewed and 22 included; seven were eligible for meta-analysis. Significantly shorter OS at RDI <80% versus ≥80% and <85% versus ≥85% was observed upon meta-analysis of four carboplatin-based studies for breast, non-small cell lung, or ovarian cancer (HR 1.17; 95% CI: 1.07-1.27) and three FOLFOX-, FOLFIRI-, or FOLFIRINOX-based studies for colorectal or pancreatic cancer (HR 1.39; 95% CI: 1.03-1.89). Grade 3 or higher hematologic toxicities were higher for carboplatin-based regimens (thrombocytopenia: 14%-22%; anemia: 15%-19%; neutropenia: 24%-58%) than FOLFOX-, FOLFIRI-, or FOLFIRINOX-based regimens (thrombocytopenia: 1%-4%; anemia: 5%-19%; neutropenia: 19%-47%). CONCLUSION: The results suggested longer OS with RDI ≥80% or ≥85% for both regimens, indicating that management of toxicities across treatment modalities may contribute to maintenance of higher RDI and benefit survival for patients with advanced solid tumors. IMPLICATIONS FOR PRACTICE: Chemotherapy-induced toxicities lead to dose reduction and/or treatment delay, thus affecting patient outcomes. Results of this systematic review and meta-analysis, evaluating the impact of relative dose intensity (RDI) on survival of patients with solid tumors on nonadjuvant-based chemotherapy regimens, demonstrate a longer overall survival with RDI levels of at least 80% for patients with solid tumors on carboplatin-based and FOLFOX-, FOLFIRI-, or FOLFIRINOX-based chemotherapy regimens, suggesting a protective effect of maintaining RDI ≥80% or ≥ -85%. Although grade 3 or higher hematologic toxicities occurred more in carboplatin-based studies, managing toxicities across treatment regimens may contribute to maintenance of higher RDI and ultimately benefit overall survival.

Do Patients Regret Having Received Systemic Treatment for Advanced Non-Small Cell Lung Cancer: A Prospective Evaluation.

BACKGROUND: Thousands of patients annually receive treatment for advanced non-small cell lung cancer (NSCLC), but little is known about their views on the decision to receive that treatment, or regret. This trial prospectively evaluated the incidence of regret and whether baseline characteristics, patient decision-making parameters, or clinical progress early in the treatment course predicts regret. MATERIALS AND METHODS: Patients receiving systemic treatment for advanced NSCLC completed every 3-week patient reported outcome (PRO) assessment using the electronic Lung Cancer Symptom Scale (eLCSS-QL), including the 3-Item Global Index (3-IGI; assessing overall distress, activities, and quality of life [QL]). A prespecified secondary aim was to determine the frequency of regret evaluated at 3 months after starting treatment. Patients were randomized to usual care or enhanced care (which included use of the DecisionKEYS decision aid). RESULTS: Of 164 patients entered, 160 received treatment and 142 were evaluable for regret. In total, 11.5% of patients and 9% of their supporters expressed regret. Baseline characteristics did not predict regret; regret was rarely expressed by those who had a less than 20% decline or improvement in the 3-IGI PRO score after two treatment cycles. In contrast, when asked if they would make the same decision again, only 1% not having a 20% 3-IGI decline expressed regret, versus 14% with a 3-IGI decline (p = .01). CONCLUSION: The majority of patients having regret were identified early using the PRO 3-IGI of the eLCSS-QL measure. Identifying patients at risk for regret allows for interventions, including frank discussions of progress and goals early in the treatment course, which could address regret in patients and their supporters. IMPLICATIONS FOR PRACTICE: This report documents prospectively, for the first time, the incidence of treatment-related regret in patients with advanced lung cancer and outlines that risk of regret is associated with patient-determined worsening health status early in the course of treatment. Identifying patients at risk for regret early in treatment (before the third cycle of treatment) appears to be crucial. Counseling at that time should include a discussion of consideration of treatment change and the reason for this change.

Effect of ischemia-reperfusion on outcomes after open mesenteric bypass for chronic mesenteric ischemia.

