Efficacy and safety of time-of-day infusion of pemetrexed plus platinum for patients with advanced non-small cell lung cancer: A retrospective study

Efficacy and safety of time-of-day infusion of pemetrexed plus platinum for patients with advanced non-small cell lung cancer: A retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Efficacy and safety of time-of-day infusion of pemetrexed plus platinum for patients with advanced non-small cell lung cancer: A retrospective study Quan-An Xu, Ke-Xin Xian, Xian Xu, Pei Xie, Meng-Di Hao, Wei-Lu Liu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6248417/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Retrospective studies suggest that administering chemotherapy infusions in the morning can enhance treatment efficacy and mitigate side effects in non-small cell lung cancer (NSCLC) patients. However, the effectiveness of chronotherapy using pemetrexed plus platinum (AP) in advanced NSCLC chemotherapy remains unexplored. This study aims to evaluate the impact of AP chrono-chemotherapy (CCT) on treatment response and adverse events in advanced NSCLC patients. Method: We retrospectively analyzed 132 advanced NSCLC patients treated with AP at Guangdong Second Provincial General Hospital from 2018 to 2023. Based on previous research, we classified patients who received chemotherapy infusions before 2:00 PM as the morning (AM) group, while the rest were categorized as the afternoon (PM) group. Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors Criteria V.1.1. The primary endpoint was progression-free survival (PFS), with safety profile serving as the secondary endpoint. All adverse events were identified and graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Result: In the AP cohort, the AM group exhibited a longer PFS compared to the PM group (AM vs. PM, n = 58 vs. n = 74, 24.0 vs. 14.0 months, p = 0.037). Subsequent subgroup analysis in the AP cohort favored the AM group across all major subgroups for PFS treatment effect. Furthermore, the analysis of adverse reactions revealed similar incidences of any treatment emergent adverse events (TEAE) in both AM and PM (AM vs. PM, 86.21% vs. 86.49% in AP cohort), and grade 3 TEAEs (AM vs. PM, 31.03% vs. 21.62% in AP cohort). The most common adverse events were anemia, leukopenia, and Neutropenia. Univariate and multivariate analyses indicated that the infusion time of AP chemotherapy (p = 0.029) was an independent prognostic factor for NSCLC. Conclusion: AP treatment administered in the morning may enhance PFS in advanced NSCLC. This suggests that CCT could potentially enhance the efficacy of individualized chemotherapy in advanced NSCLC. Biological sciences/Cancer/Cancer therapy Biological sciences/Cancer/Lung cancer Time-of-day infusion Chronochemotherapy Circadian rhythm Non-small cell lung cance biological clock chemotherapy Figures Figure 1 Figure 2 Introduction Lung cancer stands as the preeminent killer in the realm of cancer, representing the most formidable malignancy that poses the greatest threat to human health and life on a global scale [1, 2]. It imposes a substantial burden and presents significant challenges to public health systems [3, 4]. As the predominant pathological subtype, NSCLC represents the most frequently diagnosed form of lung cancer, accounting for approximately 85% of all lung cancer cases worldwide [3, 5]. This malignancy demonstrates significantly higher incidence and mortality rates compared to other pulmonary neoplasms, posing a substantial global health burden with its complex molecular pathogenesis and heterogeneous clinical manifestations [6]. According to epidemiological statistics, numerous high-risk factors have been identified for NSCLC. Among these, long-term smoking, air pollution, and environmental exposure are widely recognized as the primary contributors [7]. The therapeutic landscape of NSCLC encompasses a diverse array of modalities, including surgical intervention, chemotherapy, targeted therapy, and immunotherapy [8]. Among these approaches, surgical resection is widely regarded by both the medical community and general population as the most potentially curative treatment option when clinically indicated [9, 10]. Owing to the insidious nature of its onset, the majority of patients with NSCLC are diagnosed at an advanced stage [11], thereby missing the window for potential curative surgical intervention. In recent years, with the in-depth investigation of the molecular biological mechanisms underlying NSCLC, targeted therapy and immunotherapy have emerged as prominent areas of research