Platinum-based Doublet Research Articles

Prechemoradiotherapy Systemic Inflammation Response Index Stratifies Stage IIIB/C Non-Small-Cell Lung Cancer Patients into Three Prognostic Groups: A Propensity Score-Matching Analysis.

Purpose We explored the prognostic influence of the systemic inflammation response index (SIRI) on the survival outcomes of stage IIIB/C non-small-cell lung cancer (NSCLC) patients who underwent concurrent chemoradiotherapy. Methods Present propensity score-matching (PSM) analysis comprised 876 stage IIIB/C NSCLC patients who received 1–3 cycles of platinum-based doublets concurrent with thoracic radiotherapy from 2007 to 2017. The primary and secondary objectives were the relationships between the SIRI values and overall (OS) and progression-free survival, respectively. Propensity scores were calculated for SIRI groups to adjust for confounders and to facilitate well-balanced comparability between the SIRI groups by creating 1 : 1 matched study groups. Results The receiver operating characteristic curve analysis identified an optimal SIRI cutoff at 1.9 for OS (AUC: 78.8%; sensitivity: 73.7%; specificity: 70.7%) and PFS (AUC: 80.5%; sensitivity: 75.8%; specificity: 72.9%) and we grouped the patients into two PSM cohorts: SIRI < 1.9 (N = 304) and SIRI ≥ 1.9 (N = 304), respectively. The SIRI ≥ 1.9 cohort had significantly worse median OS (P < 0.001) and PFS (P < 0.001) than their SIRI < 1.9 companions. The further combination of SIRI with disease stage exhibited that the SIRI-1 (IIIB and SIRI < 1.9) and SIRI-3 (IIIC and SIRI ≥ 1.9) cohorts had the best and worst outcomes, respectively, with SIRI-2 cohort (IIIB and SIRI ≥ 1.9 or IIIC and SIRI < 1.9) being remained in between (P < 0.001 for OS and PFS, separately). In multivariate analysis, the two- and three-laddered stratifications per the 1.9 cutoffs and SIRI groups retained their independent significance, individually. Conclusions The SIRI ≥ 1.9 independently prognosticated significantly worse OS and PFS results and plated the stage IIIB/C patients into three fundamentally distinct prognostic groups.

In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit

BackgroundSmall cell lung cancer (SCLC) is the most aggressive lung tumor, characterized by a rapid doubling time and the development of widespread metastases, for which immune checkpoint inhibitors have been approved to overcome T cell anergy. In light of its dismal prognosis, and lack of curative options, new therapies for extensive-disease SCLC are desperately needed.MethodsRRx-001 is a small molecule Myc inhibitor and down-regulates CD47 expression on tumor cells. We evaluated the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) pre and post RRx-001 treatment in a phase 2 clinical trial, called QUADRUPLE THREAT, where patients with previously treated SCLC received RRx-001 in combination with a platinum doublet. The trial was registered with ClinicalTrials.gov, number NCT02489903. Fourteen patients with SCLC were analyzed to investigate the association between clinical outcome and PD-L1 expression on CTCs pre and post RRx-001. The correlation between the binary clinical outcome (clinical benefit vs. progressive disease) and the change of PD-L1 expression on CTCs after RRx-001 was analyzed using a logistic regression adjusting for baseline PD-L1 expression.ResultsThe logistic model McFadden goodness of fit score was 0.477. The logistic model analyzing the association between decreased PD-L1 expression on CTCs after RRx-001 and response to reintroduced platinum doublet had an approximate 92.8% accuracy in its prediction of clinical benefit. The estimated receiver operating characteristic (ROC) displayed a ROC area under the curve (AUC) of 0.93 (95% confidence interval, 0.78–0.99).ConclusionsThese results suggest that PD-L1 expression on CTCs decreased after RRx-001 was significantly correlated with response to reintroduced platinum-based doublet therapy. Monitoring PD-L1 expression on CTCs during RRx-001 treatment may serve as a biomarker to predict response to RRx-001-based cancer therapy.

Immunotherapy combinations in advanced nonsmall cell lung cancer.