OBJECTIVE: Significant physiologic perturbations can occur in patients with chronic mesenteric ischemia (CMI) undergoing open mesenteric bypass (OMB). These events have frequently been attributed to ischemia-reperfusion events and have been directly implicated in the occurrence of multiple organ dysfunction (MOD). Scoring systems (MOD score [MODS] and sequential organ failure assessment [SOFA]) have been derived within the critical care field to provide a composite metric for these pathophysiologic changes. The purpose of the present study was to describe the early pathophysiologic changes that occur after OMB for CMI and determine whether these are predictive of the outcomes. METHODS: Patients with CMI who had undergone elective OMB from 2002 to 2018 at a single institution were reviewed. Changes in the hemodynamic, pulmonary, hepatic, renal, and hematologic parameters in the first 96 hours postoperatively were analyzed. The MODSs and SOFA scores were calculated. Cox regression was used to determine the association of the MODSs and SOFA scores with the outcomes. RESULTS: The use of OMB was analyzed for 72 patients (age, 66 ± 11 years; 68% women; body mass index, 23.8 ± 6 kg/m2; 48 ± 34-lb weight loss in 59%). Previous mesenteric stent placement or bypass had been performed in 39% [stenting in 21; bypass in 8; (one patient had both)]. An antegrade configuration (93%) was most common (retrograde configuration, 7%), with revascularization of the superior mesenteric artery/celiac vessels in 85% (superior mesenteric artery only in 15%). Postoperative pathophysiologic and metabolic changes were common, and the mean MODSs and SOFA scores were 3.6 ± 2.4 (range, 1-10) and 4.0 ± 2.7 (range, 1-13), respectively. The median length of stay was 14 days (interquartile range, 9-21). The 30-day mortality was 4% (n = 3) and in-hospital morbidity was 53% (n = 38; gastrointestinal, 25%; infectious, 22%; cardiac, 18%; pulmonary, 18%; renal, 11%). The clinical follow-up period was 16 ± 20 months. The MODSs and SOFA scores correlated linearly with overall mortality (MODS: odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.7; P < .01; SOFA score: OR, 1.4; 95% CI, 1.2-1.7; P < .01 per unit), with a score of ≥5 the inflection point most predictive of mortality (MODS: OR, 3.9; 95% CI, 1.6-9.9; P ≤ .01; SOFA score: OR, 2.8; 95% CI, 1.2-6.6; P = .02). The 1- and 3-year primary bypass patency and freedom from reintervention was 91% ± 5% and 83% ± 7%, respectively, with no association with the MODSs or SOFA scores. The 1- and 3-year survival was 86% ± 4% and 71% ± 6% with significantly worse outcomes for patients with higher MODSs and/or SOFA scores. CONCLUSIONS: Most CMI patients undergoing OMB will experience significant metabolic derangements resulting from sequelae of the ischemia-reperfusion phenomenon postoperatively. These can be objectively assessed in the early postoperative period using simply applied scoring systems to reliably predict the early and long-term outcomes. A derivation of the MODS and/or SOFA score after OMB for CMI can identify the most vulnerable patients at the greatest risk of mortality.

Prophylactic pegfilgrastim to prevent febrile neutropenia among patients receiving biweekly (Q2W) chemotherapy regimens: a systematic review of efficacy, effectiveness and safety.

BACKGROUND: Pegfilgrastim, a long-acting granulocyte colony-stimulating factor (G-CSF), is commonly used to prevent febrile neutropenia (FN), a potentially life-threatening complication, following myelosuppressive chemotherapy. The FDA label for pegfilgrastim specifies that it should not be administered 14 days before or within 24 h of administration of myelosuppressive chemotherapy, precluding the use of pegfilgrastim in biweekly (Q2W) regimens. The National Comprehensive Cancer Network and the European Organisation for Research and Treatment of Cancer guidelines support the use of prophylactic pegfilgrastim in patients receiving Q2W regimens. The objective of this study was to systematically review evidence from randomized clinical trials (RCTs) and observational studies that describe the effectiveness and safety of prophylactic pegfilgrastim in preventing FN among patients receiving Q2W regimens. METHODS: An Ovid MEDLINE, Embase, and Cochrane Library literature search was conducted to evaluate the evidence regarding efficacy, effectiveness, and safety of prophylactic pegfilgrastim versus no prophylactic pegfilgrastim or prophylaxis with other G-CSF in patients who were receiving Q2W chemotherapy regimens with high (> 20%) or intermediate (10-20%) risk of FN for a non-myeloid malignancy. Studies that addressed absolute or relative risk of FN, grade 1-4 neutropenia, all-cause or any hospitalization, dose delays or dose reductions, adverse events, or mortality were included. Studies where the comparator was a Q3W chemotherapy regimen with primary prophylactic pegfilgrastim were also included. RESULTS: The initial literature search identified 2258 publications. Thirteen publications met the eligibility criteria, including eight retrospective, one prospective, one phase 1 dose escalation study, and three RCTs. In nine of the 13 studies reporting incidence of FN, and in seven of the nine studies reporting incidence of neutropenia, administration of prophylactic pegfilgrastim in patients receiving Q2W regimens resulted in decreased or comparable rates of FN or neutropenia compared with patients receiving filgrastim, no G-CSF, lipefilgrastim or pegfilgrastim in Q3W regimens. In six of the nine studies reporting safety data, lower or comparable safety profiles were observed between pegfilgrastim and comparators. CONCLUSIONS: In a variety of non-myeloid malignancies, administration of prophylactic pegfilgrastim was efficacious in reducing the risk of FN in patients receiving high- or intermediate-risk Q2W regimens, with an acceptable safety profile. TRIAL REGISTRATION: PROSPERO registration no: CRD42019155572 .