and clinical application [12-14]. However, the efficacy of targeted therapy is highly dependent on the tumor's genetic mutation profile [15], demonstrating limited effectiveness in patients without identifiable molecular targets. Moreover, tumor cells can develop resistance through multiple mechanisms, thereby restricting the long-term utility of these therapies [16]. Immunotherapy, while promising, exhibits significant interpatient variability in treatment response and is associated with immune-related adverse events (irAEs), including pneumonitis and hepatitis [17, 18]. Additionally, the emergence of acquired resistance during immunotherapy and the incomplete understanding of its underlying mechanisms necessitate further investigation [19]. Within the current therapeutic paradigm, chemotherapy remains a cornerstone in NSCLC management [20, 21], particularly for patients who are ineligible for or refractory to targeted and immunotherapeutic approaches. Chemotherapeutic agents exert their antitumor effects by targeting and destroying cancer cells [22], effectively controlling proliferation and eliminating established micrometastases. However, chemotherapy can only modestly extend the survival of patients with advanced NSCLC. Studies [23, 24] have indicated that the introduction of platinum-based chemotherapy has increased the median survival of NSCLC patients by 6-8 months. Even with the current first-line chemotherapy regimen combining paclitaxel with platinum, the median survival has only been extended to 16.9 months [25]. Thus, it can be seen that traditional chemotherapy often adversely affects patient outcomes due to its high dosage and toxicity. Chronochemotherapy, on the other hand, involves administering chemotherapeutic drugs at appropriate stages in accordance with the body's physiological rhythms [26, 27], thereby achieving the goal of high efficacy and low toxicity. Recent research has indicated that chronochemotherapy tends to demonstrate superior efficacy and safety compared to conventional chemotherapy. A retrospective study [28] categorized patients who had undergone TP regimenpaclitaxel plus cisplatinchemotherapy into a chronotherapy group and a conventional chemotherapy group. Long-term follow-up revealed that the objective response rate (ORR) in the chronotherapy group was significantly higher than that in the conventional chemotherapy group (83.66%vs.43.33%). In terms of safety, the incidence of myelosuppression and gastrointestinal reactions in the chronotherapy group was lower than that in the conventional chemotherapy group. Similarly, the advantages of chronotherapy were observed in NSCLC patients undergoing first-line GP regimengemcitabine plus cisplatinchemotherapy, with the 1-year and 2-year survival rates in the chronotherapy group being higher than those in the conventional chemotherapy group [29]. These findings provide a theoretical basis for the application of chronotherapy in NSCLC chemotherapy. To date, the efficacy and safety of the AP regimen chronochemotherapy in advanced NSCLC remain largely uncharted territory. Consequently, this retrospective study aims to investigate the survival and safety benefits of AP regimen chronochemotherapy in patients with advanced NSCLC. Methods Study population We conducted a retrospective analysis of 132 patients with advanced NSCLC who received AP regimen chemotherapy at Guangdong Second Provincial General Hospital between January 2018 and December 2023. All cases were rigorously evaluated for eligibility based on predefined inclusion and exclusion criteria. The diagnosis of NSCLC was confirmed according to either the National Comprehensive Cancer Network (NCCN) guidelines or Chinese Society of Clinical Oncology (CSCO) guidelines. The inclusion criteria were as follows: (1) histologically confirmed NSCLC; (2) age ≥18 years with adequate physiological status to tolerate chemotherapy; (3) completion of at least two cycles of AP regimen chemotherapy to ensure treatment continuity and reliable efficacy evaluation; (4) TNM stage III or IV disease, consistent with advanced NSCLC diagnosis; (5) ECOG performance status of 0-1 with expected survival ≥3 months to ensure treatment tolerance and follow-up completion; (6) no prior systemic antitumor therapy to avoid confounding effects; (7) adequate organ function as evidenced by ALT/AST ≤2.5×ULN, serum creatinine ≤1.5×ULN, ANC ≥1.5×10^9/L, and PLT ≥100×10^9/L; (8) provision of written informed consent. Exclusion criteria included: (1) previous antitumor treatments that might confound results; (2) concurrent secondary primary