The purpose of the review is to summarize immunotherapy combinations in advanced nonsmall cell lung cancer (NSCLC). First-line platinum-based chemotherapy plus an immune checkpoint inhibitor has improved progression-free and overall survival compared to chemotherapy alone in patients with advanced NSCLC. Although the benefits appear to increase with higher programmed death ligand 1 (PD-L1) expression, patients with low PD-L1 also benefit. Nivolumab plus ipilimumab has also been established as a treatment option. Combinations of immune checkpoint inhibitors with olaparib or lenvatinib are studied within phase 3 trials. Platinum-based doublets combined with an immune checkpoint inhibitor have become standard first-line therapy. Other combinations are under clinical development.

Predicting Clinical Outcomes of Patients with Stage III Non-Small-Cell Lung Cancer Treated with Concurrent Chemoradiation with and without PD-1/PD-L1 Inhibitors Using Cone Beam Computed Tomography

Currently, there are no standardized biomarkers that predict response to consolidative therapy with Programmed cell Death receptor -1(PD-1) or Programmed cell Death receptor -Ligand 1 (PD-L1) inhibitors used after concurrent chemoradiation therapy (CCRT) for patients with stage III unresectable locally advanced non-small-cell lung cancer (LA-NSCLC).We hypothesized that tumor volume reduction during CCRT may be predictive of response to consolidative PD-1/PDL-1 inhibitors. We retrospectively reviewed the medical records of patients treated with definitive CCRT, both with and without consolidative PD-1/PD-L1 inhibitors. CCRT consisted of 60Gy in 30 fractions with platinum-based chemotherapy doublet. Primary gross tumor volumes (GTV) of all patients were contoured on set-up cone-beam computed tomography (CBCT) scans acquired on day 1, 15, 29, and 43 of CCRT, as well as on follow-up CT at 1 month. GTV reduction was quantified as the percent difference in volume on each CBCT and follow-up CT, relative to CBCT Day 1. Mid-treatment shrinkage (MTS) and End of Treatment Tumor Shrinkage (ETTS) were defined at day 29 and 43, respectively. Progression-free survival (PFS) was calculated using Kaplan-Meier curves and the log-rank test was used for statistical evaluation. 93 LA-NSCLC patients completed definitive CCRT, of which 24 received consolidative PD-1/PD-L1 inhibitors. For the entire cohort, the median age was 66.5 years (range: 51-84 years) and 54% were males. Adenocarcinoma represented 51%, squamous cell carcinoma 40% and undifferentiated histology 9%. 32% had stage IIIA and 68% had stage IIIB (AJCC 7th edition). Median follow-up was 43 months (range: 36-53 months). Patients who received PD-1/PD-L1 inhibitors achieved significantly longer PFS than CCRT-only group (22.5 vs. 9.5 months, p = 0.014). For the 93 patients, median ETTS was 40.6% (range: 39.3-50.3). Median ETTS was comparable between PD-1/PD-L1 inhibitors and CCRT-only group (41.2% vs. 40%). Patients who received PD-1/PD-L1 inhibitors and achieved ETTS > 35% demonstrated a trend toward improved PFS compared to those who had ETTS ≤ 35% (median PFS was not reached vs. 11.03 months, p = 0.059). Similarly, patients who received PD-1/PD-L1 inhibitors and achieved MTS of > 35% were associated with numerically better PFS compared to patients who did not achieve the same cut off (median PFS was not reached vs. 13.15 months, p = 0.059). Patients who achieved a significant reduction in their tumor volume during CCRT are more likely to benefit from consolidative PD-1/PD-L1 inhibitors. Measuring tumor volume dynamics using the readily available CBCT images acquired during CCRT may serve as a potential biomarker to predict response to PD-1/PD-L1 inhibition therapy.

Mathematical model predicts response to chemotherapy in advanced non-resectable non-small cell lung cancer patients treated with platinum-based doublet.

We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004–2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers.

Role of Maintenance Gemcitabine in Advanced Carcinoma Gallbladder.