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer.

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality. CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Contemporary outcomes of thoracofemoral bypass.

OBJECTIVE: Thoracofemoral bypass (TFB) is an alternative to aortofemoral bypass (AFB) or extra-anatomic bypass for severe aortoiliac occlusive disease (AIOD). TFB may be particularly useful in select patients with concurrent visceral aortic branch vessel disease, infrarenal aortic occlusions, or after failed AFB. However, there are few contemporary series describing the indications and outcomes for TFB. Therefore, the purpose of this analysis was to review our experience with TFB. METHODS: All patients undergoing TFB for occlusive disease from 2002 to 2017 were reviewed. All patients underwent left thoracoretroperitoneal exposure of the supraceliac aorta with division of the diaphragmatic crus and supraceliac cross-clamping. An end-to-side aortic anastomosis was created and each graft limb was tunneled in the retroperitoneum to the femoral bifurcation. Adjunctive visceral/infrainguinal revascularization was performed selectively based on symptoms, end-organ function, and/or preoperative imaging. The primary end points were major complications and 30-day mortality. Secondary end points included limb patency, freedom from major adverse limb events, and survival. Kaplan-Meier methodology was used to characterize the end points. RESULTS: Forty-one patients (age 61 ± 9 years; 54% female; 7% in a hypercoaguable state) underwent TFB. The mean preoperative ankle-brachial index was 0.4 bilaterally. Indications included critical limb ischemia (56%), claudication (30%), acute limb ischemia (7%), and combined AIOD and mesenteric ischemia (7%). Seven patients (17%) had previously undergone AFB and 15 (38%) had previously undergone any prior aortic operation. Adjunctive visceral bypass occurred in 8 patients (20%; N = 14 grafts, n = 6 renal, n = 5 superior mesenteric artery, and n = 3 celiac). The postoperative duration of stay was 11 days (interquartile range [IQR], 7-16 days) and the 30-day mortality was 5% (n = 2). Major complications occurred in 34% of patients (N = 14; pulmonary, 15%; cardiac, 12%; bleeding, 7%; accidental splenectomy, 5%; renal, 5%; wound, 2%). The mean postoperative ankle-brachial index was 0.9 bilaterally. At a median follow-up of 7 months (IQR, 1-17 months), 5 patients (12%) underwent some form of reintervention (graft/limb related, n = 4 [n = 2 graft thrombosis, n = 2 graft infection], n = 1 mesenteric bypass revision). The estimated 3-year primary limb patency and freedom from major adverse limb events were 80 ± 10%, and 70 ± 10%, respectively. The estimated 5-year survival was 93 ± 5% (median, 27.3; IQR, 14.5-35.2; 95% confidence interval, 17.9-32.8). CONCLUSIONS: This experience represents one of the largest and most current series of retroperitoneal TFB. We demonstrate that TFB can be performed with good outcomes for patients with severe AIOD, especially if concomitant visceral/infrainguinal reconstruction is warranted. These results support a continued role for TFB in select patients.

A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer.

PURPOSE: This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS: This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS: Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION: The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE: This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.

Tibial artery duplex ultrasound-derived peak systolic velocities may be an objective performance measure after above-knee endovascular therapy for arterial stenosis.

