Multimodal Treatment in Operable Stage III NSCLC: A Pooled Analysis on Long-Term Results of Three SAKK trials (SAKK 16/96, 16/00, and 16/01)

Introduction

Long-term data on outcomes of operable stage III NSCLC are scarce.

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group

Background

Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I–III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported.

Methods

Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non–low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%–94.0%) and 95.6% (95% CI, 90.8%–100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%–100.0%) and 97.6% (95% CI, 90.0%–100.0%), respectively. Twenty-six patients with non–low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%–100.0%) and 95.8% (95% CI, 87.7%–100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%–88.8%).

Conclusions

Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non–low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.     

Phase 2 prospective open label study of neoadjuvant nab-paclitaxel,trastuzumab, and pertuzumab in patients with HER2-positive primary breast cancer

Background

The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival.

Methods

Forty-five patients with HER2+ BC Stages II–III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m² intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days).

Results

Median follow-up was 60 months (95% CI, 32.3–55.6) and pCR was 29/45 (64%). The 5-year iDFS for patients who achieved pCR (N = 29) was 96.3% (95% CI, 76.5–99.5) and non-pCR patients (N = 16) was 74.3% (95% CI, 39.1–91.0). The 5-year overall survival (N = 45) was 94.1% (95% CI, 77.6–98.5). Based on hormonal status, the 5-year iDFS for HR+ pCR patients (N = 14) was 92.3% (95% CI, 56.6–98.9) and for HR− (N = 15) was 100% (p = .3).

Conclusions

This anthracycline/carboplatin-free regimen with nab-paclitaxel achieved a pCR rate of 64% in patients with HER2+ BC. The 5-year iDFS in patients with and without pCR was 96.3% and 74.3%, respectively. The pCR rate is comparable with docetaxel, carboplatin, trastuzumab, and pertuzumab therapy in the NAT setting, but with fewer treatment-associated toxicities. This finding suggests the possibility of safe avoidance of anthracyclines and carboplatin as components of NAT in patients with HER2+ BC.     

Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial

Background

This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT).

Methods

Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost.

Results

Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54–0.86, and 65%, 95% CI, 0.52–0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78–17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT.

Conclusions

PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.     

Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia

Background

A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B-ALL.

Methods

Data from five trials of blinatumomab for R/R B-ALL were pooled for analyses. Patients were placed in one of three groups: group 1, ≥50% bBMBs; group 2, ≥25% to <50% bBMBs; group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups.

Results

Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio [OR], 3.50 [95% confidence interval (CI), 2.23–5.48] and 3.93 [95% CI, 2.50–6.18], respectively; p < .001) and minimal/measurable residual disease response (OR, 2.61 and 3.37, respectively; p < .001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio [HR], 0.63 and 0.54, respectively; p < .001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively; p < .001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab.

Conclusion

Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for R/R B-ALL.     

The Role of Prophylactic Cranial Irradiation in Patients With Extensive Stage Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Introduction

The role of prophylactic cranial irradiation (PCI) is controversial in patients with extensive stage small cell lung cancer. The aim of this study was to determine the impact of PCI in these patients.

Resection of liver metastases from breast cancer: a multicentre analysis

Background

Surgery is becoming more practical and effective than conservative treatment in improving the poor outcomes of patients with breast cancer liver metastasis (BCLM). However, there is no generally acknowledged set of standards for identifying BCLM candidates who will benefit from surgery.

Methods

Between January 2011 and September 2018, 67 female BCLM patients who underwent partial hepatectomy were selected for analysis in the present study. Prognostic factors after hepatectomy were determined. Univariate and multivariate analyses were performed to identify predictors of overall survival (OS) and intrahepatic recurrence-free survival (IHRFS).

Results

The 1-, 3- and 5-year OS of patients treated with surgery was 93.5%, 73.7% and 32.2%, respectively, with a median survival time of 57.59 months. The Pringle manoeuvre [hazard radio (HR)?=?0.117, 95% CI0.015–0.942, p?=?0.044] and an increased interval between breast surgery and BCLM diagnosis (HR0.178, 95% CI 0.037–0.869, p?=?0.033) independently predicted improved overall survival for BCLM patients. The 1-, 2- and 3-year IHRFS of patients who underwent surgery was 62.8, 32.6% and 10.9%, respectively, with a median intrahepatic recurrence-free survival time of 13.47 months. Moderately differentiated tumours (HR ?0.259, 95% CI 0.078–0.857, p?=?0.027) and the development of liver metastasis more than 2 years after breast surgery (HR ?0.270, 95% CI 0.108–0.675, p?=?0.005) might be predictors of increased IHRFS.