Objective The aim of this study is to investigate the effects of gemcitabine maintenance on progression-free survival (PFS) in patients with metastatic gallbladder cancer (GBC). Materials and Methods Sixty patients with unresectable or metastatic GBC having ongoing response to treatment with initial six cycles of gemcitabine and a platinum-based doublet chemotherapy were prospectively randomized on day 21 of the 6th cycle in 1:1 fashion to receive either maintenance gemcitabine 1 g/m 2 intravenously on day 1 and day 8 of three weekly cycle or observation. Survival analysis was performed using the Kaplan–Meier method and comparisons by the log-rank test. A p -value < 0.05 was considered as statistically significant. Results Of 60 patients, a total of 56 were available for final analysis. The median PFS was 4.7 months (3.1–6.3) in gemcitabine arm and 2.6 months (2.4–2.8) in observation arm, hazard ratio (HR) 0.196 (95% confidence interval [CI]: 0.1–0.39), p < 0.001. Median overall survival in gemcitabine arm was 12.4 months (9.15–15.6) as opposed to 9.9 months (8.29–11.5) in observation arm, HR 0.76 (95% CI: 0.43–1.35), p = 0.354. The grade 3 or 4 side effects in maintenance arm were transaminitis (17.9%), thrombocytopenia (17.8%), neutropenia (14.2%), and febrile neutropenia (7.1%). Conclusions Maintenance gemcitabine therapy in unresectable/metastatic GBC patients responding to first-line gemcitabine and platinum treatment contributes to increase PFS with minimal and manageable side effects.

Les CBNPC de stades avancés hors addiction oncogénique : les traitements systémiques de deuxième ligne: Advanced stage NSCLC excluding oncogenic addiction: Second-line systemic treatments

AbstractThe emergence of immunotherapy as the cornerstone of first line therapy in advanced stage non-small cell lung cancer, without oncogenic driver, has led to change the treatment algorithm of second line, which was previously and mainly based on anti-PD(L)-1 given as a single agent. Second-line treatment is currently based on chemotherapy, with a platinum-based doublet for patients treated in first line by pembrolizumab alone, and standard second-line chemotherapy options for patients treated by chemotherapy-immunotherapy combinations, i.e. docétaxel regardless of histology or pemetrexed for non-squamous cell carcinoma when not used in first line. Addition of an antiangiogenic agent to docétaxel only achieved a modest improvement of overall survival but neither nintedanib, nor docétaxel is available in France. The future of second line treatment would require a better knowledge and understanding of resistance mechanisms to anti-PD(L)-1, and randomized phase III clinical trials, in order to optimize therapeutic options, including or not a rechallenge to an immunotherapy, targeting to restore anti-tumour immune response.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Water only fasting and its effect on chemotherapy administration in gynecologic malignancies

ObjectiveAs a protective response, during starvation organisms withdraw energy from growth and reproduction to focus on cellular maintenance. Cancer cells cannot undergo this differential response which has been theorized as an adjunct to improve both the effect of chemotherapy treatment and reduce treatment side effects. We sought to investigate the feasibility and effect of short-term fasting in patients receiving chemotherapy for gynecologic malignancy. MethodsA randomized control trial was conducted of women with gynecologic malignancies receiving at least 6 planned chemotherapy cycles. Fasting patients maintaining a water-only fast for 24 h before and 24 h following each chemotherapy cycle were compared to nonfasting patients. Treatment related side effects and quality of life (QOL) was assessed using NCCN-FACT FOSI-18 questionnaire. ResultsAnalysis included data from 120 cycles of chemotherapy. The majority of patients had stage 3 and 4 malignancy requiring multi-agent chemotherapy. Eleven patients had ovarian, 8 had uterine, and 1 had cervical cancer. Ninety percent received taxane and platinum-based doublet therapy. Weight loss and unanticipated hospitalizations were similar between treatment groups. Fewer dose reductions or delays were seen in the fasting group. There was no significant difference in mean QOL scores, but fasting group QOL scores improved over the course of treatment to a level that reached the minimal clinically important difference. ConclusionA 48-h fast is well tolerated without increasing weight loss, hospital admissions, or chemotherapy dose reduction/delays. Fasting resulted in fewer treatment modifications and improved quality of life scores over the course of treatment.