OBJECTIVE: The ankle-brachial index (ABI) is a well-established measure of distal perfusion in lower extremity ischemia; however, the ABI is of limited value in patients with noncompressible lower extremity arteries. We sought to demonstrate whether duplex ultrasound-determined tibial artery velocities can be used as an alternative to ABI as an objective performance measure after endovascular treatment of above-knee arterial stenosis. METHODS: Thirty-six patients undergoing above-knee endovascular intervention had preprocedure and postprocedure duplex ultrasound examination within 6 months of intervention. Preprocedure vs postprocedure changes in tibial artery mean peak systolic velocity (PSV; mean of proximal, mid, and distal velocities) were compared with changes in ABI and a reference (control) cohort of 68 patients without peripheral vascular disease. RESULTS: Thirty-six patients (41 limbs) had an above-knee endovascular intervention and had preprocedure and postprocedure duplex ultrasound examinations of the ipsilateral extremity including the tibial arteries. Before the procedure, mean tibial artery PSVs in the 36 patients undergoing intervention were outside (below) the 95% confidence intervals for the control patients. In comparing preprocedure and postprocedure PSVs, the mean anterior tibial (P < .01), mean peroneal (P < .01), and mean posterior tibial (P < .01) PSVs all increased and correlated with an increase in ABI (P < .01). After endovascular intervention, duplex ultrasound-derived mean PSVs fell within or near established reference ranges for patients without peripheral arterial disease. Mean tibial artery PSV increases were similar in patients with and without noncompressible vessels. CONCLUSIONS: Tibial artery PSVs increase, correlate with an increase in ABI, and fall within or near confidence intervals for normal controls after above-knee endovascular interventions. After endovascular intervention, tibial artery PSVs can supplement ABI as an objective performance measure in patients with and in particular without compressible tibial arteries.

Intraluminal thrombus is associated with early rupture of abdominal aortic aneurysm.

BACKGROUND: The implications of intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) are currently unclear. Previous studies have demonstrated that ILT provides a biomechanical advantage by decreasing wall stress, whereas other studies have associated ILT with aortic wall weakening. It is further unclear why some aneurysms rupture at much smaller diameters than others. In this study, we sought to explore the association between ILT and risk of AAA rupture, particularly in small aneurysms. METHODS: Patients were retrospectively identified and categorized by maximum aneurysm diameter and rupture status: small (<60 mm) or large (≥60 mm) and ruptured (rAAA) or nonruptured (non-rAAA). Three-dimensional AAA anatomy was digitally reconstructed from computed tomography angiograms for each patient. Finite element analysis was then performed to calculate peak wall stress (PWS) and mean wall stress (MWS) using the patient's systolic blood pressure. AAA geometric properties, including normalized ILT thickness (mean ILT thickness/maximum diameter) and % volume (100 × ILT volume/total AAA volume), were also quantified. RESULTS: Patients with small rAAAs had PWS of 123 ± 51 kPa, which was significantly lower than that of patients with large rAAAs (242 ± 130 kPa; P = .04), small non-rAAAs (204 ± 60 kPa; P < .01), and large non-rAAAs (270 ± 106 kPa; P < .01). Patients with small rAAAs also had lower MWS (44 ± 14 kPa vs 82 ± 20 kPa; P < .02) compared with patients with large non-rAAAs. ILT % volume and normalized ILT thickness were greater in small rAAAs (68% ± 11%; 0.16 ± 0.04 mm) compared with small non-rAAAs (53% ± 16% [P = .02]; 0.11 ± 0.04 mm [P < .01]) and large non-rAAAs (57% ± 12% [P = .02]; 0.12 ± 0.03 mm [P < .01]). Increased ILT % volume was associated with both decreased MWS and decreased PWS. CONCLUSIONS: This study found that although increased ILT is associated with lower MWS and PWS, it is also associated with aneurysm rupture at smaller diameters and lower stress. Therefore, the protective biomechanical advantage that ILT provides by lowering wall stress seems to be outweighed by weakening of the AAA wall, particularly in patients with small rAAAs. This study suggests that high ILT burden may be a surrogate marker of decreased aortic wall strength and a characteristic of high-risk small aneurysms.

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim.

PURPOSE: Filgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports. METHODS: A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes. RESULTS: A total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53-0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37-0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29-5.27 in CIN). Additional efficacy and safety outcomes are described within indications. CONCLUSIONS: This systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials.

PURPOSE: The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. MATERIALS AND METHODS: Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)-log HROS and log HRPFS-measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. RESULTS: The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8-3.5 months) and the median OS was 7.2 months (95% CI, 6.5-8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. CONCLUSIONS: The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:189-198Implications for Practice: For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.

Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients had minor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed. Dasatinib 70 mg twice daily does not have activity nor is it well tolerated in unselected patients with advanced stage, previously treated NSCLC.