Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings

BackgroundML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Patients and methodsEvaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.ResultsOf 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49–0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56–0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53–0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71–1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).ConclusionsBevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.     

Final results of the CAVE trial in RAS wild type metastatic colorectal cancer patients treated with cetuximab plus avelumab as rechallenge therapy: Neutrophil to lymphocyte ratio predicts survival

BackgroundHigh neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic factor in metastatic colorectal cancer (mCRC). Here we provide final results of CAVE mCRC trial, of cetuximab plus avelumab rechallenge in chemo-refractory mCRC patients and investigated the predictive role of NLR.MethodsAll the 77 patients enrolled were included in the analysis. A cut-off of 3 was used to correlate baseline NLR with with overall survival (OS) and with progression free survival (PFS), in intention to treat (ITT) and in circulating tumor DNA (ctDNA) RAS/BRAF Wild Type (WT) patients.ResultsIn ITT population, NLR <3 (49%) group had median overall survival (mOS) of 17.8 months, vs. 8.9 months in NLR ≥ 3 group (51%) [HR 0.50, (CI 95% 0.3-0.8), P = .006]. Median progression free survival (mPFS) was 3.9 months in NLR <3 group and 3.5 months in NLR≥3 [HR 0.79, (CI 95% 0.5-1.24), P = .3]. In ctDNA RAS/BRAF WT population, mOS was 22 months in NLR <3 group (48%), vs. 8.9 months in NLR ≥3 group (52%), [HR 0.38, (CI 95% 0.19-0.75), P = .005]. A trend towards increased mPFS was observed in patients with NLR <3 versus NLR ≥3: 5.3 vs. 3.6 months [HR: 0.79, (CI 95% 0.44-1.4), P = .43]. In contrast, NLR did not correlate either with PFS or OS in ctDNA RAS/BRAF mutated patients.ConclusionIn the exploratory analysis of the CAVE mCRC trial, baseline NLR <3 significantly correlated with improved survival and may represent a potential predictive biomarker of cetuximab plus avelumab rechallenge activity in ctDNA RAS/BRAF WT patients, that must be confirmed in randomized studies.     

Prognostic value of health-related quality of life for overall survival in elderly non-small-cell lung cancer patients

BackgroundWe investigated whether the health-related quality of life (HRQoL) score is a prognostic factor for overall survival (OS) in elderly patients with advanced non-small-cell lung cancer (NSCLC).MethodsWe included 451 NSCLC patients aged 70–89 years enrolled in the Intergroupe Francophone de Cancérologie Thoracique 0501 trial, using scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 at baseline to investigate the prognostic value of HRQoL for OS, in addition to conventional factors. Cox regression model was used for both univariate and multivariate analyses of OS.ResultsGlobal health status (GH) dimension score at baseline was associated with favourable OS when adjusted for clinical, functional, and histological factors (hazard ratio [HR]: 0.986; 95% confidence interval [CI]: 0.980–0.992).We distinguished three groups according to GH score: high (GH <46), intermediate (46 ≤GH ≤67), and low (GH >67) mortality risk. The median OS values were 14.5, 8.2, and 5.3 months in the low-, intermediate-, and high-risk categories, respectively (log-rank P <0.0001).In the high-risk group, doublet chemotherapy was not associated with favourable OS (HR: 0.70; 95% CI: 0.49–1.003; P=0.052), whereas in the intermediate- and low-risk groups, doublet chemotherapy was associated with favourable OS (HR: 0.72; 95% CI: 0.54–0.96; P=0.023 and HR: 0.50; 95% CI: 0.30–0.84; P=0.0089, respectively).ConclusionThis study supports the additional prognostic value of HRQoL data at diagnosis to identify vulnerable subpopulations in elderly NSCLC patients. HRQoL could thus be valuable in selecting patients who will benefit from doublet chemotherapy.     

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.     

Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer

BackgroundBiliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis.Patients and methodsBaseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model.ResultsEight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ⩽2. A NLR ⩾3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ⩾3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ⩾3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06–1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR-1.26, 95% CI; 1.02–1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR-1.70, 95% CI; 1.10–2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04–2.44, P = 0.048).ConclusionBaseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials.     

Assessment of Prognostic Value of “Neutrophil to Lymphocyte Ratio” and “Prognostic Nutritional Index” as a Sytemic Inflammatory Marker in Non-small Cell Lung Cancer

Background: Systemic inflammatory response was shown to play an important role in development andprogression of many cancer types and different inflammation-based indices were used for determining prognosis.We aimed to investigate the prognostic effects of neutrophil to lymphocyte ratio (NLR) and prognostic nutritionalindex (PNI) in patients with non-small cell lung cancer (NSCLC). Materials and Methods: NSCLC patientsdiagnosed in our institution were retrospectively reviewed. Demographic and clinicopathologic characteristicswere recorded. NLR and PNI was calculated before the application of any treatment. Results: A total of 138patients were included in the study. Patients were divided into two groups according to NLR (<3.24 or ≥3.24)and PNI (<49.5 or ≥49.5). While median overall survival was 37.0 (95% CI 17.5-56.5) months in the group withlow NLR, it was calculated as 10.0 (95%CI 5.0-15.0) months in the group with high NLR (p<0.0001). Whilemedian overall survival was 7.0 (95%CI 3.5-10.5) months in the group with low PNI, it was calculated as 33.0(95% CI 15.5-50.4) months in the group with high PNI (p<0.0001). Stage, NLR and PNI levels were evaluatedas independent risk factors for overall survival for all patients in multivariate analysis (p<0.0001, p=0.04 andp<0.001, respectively). Conclusions: NLR (≥3.24) and PNI (<49.5) at diagnosis is an independent marker ofpoor outcome in patients with NSCLC. NLR and PNI is an easily measured, reproducible prognostic tests thatcould be considered in NSCLC patients.     

Osimertinib Improves Overall Survival in Patients With EGFR-Mutated NSCLC With Leptomeningeal Metastases Regardless of T790M Mutational Status

IntroductionOsimertinib, a third-generation EGFR tyrosine kinase inhibitor, efficiently penetrates the blood-brain barrier. This study explored whether treatment with osimertinib leads to improved overall survival (OS) for patients with EGFR-mutated NSCLC with leptomeningeal metastases (LM) compared with those not treated with osimertinib.MethodsFrom October 2008 to October 2019, patients with EGFR-mutated NSCLC and cytologically confirmed LM were retrospectively analyzed for OS according to osimertinib treatment and T790M mutational status. The OS was defined as the time from the diagnosis of LM to death.ResultsFor the 351 patients with LM included in the analysis, the median OS (mOS) was 8.1 months (95% confidence interval [CI]: 7.2–9.0). T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No difference in mOS according to T790M mutational status (10.1 mo [95% CI: 4.31–15.82] versus 9.0 [95% CI: 6.81–11.21], p = 0.936) was found. Nevertheless, patients treated with osimertinib had a superior OS of 17.0 months (95% CI: 15.13–18.94) compared with those not treated with osimertinib who had a mOS of 5.5 months (95% CI: 4.34–6.63), regardless of T790M mutational status (hazard ratio: 0.36 [95% CI: 0.28–0.47], p < 0.001). This was also considerably longer even than the mOS of 8.7 months (95% CI: 7.01–10.39) of those who were never treated with osimertinib but had first- or second-generation EGFR tyrosine kinase inhibitors.ConclusionsOsimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.     

Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio in Different Phenotypes of Locally Advanced Breast Cancer During Neoadjuvant Systemic Treatment

PurposeNeutrophils are among the key cellular players in the inflammatory milieu produced in patients with breast cancer (BC), and strong evidence exists in terms of the prognostic value of assessing the neutrophil-to-lymphocyte ratio (NLR) in patients with BC. In this study we sought to determine whether the baseline NLR correlates with pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS) in patients with locally advanced BC in the neoadjuvant chemotherapy (NAC) setting.MethodsWe analyzed the pretreatment NLR from the first blood count of patients treated from 2007 to 2015 in terms of pCR, DFS, and OS in patients with locally advanced BC. Patients received standard medical care based on national guidelines.ResultsA total of 1519 patients were included in the study. Median age was 49 years (22-88). The cutoff point for NLR was 2.0. NLR was not associated with pCR or DFS. However, patients with high NLR had worse OS in the presence of triple-negative BC (105.9 months; 95% confidence interval [CI], 100.2-111.5] vs. 98.7 months; 95% CI, 91.1-106.3; P = .029), Her2 overexpression (114.0 months; 95% CI, 110.5-118.0 vs. 100.8 months; 95% CI 95.7-105.9; P = .019), and residual disease after NAC for both phenotypes. Multivariate analysis showed that NLR was independently associated with OS (hazard ratio, 1.4; 95% CI, 1.02-1.95; P = .037).ConclusionsPretreatment NLR in patients with locally advanced BC correlates with OS as an independent prognostic factor. This influence depends on phenotype and residual disease. Routine assessment of this parameter could be an easy and affordable tool for defining prognosis.     

Effect of Coexisting KRAS and TP53 Mutations in Patients Treated With Chemotherapy for Non–small-cell Lung Cancer

BackgroundKRAS and TP53 are common mutations in non–small-cell lung cancer (NSCLC). The Lung Adjuvant Cisplatin Evaluation Biological Program group found adjuvant chemotherapy to be deleterious in patients with coexisting KRAS/TP53 mutations.Patients and MethodsTo validate these results, patients with NSCLC tested for KRAS and TP53 mutations and receiving chemotherapy for any stage NSCLC were selected. Mutation status was analyzed using next generation sequencing (Illumina) or multiplex recurrent mutation detection (MassARRAY, Agena Biosciences) assays, and was correlated with clinical and demographic data. Disease-free (DFS) or progression-free survival (PFS) was the main endpoint, and overall survival (OS) was the secondary endpoint.ResultsAmong 218 patients, 28 had coexisting KRAS/TP53 mutations, 77 TP53, 37 KRAS, 76 had neither KRAS nor TP53 mutation (WT/WT). There was no DFS/PFS difference for the KRAS/TP53 group versus all others among 99 patients who received adjuvant chemotherapy (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.61-2.44; P = .57), 27 stage III patients who received chemo-radiation (HR, 0.87; 95% CI, 0.32-2.38; P = .8), and 63 patients who received palliative chemotherapy (HR, 0.68; 95% CI, 0.31-1.48; P = .33). OS was longer in the WT/WT group compared with any other group (KRAS: HR, 1.87; 95% CI, 1.02-3.43; P = .043; TP53: HR, 2.17; 95% CI, 1.3-3.61; P = .0028; KRAS/TP53: HR, 2.06; 95% CI, 1.09-3.88; P = .026). No OS difference was seen for KRAS/TP53 compared with the other groups (HR, 1.26; 95% CI, 0.75-2.13; P = .38).ConclusionsThere was no significant difference in DFS/PFS between the 4 groups. However, OS was longer for patients with TP53 and KRAS wild-type NSCLC who received chemotherapy for any stage compared with patients with KRAS, TP53 mutation, or double mutant tumors.     

Prognostic value of neutrophil-to-lymphocyte ratio in advanced oesophago-gastric cancer: exploratory analysis of the REAL-2 trial