Conclusions

An interval of more than 2 years between breast cancer surgery and liver metastasis seems to be an indication of liver surgery in BCLM patients. The Pringle manoeuvre and moderately differentiated tumours are potential predictors associated with OS and IHRFS, respectively, as benefits from liver resection. Studies with increased sample sizes are warranted to validate our results.

     

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial

Background

The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer.

Methods

In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose.

Results

Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46–0.76] vs. ISD HR, 0.69 [95% CI, 0.48–0.98]) and the homologous recombination–deficient (FSD HR, 0.44 [95% CI, 0.30–0.64] vs. ISD HR, 0.39 [95% CI, 0.22–0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD.

Conclusions

In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.     

Long-term oncologic outcomes of robotic gastrectomy for gastric cancer compared with laparoscopic gastrectomy

Background

Initial experiences with robotic gastrectomy (RG) for gastric cancer have demonstrated favorable short-term outcomes, suggesting that RG is an effective alternative to laparoscopic gastrectomy (LG). However, data on long-term survival and recurrence after RG for gastric cancer have yet to be reported. The objective of this study was to assess long-term outcomes after RG compared with LG.

Methods

We retrospectively evaluated 313 and 524 patients who underwent RG or LG, respectively, for gastric cancer between July 2005 and December 2009. We compared long-term outcomes using the entire and a propensity-score matched cohort.

Results

The entire cohort analysis revealed no statistically significant differences in 5-year overall survival(OS) or relapse-free survival(RFS) (p = 0.4112 and p = 0.8733, respectively): 93.3% [95% confidence interval (CI) 89.9–95.6] and 90.7% (95% CI, 86.9–93.5) after RG and 91.6% (95% CI 88.9–93.7) and 90.5% (95% CI 87.6–92.7) after LG, respectively; hazard ratios for death and recurrence in the robotic group were 0.828 (95% CI, 0.528–1.299; p = 0.4119) and 0.968 (95% CI, 0.649–1.445; p = 0.8741), respectively. The propensity-matched cohort analysis demonstrated no statistically significant differences for 5-year OS or RFS (p = 0.5207 and p = 0.2293, respectively): 93.2% and 90.7% after RG and 94.2% and 92.6% after LG, respectively; hazard ratios for death and recurrence in the robotic group were 1.194 (95% CI, 0.695–2.062; p = 0.5214) and 1.343 (95% CI, 0.830–2.192; p = 0.2321), respectively.

Conclusion

The potential technical superiority of robotic system over laparoscopy did not improve oncological outcomes after gastrectomy. Long-term oncological outcomes were not different between RG and LG. Nevertheless, robotic applications in minimally invasive gastric cancer surgery may be an oncologically safe alternative.

     

Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non–small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3

Background

EMPOWER-Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimab plus platinum-doublet chemotherapy versus placebo plus chemotherapy for first-line treatment of advanced non–small cell lung cancer. This study evaluated patient-reported outcomes (PROs).

Methods

PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) and Quality of Life-Lung Cancer Module (QLQ-LC13) questionnaires. Prespecified analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and proportional hazards model.

Results

A total of 312 patients were assigned to receive cemiplimab plus platinum-doublet chemotherapy and 154 to receive placebo plus chemotherapy; 391 (83.9%) were male and the median age was 63.0 years (range, 25–84). For pain symptoms (EORTC QLQ-C30), a statistically significant overall improvement from baseline (−4.98, 95% confidence interval [CI] −8.36 to −1.60, p = .004) and a statistically significant delay in TTD (hazard ratio, 0.39; 95% CI, 0.26–0.60, p < .0001) favoring cemiplimab plus chemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimab plus chemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimab plus chemotherapy compared with nonsignificant overall change from baseline for placebo plus chemotherapy (1.69, 95% CI, 0.20–3.19 vs. 1.08, 95% CI, –1.34 to 3.51; between arms, p = .673). No analyses yielded statistically significant PRO results favoring placebo plus chemotherapy for any QLQ-C30 or QLQ-LC13 scale.

Conclusion

Cemiplimab plus chemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer-related and lung cancer–specific symptoms and functions.     

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded,Placebo-Controlled,Randomized Phase III Trial (ALTER0703)

Background

Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC.

Materials and Methods

This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1–14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.

Results

A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4–4.5) over placebo group (1.5 months; 95% CI, 1.4–1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27–0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8–9.7 vs. 7.2 months; 95% CI, 6.2–8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%).

Conclusion

Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients.