Switch maintenance chemotherapy versus observation after carboplatin and weekly paclitaxel doublet chemotherapy in elderly patients with advanced non–small cell lung cancer: IFCT-1201 MODEL trial

PurposeMaintenance chemotherapy is a reasonable choice for patients with metastatic non–small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients. Patients and methodsWe conducted a randomised trial in patients aged 70–89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m2 d1, 22) in patients with non–squamous cell carcinoma or gemcitabine (1,150 mg/m2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0–2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS). Results632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0–17.0) in the observation arm and 14 months (95% CI: 10.9–16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6–3.1) in the observation arm versus 5.7 months (95% CI: 4.8–7.1) in the maintenance arm (p < 0.001). ConclusionSwitch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC.

S1 versus Doublet Regimens as Adjuvant Chemotherapy in Patients with Advanced Gastric Cancer after Radical Surgery with D2 Dissection-A Propensity Score Matching Analysis.

Background: Fluoropyrimidine- and platinum-based doublet regimen is the standard treatment of adjuvant chemotherapy (AC) for gastric cancer (GC). Our study aims to compare S1 with doublet regimens as AC in patients with advanced GC after radical surgery with D2 dissection. Methods: Patients who were diagnosed with GC and underwent a curative surgery with D2 dissection followed by AC were enrolled into our study. A propensity score matching analysis was performed to reduce the selection bias. Kaplan–Meier curves were estimated for recurrence-free survival (RFS) and overall survival (OS). Cox regression models were conducted for survival. Results: After propensity sore matching, 64 patients with S1 and 64 patients with doublet regimens were identified. The median RFS (p = 0.355) and OS (p = 0.309) were both insignificant between S1 and ST. Cox regression analysis demonstrated that pathologic stage and lymph node ratio (LNR) were independently correlated with survival. Patients were then stratified into low risk and high risk groups. The median RFS (p < 0.001) and OS (p < 0.001) had significant differences between low risk and high risk. In the high-risk group, doublet regimens were strongly associated with survival (p = 0.020) as compared with S1. While in the low-risk group, doublet regimen and S1 did not have statistically different survival benefits. Conclusions: Our study demonstrated that doublet regimens are superior to S1 in high-risk groups, and that survival outcomes are similar between doublet regimens and S1 in low-risk groups. Our prognostic model might have clinical implications for AC.

Impact of provider volume on front-line chemotherapy guideline compliance and overall survival in elderly patients with advanced ovarian cancer

PurposeWe sought to evaluate whether provider volume or other factors are associated with chemotherapy guideline compliance in elderly patients with epithelial ovarian cancer (EOC). MethodsWe queried the SEER-Medicare database for patients ≥66 years, diagnosed with FIGO stage II-IV EOC from 2004 to 2013 who underwent surgery and received chemotherapy within 7 months of diagnosis. We compared NCCN guideline compliance (6 cycles of platinum-based doublet) and chemotherapy-related toxicities across provider volume tertiles. Factors associated with guideline compliance and chemotherapy-related toxicities were assessed using logistic regression. Overall survival (OS) was compared across volume tertiles and Cox proportional-hazards model was created to adjust for case-mix. Results1924 patients met inclusion criteria. The overall rate of guideline compliance was 70.3% with a significant association between provider volume and compliance (64.5% for low-volume, 72.2% for medium-volume, 71.7% for high-volume, p = .02). In the multivariate model, treatment by low-volume providers and patient age ≥ 80 years were independently associated with worse chemotherapy-guideline compliance. In the survival analysis, there was a significant difference in median OS across provider volume tertiles with median survival of 32.8 months (95%CI 29.6, 36.4) low-volume, 41.9 months (95%CI 37.5, 46.7) medium-volume, 42.1 months (95%CI 38.8, 44.2) high-volume providers, respectively (p < .01). After adjusting for case-mix, low-volume providers were independently associated with higher rates of mortality (aHR 1.25, 95%CI: 1.08, 1.43). ConclusionsIn a modern cohort of elderly Medicare patients with advanced EOC, we found higher rates of non-compliant care and worse survival associated with treatment by low-volume Medicare providers. Urgent efforts are needed to address this volume-outcomes disparity.

Changes and Influential Factors of Chemotherapy Usage for Non-Small Cell Lung Cancer Patients in China: A Multicenter 10-Year (2005-2014) Retrospective Study.