malignancies; (3) severe cardiac, hepatic, or renal dysfunction; (4) known hypersensitivity to study drug components; (5) inability to evaluate tumor response; (6) loss follow-up. Treatment discontinuation criteria were: (A) disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by contrast-enhanced chest CT; (B) occurrence of severe or life-threatening adverse events (grade 4 hematological toxicity or grade ≥3 non-hematological toxicity) unresponsive to supportive care; (C) death from any cause. The institutional review board granted ethical approval for this retrospective study. The investigation adheres to the principles outlined in the Declaration of Helsinki. All patients included in this study provided informed consent for treatment. Treatment procedure All enrolled patients received platinum-based doublet chemotherapy with the AP regimen, which consisted of pemetrexed (500 mg/m², intravenous infusion, day 1) and nedaplatin (80-100 mg/m², intravenous infusion, day 1). The treatment cycle was repeated every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity occurred. To ensure patient safety and tolerance to pemetrexed-based chemotherapy, all patients received the following premedication regimen: oral folic acid supplementation (400 ug/day) was initiated 1 week before pemetrexed administration and continued until 21 days after the last chemotherapy cycle, aiming to reduce pemetrexed-induced myelosuppression and gastrointestinal toxicity. Intramuscular vitamin B12 (1000 ug) was administered every 9 weeks to prevent megaloblastic anemia associated with pemetrexed. Oral dexamethasone (4 mg twice daily) was administered from the day before to 2 days after pemetrexed infusion to minimize cutaneous reactions and hypersensitivity. Treatment modifications or dose adjustments were implemented based on individual patient tolerance and disease progression. For instance, dose reduction of pemetrexed or platinum agents was considered for patients experiencing severe myelosuppression. Second-line therapy was initiated upon withdrawal of consent, occurrence of intolerable adverse events, or disease progression, with treatment selection guided by patient-specific factors and current clinical guidelines. Patients were stratified into morning and afternoon groups based on pemetrexed infusion timing, with the cutoff set at 14:00. Platinum-based agents were administered 30 minutes after pemetrexed infusion in both groups to optimize drug synergy. Treatment efficacy was evaluated radiologically after every two chemotherapy cycles. Survival outcomes and tumor response PFS, serving as the primary endpoint, was defined as the duration from treatment initiation to either disease progression (characterized by tumor growth or emergence of new lesions) or death from any cause. Treatment efficacy was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST 1.1) [30], categorizing responses into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). These classifications not only facilitate the quantification of short-term therapeutic outcomes but also provide critical guidance for subsequent treatment decisions. To ensure the objectivity and accuracy of efficacy assessments, two experienced radiologists independently evaluated chest CT images. Radiographic assessments were conducted after every two treatment cycles to monitor disease evolution. Interobserver agreement was statistically analyzed, and any discrepancies were resolved through adjudication by a third senior radiologist, thereby ensuring the reliability of the final assessment. The secondary endpoint focused on adverse events, which were systematically documented and evaluated using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Comprehensive safety assessments, including hematological, hepatic, renal, and gastrointestinal evaluations, were regularly performed throughout the treatment period. All AEs were meticulously recorded and graded according to CTCAE v5.0 criteria. Particular attention was given to serious adverse events (grade ≥3 or those leading to treatment discontinuation), with detailed documentation of their clinical course and outcomes. This systematic AE monitoring and evaluation protocol was designed to thoroughly characterize the safety profile of the treatment regimen and provide robust safety data for future clinical applications. Data collection and follow-up protocol The baseline clinical characteristics evaluated in this study encompassed: (1) including age, gender, smoking status, alcohol consumption, family history, tumor stage, and survival outcomes; (2) laboratory