Implications for Practice

In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

     

Spinal metastases from thyroid cancer: Some prognostic factors

BackgroundSpinal metastases (SpMs) from thyroid cancers (TC) significantly reduce quality of life by causing pain, neurological deficits in addition to increasing mortality. Moreover, prognosis factors including surgery remain debated.MethodsData were stored in a prospective French national multicenter database of patients treated for SpM between January 2014 and 2017. Fifty-one consecutive patients affected by TC with 173 secondary SpM were included.ResultsMean overall survival (OS) time for all patients from the diagnosis of a thyroid SpM event was 9.1 years (SD 8.7 months). The 1-year, 5-year and 10-year survival estimates were 94% (SD 3.3), 83.8.0% (SD 5.2), and 74.5% (SD 9.9). The median period of time between primary thyroid tumor diagnosis and the SpM event was 31.4 months (SD 71.6). In univariate analysis, good ECOG-PS (status 0 and 1) (p < 0.0001), ambulatory status (Frankel score) (p < 0.0001) and no epidural involvement (p = 0.01), were associated with longer survival, whereas cancer subtype (p = 0.436) and spine surgery showed no association (p = 0.937). Cox multivariate proportional hazard model only identified good ECOG-PS: 0 [HR: 0.3, 95% CI 0.1–0.941; p < 0.0001], 1 [HR: 0.8, 95% CI 0.04–2.124; p = 0.001] and ambulatory neurological status: Frankel E [HR: 0.262, 95% CI 0.048–1.443; p = 0.02] to be independent predictors of better survival.ConclusionFor cases presenting SpM from TC, we highlighted that the only prognostic factors were the progression of the cancer (ECOG-PS) and the clinical neurological impact of the SpM (Frankel status). Surgery should be discussed mainly for stabilization and neurological decompression.     

Résultats de la radiothérapie dans les carcinomes épidermoïdes du larynx avec atteinte sous-glottique

BackgroundSquamous cell carcinoma of larynx with subglottic extension is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of definitive radiotherapy in patients with squamous cell carcinoma.Patients and methodsBetween 1998 and 2012, 56 patients with squamous cell carcinoma were treated at our institution and included in the analysis. Patients received definitive radiotherapy/chemoradiotherapy alone (63%) or after induction chemotherapy (37%) at our institute.ResultsThe 5-year actuarial overall survival, progression-free survival and specific survival were 64% (CI 95%: 48–90), 45% (CI 95%: 28–61), 88% (CI 95%: 78–98), respectively, with median follow-up of 74 months. The 5-year locoregional control was 69% (CI 95%: 56–83) and the 5-year distant control was 95% (CI 95%: 89–100). There was no difference in overall survival and locoregional control according to front-line treatments or between primary subglottic cancer and glotto-supraglottic cancers with subglottic extension. In the multivariate analysis, performance status of at least 1 and positive N stage were the only predictors for overall survival (hazard ratio [HR] [CI 95%]: 6.5 [1.3–34; P = 0.03] and 11 [1.6–75; P = 0.02], respectively). No difference of locoregional control was observed according to the first received therapy. The univariate analysis retrieved that T3–T4 patients had a lower locoregional control (HR: 3.1; CI 95%: 1.1–9.2, P = 0.04), but no prognostic factor was retrieved in the multivariate analysis. In patients receiving a larynx preservation protocol, 5-year larynx preservation rate was 88% (CI 95%: 78–98), and 58% in T3 patients. The 5-year larynx preservation rate was 91% (CI 95%: 79–100) and 83% (CI 95%: 66–100) for patients who received radiotherapy/chemoradiotherapy or induction chemotherapy as a front-line treatment, respectively.ConclusionThis analysis suggests that the results for squamous cell carcinoma patients treated with radiotherapy/chemoradiotherapy are comparable to those obtained for other laryngeal tumors. This thus suggests the feasibility of laryngeal preservation protocols for infringement subglottic for selected cases. Further studies are needed to clarify these preliminary data.     

A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non–Small Cell Lung Cancer

Introduction

We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC.

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial

IntroductionEMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53–0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results.MethodsPatients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates.ResultsAfter 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9–23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6–15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51–0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4–9.0) versus 5.5 months (95% CI: 4.3–6.2) (HR = 0.55, 95% CI: 0.44–0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone.ConclusionsAt protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.     

