Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug "CHOP" regimen in peripheral T-cell lymphoma (PTCL) cell lines and found that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using in vitro models of concurrent or staggered treatments. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiotherapy-the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a "single hit," to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not contingent on positive drug-drug interactions.

Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug 'CHOP' regimen in Peripheral T-Cell Lymphoma (PTCL) cell lines, and found that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using month-long in vitro models of concurrent or staggered treatments. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiation - the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a 'single hit', in order to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not reliant on positive drug-drug interactions.

Objective: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been recommended as the first-line treatment for advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. This study retrospectively evaluated patients' survival and related prognostic factors from single-center, real-world data. Methods: From January 2015 to December 2020, patients detected with EGFR mutation showing unresectable clinical stages III to IV advanced lung adenocarcinoma and receiving EGFR-TKIs and radiotherapy (RT) were recruited for the study. The overall survival (OS) and progression-free survival (PFS) were statistically analyzed with SPSS 22.0 software. Results: This study included 238 patients who completed their follow-up by December 30, 2020. The 1-, 2-, 3-year and median OS were 84.4%, 59.7%, 38.7%, and 30.3 months for OS, 57.0%, 28.8%, 15.7%, and 14.1 months for progression-free survival (PFS1), and 78.9%, 71.7%, 33.3%, and 25.0 months for PFS2, respectively. Multivariate analysis showed that, the independent factors for OS are age, clinical stage, the sequence of TKI and CT, and the total treatment response, and total response; the independent factors for progression-free survival 1 are clinical stage and total treatment response; the independent factors for PFS2 are clinical stage, type of TKI, sequence of TKI and CT, and total treatment response. The univariate analysis also showed a significant association between RT duration (P = 0.041) and dose (P = 0.026) with PFS1. Conclusion: EGFR-TKIs combined with RT was tolerable and efficient for patients with advanced lung adenocarcinoma. OS and PFS prove CT sequential with TKIs. Better treatment response with CR + PR was associated with a longer duration of OS, PFS1, and PFS2. However, further study is required in a larger sample size to confirm the results.

This study focused on comparing the safety and therapeutic effects between icotinib monotherapy and icotinib plus bevacizumab combined therapy in non-small cell lung cancer (NSCLC) cases harboring EGFR mutations.

Data were collected retrospectively from the Cancer Institute and Hospital of Tianjin Medical University between October 2018 and December 2019, where the NSCLC cases that harbored EGFR mutations underwent first-line therapy with icotinib in the presence or absence of bevacizumab. This study included 90 cases, of which 60 patients were in the icotinib group (I) and 30 in the icotinib plus bevacizumab group (IB).

The follow-up period to evaluate median PFS in our study was 18 months. Median PFS was 18.0 months (95% confidence interval [CI]: 14.7-21.3) with icotinib plus bevacizumab and 11 months (95% CI: 8.9-13.1) with icotinib alone (hazard ratio 0·54, 95% CI: 0.31-0.92; p = 0.029). According to the subgroup analyses based on the type of EGFR genomic aberration, a prolonged median PFS was observed in the cases harboring exon 21 point mutation (Ex21.L858R) in the IB group compared to the I group (not reached vs. 11 months [8.8-13.2], p = 0.021). However, the difference between the cases harboring exon 19 deletions in the EGFR gene was not significant. The DCR and ORR were comparable between both groups. Substantially higher incidences of hypertension and proteinuria were observed in the combined group compared to the icotinib monotherapy group.

This is the first study to provide further evidence of the benefits of applying icotinib in combination with bevacizumab as first-line treatment for advanced NSCLC cases harboring EGFR mutations. However, these findings need to be verified through prospective phase 3 clinical studies.