BackgroundChemotherapy has improved the survival of non-small cell lung cancer (NSCLC) patients over the past few decades. However, there have not been any epidemiological studies on chemotherapy for Chinese NSCLC patients.Patients and MethodsThe patients diagnosed as primary lung cancer between January 1, 2005, and December 31, 2014, in eight hospitals from eight provinces in China were retrospectively reviewed. Demographic and clinical data were extracted from medical history systems. Chi-square test and logistic regression were used to analyze the changes of chemotherapy usage and influential factors.ResultsA total of 7184 lung cancer cases were eligible, among which 6481 NSCLC cases were included in this analysis. Among stage I/II patients, the percentages of receiving adjuvant chemotherapy did not change significantly between the earlier (28.5%) and the latter five years (25.7%) (p = 0.1288). Among stage IIIA patients, the percentages of chemotherapy usage did not change significantly between the earlier and the latter five years in neo-adjuvant (7.5% vs 5.6%, p = 0.1478) and adjuvant (23.1% vs 26.8%, p = 0.1129) treatment. The proportions of first-line platinum-based doublets for stage IIIB/IV patients changed significantly over the 10 years (p < 0.0001). Patients from provinces with inferior gross domestic product, with lower medical reimbursement rates and without smoking history were more likely to use the docetaxel/paclitaxel doublets, comparing with the gemcitabine doublets.ConclusionFrom 2005 to 2014, there was no significant change in the chemotherapy pattern of early NSCLC. Economic factors mainly contributed to the significant changes in the first-line chemotherapy regimen selection for advanced patients.

The association between initial chemotherapy treatment timing, intensity, and end-of-life (EOL) care trajectory among older adults with advanced stage lung cancer (aLC).

e24009 Background: The use of chemotherapy regimens with varying intensities at specific time points may have an effect on EOL care trajectories among older adults with aLC (IIIB &amp; IV). Methods: Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry and claims data, we selected decedents diagnosed with aLC (small cell: SCLC and non-small cell: NSCLC) between 2008 and 2013 who survived ≥6 months (death between 2008 and 2014). Main outcome measures were EOL care trajectories in the 6 months prior to death among patients receiving chemotherapy characterized by intensity levels. A multinomial logit model was used to determine the association between intensity of initial chemotherapy regimen and EOL care trajectory. Results: Our sample (N = 10,594) was mostly NSCLC (77%) of whom only 63% received chemotherapy. Patients receiving chemotherapy were predominantly males (70.4%), age 66-69 years (80%), non-Hispanic white (68.1%) and 78.4% were married. 41 % received treatment prior to EOL-6 and 10.4 % first initiated treatment during EOL-6. The majority of patients received a platinum-based doublet as a first line therapy. Compared to non-cisplatin platinum doublet chemotherapy, patients receiving cisplatin were least likely to be in the decreasing intensity EOL group and most likely to be in increasing intensity EOL group (see table). Conclusions: Among aLC decedents, patients who received cisplatin chemotherapy as compared to non-cisplatin doublet chemotherapy were least likely to be in the decreasing EOL intensity group and most likely to be in the increasing EOL intensity group. EOL care preferences may need to be considered when choosing initial chemotherapy treatment regimens. [Table: see text]

Concordance of provider treatment patterns with NCCN oncology treatment guidelines (NCCN Guidelines) for metastatic non-small cell lung cancer (mNSCLC).