Esophagectomy With Three-Field Versus Two-Field Lymphadenectomy for Middle and Lower Thoracic Esophageal Cancer: Long-Term Outcomes of a Randomized Clinical Trial

IntroductionThe optimal extent of lymphadenectomy during esophagectomy remains unclear. In this trial, we aim to clarify whether three-field (cervical-thoracic-abdominal) lymphadenectomy improved patient survival over two-field (thoracic-abdominal) lymphadenectomy for esophageal cancer.MethodsBetween March 2013 and November 2016, a total of 400 patients with middle and lower thoracic esophageal cancer were included and randomly assigned to undergo esophagectomy with either three- or two-field lymphadenectomy at a 1:1 ratio. Analyses were done according to the intention-to-treat principle. The primary end point was overall survival (OS), calculated from the date of randomization to the date of death from any cause.ResultsDemographic characteristics were similar in the two arms. The median follow-up time was 55 months (95% confidence interval [CI]: 52–58). OS (hazard ratio [HR] = 1.019, 95% CI: 0.727–1.428, p = 0.912) and the disease-free survival (DFS) (HR = 0.868, 95% CI: 0.636–1.184, p = 0.371) were comparable between the two arms. The cumulative 5-year OS was 63% in the three-field arm, as compared with 63% in the two-field arm; 5-year DFS was 59% and 53%, respectively. On the basis of whether the patients had mediastinal or abdominal lymph node metastasis or not, OS was also comparable between the two arms. In this cohort, only advanced tumor stage (pathologic TNM stages III–IV) was identified as the risk factor associated with reduced OS (HR = 3.330, 95% CI: 2.140–5.183, p < 0.001).ConclusionsFor patients with middle and lower thoracic esophageal cancer, there was no improvement in OS or DFS after esophagectomy with three-field lymphadenectomy over two-field lymphadenectomy.     

LAG-3 Protein Expression in Non–Small Cell Lung Cancer and Its Relationship with PD-1/PD-L1 and Tumor-Infiltrating Lymphocytes

IntroductionImmunotherapy targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint has shown promising efficacy in patients with NSCLC. Lymphocyte activating 3 gene (LAG-3) is another important checkpoint, and its role in NSCLC is still not clear. In this study we investigated lymphocyte activing 3 (LAG-3) protein expression; its correlation with PD-1, PD-L1, and tumor-infiltrating lymphocytes (TILs); and its association with survival in NSCLC.MethodsThe expression of LAG-3 (EPR4392 [Abcam, Cambridge, MA]) protein was assessed in 55 NSCLC cell lines by immunohistochemistry. LAG-3, PD-1 (NAT 105 [Cell Marque, Rocklin, CA]), and PD-L1 (22C3 [Dako, Carpenteria, CA]) protein expression was evaluated by immunohistochemistry, and TIL abundance was scored in 139 surgically resected specimens from patients with NSCLC. We also verified results in samples from 62 patients with untreated NSCLC and detected a correlation between LAG-3 expression and EGFR and KRAS mutation and echinoderm microtubule associated protein like 4 gene (EML4)–anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement.ResultsLAG-3 was not expressed on any of the 55 NSCLC cell lines. However, LAG-3 was expressed on the TILs in 36 patients with NSCLC (25.9%). Sixty patient samples (43.2%) were positive for PD-1 on the TILs, and 25 (18.0%) were positive for PD-L1 on tumor cells. Neither LAG-3 nor PD-1 was expressed on the tumor cells. LAG-3 was overexpressed on the TILs in nonadenocarcinoma compared with in adenocarcinoma (p = 0.031). LAG-3 expression on TILs was significantly correlated with that of PD-1 on TILs (p < 0.001) and PD-L1 on tumor cells (p = 0.041) but not with TIL percentage (p = 0.244). With the logistic regression model, the ORs for LAG-3 were 0.320 (95% confidence interval [CI]: 0.110–0.929) and 4.364 (95% CI: 1.898–10.031) when nonadenocarcinoma was compared with adenocarcinoma and TILs that were negative for PD-1 were compared with those positive for PD-1. Recurrence-free survival was significantly different in patients whose TILs were LAG-3–negative as opposed to LAG-3–positive (1.91 years [95% CI: 0.76–3.06] versus 0.87 years [95% CI: 0.27–1.47] [p = 0.025]). Likewise, LAG-3 status of TILs (negative versus positive) did significantly affect overall survival (OS) (3.04 years [95% CI: 2.76–3.32] versus 1.08 years [95% CI: 0.42–1.74] [p = 0.039]). Using Kaplan-Meier analysis, we found that patients with both PD-L1–negative tumor cells and LAG-3–negative TILs have longer recurrence-free survival than patients who are either PD-L1– or LAG-3–positive or both PD-L1– and LAG-3–positive (2.09 years [95% CI: 0.90–3.28] versus 1.42 years [95% CI: 0.46–2.34] versus 0.67 years [95% CI: 0.00–1.45] [p = 0.007]). In the verification stage, high expression of LAG-3 was also significantly correlated with higher expression of PD-1 on TILs (p = 0.016) and PD-L1 on tumor cells (p = 0.014). There was no correlation between LAG-3 expression and EGFR (p = 0.325) and KRAS mutation (p = 1.000) and ALK fusion (p = 0.562).ConclusionsLAG-3 is expressed on TILs in tumor tissues of some patients with NSCLC. Its expression was higher in nonadenocarcinoma and correlated with PD-1/PD-L1 expression. LAG-3 positivity or both LAG-3 and PD-L1 positivity was correlated with early postoperative recurrence. LAG-3 was related to poor prognosis.     