BackgroundThe REAL-2 trial demonstrated that capecitabine and oxaliplatin were effective alternatives to fluorouracil and cisplatin, respectively, when used in triplet chemotherapy regimens for previously untreated oesophago-gastric cancer. The aim of the current analysis was to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in the REAL-2 cohort.Material and methodsA post hoc exploratory analysis was carried out on REAL-2 patients with the available absolute neutrophil count and absolute lymphocyte count. A high NLR was defined using a cut-off value of >3.0. The NLR was then correlated with clinical outcomes including overall survival (OS), progression-free survival (PFS) and objective response rate. Survival curves were generated using the Kaplan–Meier method and comparison between groups was carried out using Cox regression.ResultsData were available in 908 of the 1002 REAL-2 participants. Of these, 516 (56.8%) were deemed to have a high NLR. In univariate analysis, high NLR was associated with a hazard ratio (HR) for OS of 1.73 (1.50–2.00), P < 0.001, compared with low NLR, equating to median OS values of 9.1 [95% confidence interval (CI) 8.0–9.6] and 12.7 months (95% CI 10.8–14.4), respectively. The NLR remained highly significant for OS (P < 0.001) in a multivariate model including performance status, age, disease extent, presence of liver metastases and presence of peritoneal metastases. For PFS, high NLR was associated with an HR of 1.63 (1.41–1.87), P < 0.001, compared with low NLR in univariate analysis. No significant interaction was found between NLR status and treatment arm, 13% of all patients with low NLR achieving survival beyond 24 months compared with only 6% of patients with high NLR (P < 0.001).ConclusionOur results confirm that high NLR status had a significant negative prognostic effect in the REAL-2 trial population. Based on the multivariate analysis, this effect was independent of other known prognostic factors.     

Baseline neutrophil–lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use

We investigated the value of the neutrophil–lymphocyte ratio (NLR) in patients with CRPC treated with chemotherapy in the phase III TROPIC trial. High NLR was associated with worse survival (OS) and reduced PSA and radiographic response. Conversion (high to low NLR) was associated with improved OS. NLR can be a useful biomarker to assess prognosis and response to treatment.BackgroundThe neutrophil–lymphocyte ratio (NLR), proposed as an indicator of cancer-related inflammation, has known prognostic value in prostate cancer. We examine its association with survival (OS) and response in patients treated with second-line chemotherapy.MethodsWe analysed patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the TROPIC trial, evaluating cabazitaxel versus mitoxantrone. Cox regression models were used to investigate the association of baseline NLR (BLNLR) with OS and the significance of a change in NLR count with treatment. Logistic regression models were used to determine the association of BLNLR counts with prostate specific antigen (PSA) and RECIST responses. The optimal NLR cut-off was established based on the concordance index of different values.ResultsData from 755, 654 and 405 patients was available for OS, PSA and RECIST response analysis respectively. Median OS was 14.0 months [95% confidence interval (CI) 13.2–14.8]. Median NLR was 2.9 (IQR: 1.9–5.1). BLNLR was associated with survival (HR 1.5, 95% CI 1.1–2.1,P = 0.011) in multivariable analysis (MVA) independently of variables included in the Halabi nomogram, treatment arm and corticosteroid use. The optimal cut-off for a dichotomous NLR was selected at 3.0 based on its higher c-index related to survival. BLNLR ≥3.0 was associated with lower PSA response (40.1% versus 59.9%;P < 0.001) and RECIST response (7.7% versus 15.6%,P = 0.022) in MVA. Conversion from high (≥3) to low (<3) NLR was associated with improved survival (HR 0.66; 95% CI 0.51–0.85;P = 0.001) and higher PSA response rates (66.4% versus 33.6%;P = 0.000). Use of corticosteroids at baseline did not modify the association between NLR and survival.ConclusionsNLR is a valid prognostic biomarker in CRPC and is associated with survival, PSA and RECIST responses in patients treated with second-line chemotherapy. Changes in NLR counts with treatment may indicate benefit. NLR prognostic value is independent of prior use of corticosteroids.ClinicalTrials.govNCT00417079.     

EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC

BackgroundThe phase III S0819 trial investigated addition of cetuximab to first-line chemotherapy (CT) in NSCLC. Subgroup analyses suggested an OS benefit among patients with EGFR copy number gain in squamous cell carcinomas (SCC), (HR = 0.58 [0.39-0.86], P = .0071). A more detailed model based on EGFR FISH, EGFR IHC and KRAS mutation status was evaluated to yield a more precise predictive paradigm of cetuximab-based therapy in advanced NSCLC.MethodsFISH was performed using the Colorado Scoring Criteria; H-Score was used to quantify EGFR IHC expression (cut-off ≥ 200). A Cox model was used to assess treatment effects for OS and PFS within biomarker and clinical subgroups. KRAS mutation was analyzed using Therascreen. The false discovery rate controlled for multiple comparisons. S0819 ClinicalTrials.gov Identifier: NCT00946712.ResultsOf 1,313 eligible patients, assay results were obtained for FISH on 976 patients (41% positive), for IHC on 945 patients (31% positive), and KRAS mutation status on 627 patients (26% positive). In SCC patients, OS was significantly improved with addition of cetuximab when both EGFR FISH and EGFR IHC were positive (N = 58), (OS HR: 0.32 [95% CI 0.18-0.59]; P = .0002, q = 0.08), median 12.6 versus 4.6 months. The results were independent of KRAS mutation status. In Non-SCC, no predictive value of EGFR IHC, EGFR FISH status and/or KRAS status was seen.ConclusionsIn NSCLC SCC, a combination index of EGFR FISH plus EGFR IHC results was associated with improved OS when cetuximab was added to CT, representing a potential predictive molecular paradigm for patients suitable for EGFR-antibody therapy.     

Prognostic value of visceral pleural invasion in the stage pT1-2N2M0 non-small cell lung cancer: A study based on the SEER registry

BackgroundVisceral pleural invasion (VPI) is considered an adverse prognostic factor in non-small cell lung cancer (NSCLC). However, the prognostic roles of VPI in Ⅲ/N2 NSCLC remain controversial. Therefore, this study aims to evaluate the prognostic value of VPI in patients with postoperative stage pT_1-2N₂M₀ NSCLC.MethodsUsing the Surveillance, Epidemiology, and End Results (SEER) database, we screened for patients with stage T1-2N2M0 NSCLC who received surgery from 2010 to 2015. To reduce baseline differences between Non-VPI group and VPI group, two-to-one propensity score matching (PSM) was performed. Cox proportional hazards regression was used to identify factors associated with survival. Overall survival (OS) was between the Non-VPI group and the VPI+ group by the Kaplan-Meier analysis.ResultsWe identified 1374 postoperative NSCLC patients with stage pT_1-2N₂M₀. The majority of cases (N = 1047, 76.8%) are Non-VPI patients. The factors associated with VPI+ group included white race (P < 0.0001), and adenocarcinoma (P < 0.0001).When analyzed in the total study population, VPI status remained a significant independent predictor of worse OS compared with the Non-VPI group (HR, 1.343; 95% CI, 1.083–1.665 [P=0.007]). Besides, in a subgroup analysis by VPI status, the results showed that patients without treatment exhibited a higher risk level in the Non-VPI group (P<0.0001). However, we did not find statistically significant differences among treatments in the VPI+ group (P=0.199). Mean survival time was 49.5 months (95% CI: 45.7–53.3 months) for chemotherapy alone in the Non-VPI group, compared with 41.2 months (95% CI: 35.8–46.6 months) in VPI+ groups. In both the VPI group and the non-VPI group, there is no statistical difference between adjuvant chemotherapy combined with PORT and chemotherapy alone.ConclusionThis study emphasizes that the presence of VPI is a poor prognostic factor, even in patients with Ⅲ/N2 NSCLC. As the study shows, chemotherapy significantly improved overall survival of patients with postoperative stage pT_1-2N₂M₀ NSCLC, especially for Non-VPI patients. However, the significance of PORT is still worth further exploration.     