e21574 Background: mNSCLC clinical treatment guidelines are rapidly evolving, however, their influence on prescriber use of anti-cancer treatment regimens is not known. This retrospective study evaluated whether US patients with mNSCLC received first line (1LOT), second (2LOT), or third (3LOT) line treatment regimens that were concordant with NCCN Category 1-2A recommendations. Methods: mNSCLC patients who initiated treatment between 2014-2017 were identified using medical and pharmacy claims from the 100% Medicare Fee-for-Service (FFS) Part A/B/D sample and multi-payer Inovalon MORE2 Registry. Claims-based algorithms identified mNSCLC and LOT following diagnosis; patients with other primary cancers or &lt; 6 months follow-up were excluded. Treatment regimens were compared to active NCCN Guidelines at time of treatment to determine if regimen was concordant with Category 1-2A recommendations. Genetic mutation/biomarker status was not available. Results: 6,523 patients with mNSCLC met criteria for analysis (FFS/Medicare Advantage:78.6%; commercial:14.0%, managed Medicaid:7.4%; mean age:69.3 [SD:9.2]). For 1LOT, 81% received platinum-based doublet regimens; most common monotherapy included erlotinib, nivolumab, and pembrolizumab; 18% of 1LOT patients received maintenance therapy. For 2LOT, approximately one-third received nivolumab monotherapy, one-third received platinum-based doublets, and remainder received other regimens. Most common 3LOT included monotherapy nivolumab, pemetrexed, paclitaxel, and docetaxel. NCCN Guidelines concordance varied: 1LOT (90.5%), 2LOT (58.5%), 3LOT (71.9%). Non-concordant regimens included nivolumab as 1LOT and early adoption of platinum agent+(pemetrexed or paclitaxel) in 2LOT, and chemotherapy as 2LOT in anaplastic lymphoma kinase rearrangement-positive or epidermal growth factor receptor mutation-positive disease. Conclusions: In Medicare and non-Medicare patients with mNSCLC, 1LOT closely followed NCCN Guidelines. Most variability was observed in 2LOT where 58.5% regimens were concordant with Category 1-2A recommendations. Non-concordance may be driven by lack of effective second-line regimens and early adoption of innovative therapies.

Outcomes of concurrent radiotherapy with weekly docetaxel and platinum-based chemotherapy in stage III non-small-cell lung cancer

PurposeThe present study evaluated the outcomes of concurrent weekly docetaxel and platinum-based drug doublet in association with concurrent thoracic radiotherapy (TR) in the curative treatment of stage III locally advanced non-small-cell lung cancer (NSCLC). Patients and MethodsPatients with stage IIIA/B NSCLC were retrospectively included. Patients received weekly docetaxel and either cisplatin or carboplatin intravenous injections during concurrent TR (60 to 66Gy). Patients who received induction chemotherapy with the same drug doublet were also included. The endpoints were: disease control rate (DCR), overall recurrence rate, survival rates [disease-free survival (DFS) and overall survival (OS)] and toxicity. ResultsEighty-nine consecutive patients treated with this association were included. Median follow-up time was 57.8 months. DCR was 76.5% at the first follow-up CT scan (6 to 12 weeks after the end of concurrent treatment). Median DFS and OS was 14.3 and 29.9 months respectively. Three-year survival was 43%. The overall recurrence rate was 65.9%. During overall treatment, grade 3 to 4 adverse events occurred in 29.2% of patients, the most common being esophagitis (12.4% of patients). Only 13.5% of patients presented with a grade 3 or higher adverse event after the end of concurrent treatment. ConclusionsWeekly docetaxel and platinum-based drug doublet combined with TR yielded promising results in stage III NSCLC, with high survival rates. The toxicity of this association is acceptable, with mainly manageable esophagitis. These findings warrant validation in a prospective study before considering this association for standard of care.

Multicenter Retrospective Analysis of Second-Line Therapy after Gemcitabine Plus Nab-Paclitaxel in Advanced Pancreatic Cancer Patients.

Pancreatic cancer is one of the most lethal solid tumors. In many European countries gemcitabine plus nab-paclitaxel is the preferred first-line treatment. An increasing number of patients are eligible for second-line therapy, but the best regimen is still controversial. This study aimed to evaluate the efficacy of oxaliplatin-based compared to irinotecan-based therapies in this setting. 181 advanced pancreatic cancer patients consecutively treated in three centers with a second-line therapy progressed on gemcitabine plus nab-paclitaxel were retrospectively enrolled. OS and PFS were calculated using the Kaplan-Meier method and survival of the two groups was compared using the log-rank test. The median PFS and OS were respectively 3.5 (95%CI 3.2–3.8) and 8.8 months (95%CI 7.9–9.8) from second-line therapy in the overall population. The median PFS and OS were respectively 3.3 (95%CI 3.1–3.5) and 8.2 months (95%CI 7.24–9.34) with an irinotecan-based combination compared to 4.0 (95%CI 2.4–5.7) and 10.3 months (95%CI 8.62–12.02) in patients receiving an oxaliplatin-based combination. We observed a clear trend for longer survival outcomes with platinum-based doublet compared to regimens including irinotecan or nal-IRI. Head-to-head trials are still lacking. The neutrophil-to-lymphocyte ratio and the presence of liver metastases could drive physicians in tailoring the treatment strategy.

Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non–small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study

PurposeSecond-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non–small-cell lung cancer (nsNSCLC). MethodsIn this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671. ResultsOne hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44–0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8–30·3) and 5·5% (95% CI: 0·0–11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group). ConclusionWeekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. Clinical trials registration numberClinicalTrials.gov Identifier: NCT01763671.

Survival and Toxicity of Hypofractionated Intensity Modulated Radiation Therapy in 4 Gy Fractions for Unresectable Stage III Non-Small Cell Lung Cancer

To assess the survival, local and distant control, and toxicity in patients with unresectable locally advanced non-small cell lung cancer treated with radical-intent hypofractionated radiation therapy delivering approximately 60 Gy in 4-Gy fractions. Consecutive patients with unresectable stage III non-small cell lung cancer (n = 42) who received hypofractionated intensity modulated radiation therapy were retrospectively analyzed (2012-2016). Treatments consisted of first-line platinum-based doublet induction chemotherapy followed by an intended dose of 60 Gy in 15 fractions. During a median follow-up period of 46 months (95% confidence interval, 41-59) the median overall survival was 47 months (95% confidence interval, 31 to not reached). The 1-, 2-, 3-, and 5-year overall survival rates were 81%, 69%, 64%, and 32%, respectively. The 1-, 2-, 3-, and 5-year progression-free survival rates were 58%, 35%, 25%, and 25%, respectively. An isolated locoregional recurrence was seen in 12% of the patients (n = 5). The incidence of grade (G) 3 or higher treatment-related lung toxicity was 14% (n = 6), among which G3 toxicity was 9.5% (n = 4) and G5 toxicity was 4.8% (n = 2). Twelve percent of patients (n = 5) experienced G3 radiation esophagitis, and 2% (n = 1) had G4 esophageal toxicity. Patients with unresectable locally advanced non-small cell lung cancer treated with hypofractionated intensity modulated radiation therapy in doses up to 60 Gy at 4 Gy per fraction had promising survival, although high-grade esophageal and lung toxicities were seen. Our findings deserve further evaluation in prospective studies.

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer

ObjectivesEfficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. Materials and methodsThis single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR). ResultsIn 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %–35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4–6.9 months) and OS at 6 months was 74.7 % (61.5%–83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5–75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. ConclusionResults suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities.

Lactate dehydrogenase kinetics predict chemotherapy response in recurrent metastatic nasopharyngeal carcinoma.

Background:Lactate dehydrogenase (LDH) is a known prognostic biomarker for the endemic variant of nasopharyngeal carcinoma (NPC). Here, we investigate whether serial changes in LDH level between chemotherapy (CT) cycles are associated with tumour response to CT.Methods:Patients with biopsy-proven, recurrent or treatment-naïve metastatic NPC (mNPC) were recruited. All patients had received at least two cycles of platinum-based doublet or triplet CT, with serial assessment of LDH prior to every cycle of chemotherapy (CT1–6). Patients harbouring conditions that affect LDH levels (IU/L) were excluded. Tumour response was assessed after every two cycles of CT by RECIST v1.1.Results:A total of 158 patients were analysed, including 77 with recurrent and 81 with treatment-naïve mNPC. High pre-CT LDH was associated with an inferior overall survival [hazard ratio 1.93 for ⩾240 versus <240 (1.34–2.77), p < 0.001], which is consistent with published literature. We found that both absolute LDH levels and LDH ratios (LDHCTn: LDHCTn–1) were associated with tumour response [partial response versus progressive disease: median value across CT1–6 = 168–190 versus 222–398 (absolute); 0.738–0.988 versus 1.039–1.406 (ratio)], albeit LDH ratio had a tighter variance between patients. Finally, we showed that an LDH ratio cut-off of 1.0 at CT1, CT3 and CT5 was predictive of progressive disease at CT2, CT4, CT6 [area under the curve of 0.73 (0.65–0.80)].Conclusion:Herein, we characterised the longitudinal variation of LDH in response to CT in mNPC. Our findings suggest the potential utility of interval LDH ratio to predict subsequent tumour response to CT.