Partial hepatectomy vs. transcatheter arterial chemoembolization for multiple hepatocellular carcinomas of BCLC-B stage: A meta-analysis of high-quality studies

Background/aimThe Barcelona Clinic Liver Cancer (BCLC) recommends that transcatheter arterial chemoembolization (TACE) are indicated in patients with multiple hepatocellular carcinomas (HCCs) of BCLC-B stage. However, partial hepatectomy (PH) has increasely performed in these patients. The purpose of this meta-analyses is to illustrate the comparative survival benefits of PH and TACE for patients with multiple HCCs of BCLC-B stage.MethodElectronic databases were systematically searched for eligible studies that compared PH and TACE performed in patients with multiple HCCs of BCLC-B stage. Studies that met the inclusion criteria were reviewed systematically. The reported data were aggregated statistically using the RevMan5.3 software. Primary endpoint was overall survival (OS), and secondary endpoint were the 1-, 3-, and 5-year survival rates, postoperative 30-day mortality and postoperative complications.ResultsA total of seven high-quality studies (one randomized controlled trial [RCT], six propensity-score matching (PSM) nonrandomized comparative trials [non-RCTs] that met the inclusion criteria, which comprised of 2487 patients (1245 PH and 1242 TACE) in the meta-analysis. When compared with the TACE group, the PH group had a significantly higher OS (HR, 1.65; 95% CI, 1.48–1.84; P = 0.26; I² = 22%) and 1-, 3-, 5-year survival rates (OR, 1.96; 95% CI, 1.59–2.41; P = 0.0005; I² = 75%; P < 0.00001; OR, 2.92; 95% CI, 1.94–4.42; P = 0.0001; I² = 78%; P < 0.00001; OR, 2.60; 95% CI, 2.17–3.11; P = 0.13; I² = 44%; P < 0.00001; respectively). Survival benefits persisted across sensitivity and subgroup analyses; High heterogeneity remained after sensitivity and subgroup analyses for 3-year survival rates.ConclusionPH can provide more survival benefit for patients with multiple HCCs of BCLC-B stage compared with TACE.     

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis

Background

The prognostic significance of CC chemokine receptor type 7 (CCR7) for survival of patients with gastric cancer remains controversial. To investigate the impacts of CCR7 on clinicopathological findings and survival outcome in gastric cancer, we performed a meta-analysis.

Methods

A comprehensive search in PubMed, Embase, the Cochrane Library, and the CNKI database (1966 to November 2015) was undertaken for relevant studies. The relative risk and hazard ratios with their 95 % confidence intervals were used as measures to investigate the correlation between CCR7 expression and clinicopathological findings and overall survival rate. Sensitivity analysis was conducted to assess the stability of outcomes.

Results

Fifteen eligible studies comprising 1697 participants were included in our analysis. The pooled relative risks indicated CCR7 expression was significantly associated with deeper tumor invasion [0.61, 95 % confidence interval (CI) 0.45–0.84, p = 0.003], advanced stage (0.47, 95 % CI 0.32–0.69, p < 0.001), vascular invasion (2.12, 95 % CI 1.20–3.73, p = 0.009), lymph node metastasis (2.00, 95 % CI 1.48–2.70, p < 0.001), and lymphatic invasion (1.98, 95 % CI 1.43–2.72, p < 0.001) but not with age, tumor size, and histological type. The pooling of hazard ratios showed a significant relationship between positive CCR7 expression and worse 5-year overall survival rate (0.46, 95 % CI 0.31–0.70, p < 0.001).

Conclusions

Our meta-analysis indicated high CCR7 expression is likely to be a negative clinicopathological prognostic factor for patients with gastric cancer and to predict a worse long-term survival outcome.