Prognostic Significance of Total Lymphocyte Count,Neutrophil-to-lymphocyte Ratio,and Platelet-to-lymphocyte Ratio in Limited-stage Small-cell Lung Cancer

BackgroundWe sought reliable markers of survival and disease control among patients treated for limited-stage small-cell lung cancer (LS-SCLC).Patients and MethodsSubjects were 122 patients given (chemo)radiotherapy for LS-SCLC at MD Anderson in 2002 through 2015. Pretreatment total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were analyzed for associations with overall (OS) and progression-free survival. Optimal cutoff values were identified with receiver operating characteristic curves and survival probabilities with the Kaplan-Meier method.ResultsPretreatment TLC was 1.86 × 10³/μL (±0.88); NLR, 3.44 (±3.69); and PLR, 170.53 (±101.56); corresponding cutoffs were 1.9, 2.9, and 140.1. Higher TLC was associated with superior median and 2-year OS (17.4 vs. 15.7 months and 33% vs. 29%; P = .029), and higher NLR and PLR with worse median and 2-year OS (NLR: 14.9 vs. 17.8 months, 29% vs. 31%; P = .026; PLR: 14.8 vs. 18.9 months, 24% vs. 37%; P = .009). Multivariate Cox regression adjusted for age, disease stage, number of chemotherapy cycles, and use of prophylactic cranial irradiation confirmed the links between high TLC and superior OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.32-0.94; P = .028) and between high NLR and PLR and inferior OS (NLR: HR, 1.86; 95% CI, 1.15-3.01; P = .011; PLR: HR, 1.72; 95% CI, 1.06-2.82; P = .030).ConclusionsBaseline lymphopenia was an indicator of poor prognosis in patients with LS-SCLC.     

Glasgow Prognostic Score As a Prognostic Factor in Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel-Based Chemotherapy

BackgroundThe modified Glasgow Prognostic Score (mGPS), derived from C-reactive protein (CRP) and albumin levels, and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic significance in a number of malignancies.Patients and MethodsBaseline mGPS and NLR were calculated in a prospective cohort of chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) (AT-101-CS-205 trial) who received docetaxel and prednisone ± AT101. Cox proportional hazards regression models estimated their effects on overall survival (OS).ResultsOf 220 eligible patients, mGPS and neutrophil and lymphocyte counts were available for 184, 193, and 112 patients, respectively. Albumin (hazard ratio [HR], 0.28; 95% confidence interval [CI]: 0.14-0.56; P < .001) and CRP (HR, 1.22; 95% CI, 1.00-1.48; P = .048) were independently prognostic for OS. An association between mGPS and OS was found (HR, 1.87; 95% CI, 1.35-2.59; P < .001; median survival, 23.5 months at mGPS 0 vs. 9.8 months at mGPS 2). mGPS was significant after controlling for 3 previously published nomograms or NLR (P ≤ .001). NLR was not prognostic for OS (HR, 0.98; P = .91), and no association between mGPS and toxicity was noted.ConclusionOur results demonstrate the prognostic role of the mGPS in mCRPC over variables previously identified. mGPS is inexpensive, easily measured, and could be incorporated into routine clinical testing if our results are confirmed in a subsequent validation study. The utility of the NLR in mCRPC remains uncertain despite evidence in other malignancies.     

The Effects of Time to Treatment Initiation for Patients With Non–small-cell Lung Cancer in the United States

BackgroundThe purpose of this study was to determine the effects of time from diagnosis to treatment (TTI) on survival in patients with nonmetastatic non–small-cell lung cancer (NSCLC).Materials and MethodsThe National Cancer Database was queried for patients with stages 1 to 3 NSCLC between 2004 and 2013. Patients with missing survival status/time, unknown TTI, or receipt of palliative therapy were excluded. Multivariable Cox proportional hazards modeling, logistic regression, and recursive partitioning analysis were performed to determine associated variables and survival outcomes.ResultsAltogether, 1,393,232 patients met inclusion criteria. The median follow-up was 36 months. The median TTI increased between 2004 and 2013 from 35 to 39 days (P < .001). On multivariable Cox proportional hazards modeling, TTI groups 31 to 60 days, 61 to 90 days, and > 90 days were independently related to poorer overall survival (OS) compared with TTI 1 to 30 days (hazard ratio, 1.04, 1.10, and 1.14; 95% confidence interval [CI], 1.02-1.06, 1.07-1.12, and 1.11-1.17, respectively; P < .001 for all). Recursive partitioning analysis revealed that TTI of ≤ 45 days was the most optimal threshold for survival (P < .001); patients with TTI ≤ 45 days had a median OS of 70.2 months (95% CI, 69.3-71.1 months) versus 61.5 months (95% CI, 60.5-62.4) (P < .001). There were significant disparities by age, race, ethnicity, and income for delayed (> 45 days) TTI (P < .001 for all). Subgroup analysis revealed that stage 1 and 2 patients with TTI > 45 days had a higher risk of mortality compared with TTI ≤ 45 days (hazard ratio, 1.15 and 1.05; 95% CI, 1.12-1.17 and 1.01-1.09, respectively) (P < .001).ConclusionsIncreased TTI is independently associated with poorer survival in non-metastatic NSCLC. TTI ≤ 45 days is a clinically targetable time frame associated with improved outcomes and ought to be considered for patients with lung cancer undergoing definitive therapy.     

Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC

BackgroundCrizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit.Patients and methodsPatients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as >3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and post-progression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.ResultsAmong 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P = 0.02). CBPD patients had significantly longer OS from the time of PD [median 16.4 versus 3.9 months; hazards ratio (HR) 0.27, 95% confidence interval (CI): 0.17–0.42; P < 0.0001] and from the time of initial crizotinib treatment (median 29.6 versus 10.8 months; HR 0.30, 95% CI: 0.19–0.46; P < 0.0001). The multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS after adjusting for relevant factors.ConclusionsPatients who continued CBPD were more likely to have good ECOG PS (0/1) at the time of PD. Continuing ALK inhibition with crizotinib after PD may provide survival benefit to patients with advanced ALK-positive NSCLC.     

Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis

IntroductionWe performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.MethodsRandomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation–defined subgroups. We used the fixed-effects inverse variance–weighted method to pool estimates of treatment efficacy. Statistical tests were two sided.ResultsIn the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58–0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70–1.55, p < 0.81; treatment-mutation interaction p = 0.03).ConclusionIn EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.     

The pre-operative neutrophil–lymphocyte ratio predicts overall and disease-free survival following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with pseudomxyoma peritonei of appendiceal origin

Aim: The neutrophil–lymphocyte ratio (NLR) and other inflammation-based scores have been used as a prognostic tool to predict survival in solid tumours including pseudomyxoma peritonei (PMP). The aim was to evaluate the prognostic value of this marker and risk stratify PMP patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods: Retrospective analysis was conducted of a prospectively collected database of patients with PMP who underwent CRS and HIPEC between 1994 and 2015. The NLR was calculated by dividing the pre-operative neutrophil count by lymphocyte count. Predicted overall survival (OS) and disease-free interval (DFI) were calculated using a Kaplan–Meier survival model.

Results: The study included 699 patients, stratified into four groups as defined by their NLR. Group A: 200 (28.6%) patients (NLR?=?0.10–2.00), Group B: 160 (22.8%) patients (NLR?=?2.10–2.78), Group C: 184 (26.3%) patients (NLR?=?2.79–4.31) and Group D: 155 (22.2%) patients (NLR?≥?4.32). The median follow-up for this cohort was 36?months. The predicted DFI was 132.2, 113.1, 84.4 and 47.9?months and the OS was 141.1, 117.6, 88.7 and 51.2?months for Groups A, B, C and D, respectively. As the NLR increases, there is a reduction in long-term survival.

Conclusion: The pre-operative NLR is cost effective and has equivalent prognostic value to pre-operative tumour markers for patients with PMP treated with CRS and HIPEC. The NLR is a reliable tool that may have a role in predicting outcomes following CRS and HIPEC for patients with PMP of appendiceal origin.     

Evaluation of survival across several treatment lines in metastatic colorectal cancer: Analysis of the FIRE-3 trial (AIO KRK0306)

BackgroundWe explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment.Patients and methodsOS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time.ResultsThe fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS–intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44–0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35–0.75]).ConclusionThe differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.