parameters, specifically hemoglobin, white blood cell count, neutrophil count, lymphocyte count, platelet count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN), uric acid, serum albumin, potassium, triglycerides, and sodium levels. This retrospective study included NSCLC patients who received AP regimen chemotherapy at Guangdong Second Provincial General Hospital between January 2018 and December 2023. The follow-up period commenced on the date of initial AP chemotherapy administration and concluded at the date of death, disease progression, or last follow-up. Follow-up assessments were conducted by two independent radiologists who evaluated chest CT and abdominal MRI scans. During the treatment phase, serological tests were performed every treatment cycle, while imaging studies were conducted every two cycles. Post-treatment surveillance involved imaging evaluations every 3 months during the first year, followed by semi-annual assessments thereafter. Additional diagnostic procedures, including bone scans, cranial CT, and comprehensive systemic examinations, were performed when metastatic progression was suspected. Statistical analysis The statistical analysis was conducted using GraphPad (version 8.0) and SPSS (version 13.0) software. Quantitative data with normal distribution were expressed as the mean ± standard deviation (x±S). Intergroup comparisons for continuous variables were performed using the Student's t-test or the Welch's t' test, as appropriate. Categorical data were compared using Fisher's exact test, and ordinal data were analyzed using the Mann-Whitney U test. The Kaplan-Meier method was employed to estimate the PFS curves for the overall cohort and the matched groups. To identify independent risk factors associated with PFS, we utilized the Cox proportional hazards regression model. Statistical significance was determined using a two-tailed p-value of less than 0.05. Result Patients characteristics Through eligibility review, a total of 132 patients with advanced NSCL adenocarcinoma who received first-line AP regimen chemotherapy were ultimately included in the study. Baseline characteristics and patient selection fowchart are illustrated in Table. 1 and Fig. 1. In the morning cohort, comprising 58 non-small cell lung cancer patients, the median age was 61 years, with 43 males (74.1%), 20 smokers (34.5%), and 45 cases (77.6%) with distant metastasis. In contrast, the afternoon cohort consisted of 74 patients with a median age of 59 years, 61 males (82.4%), 23 smokers (31.1%), and 54 cases (73.0%) with distant metastasis. Table 1. Baseline characteristics of enrolled patients in the entire cohort. Comparison of survival outcomes According to the mRECIST 1.1 criteria, no patients in either treatment group achieved CR. In the morning group, 12 patients achieved PR, 30 were assessed as SD, and 16 exhibited PD. In the afternoon group, 20 patients achieving PR, 29 as SD, and 25 with PD. In terms of overall treatment response, the morning group fared better than the afternoon group. Compared to the afternoon groups median PFS of 14 months, the morning group achieved a better survival outcome,with a median PFS of 24 months, as illustrated in Fig. 2. The hazard ratio (HR) between the two groups was 0.50, with a 95% confidence interval (CI) of 0.26-0.99, and a p-value of 0.037, indicating a significant 50% reduction in the risk of disease progression and death for the morning group. In subgroup analyses, the treatment effect on PFS was consistently more favorable for the morning group across all major subgroups, with particularly pronounced advantages observed in subgroups of patients under 65 years old, non-smokers, and those without a family history of cancer, as detailed in Table 2. Table 2. Subgroup analysis of NSCLC patients between the AM group and PM groups. Factors contributing to survival outcomes We employed the Cox proportional hazards regression model to analyze both univariate and multivariate factors. The univariate and multivariate factors influencing the PFS of patients NSCLC are presented in Table 3. Factors with a p-value less than 0.05 in the univariate analysis, including age, gender, and the time of drug infusion, were incorporated into the multivariate analysis. Ultimately, the multivariate analysis identified age and the time of drug infusion as independent prognostic factors affecting PFS. Safety We conducted an analysis of the incidence of adverse reactions in the morning and afternoon groups, which included blood routine, liver and kidney function, metabolic status, and gastrointestinal reactions. There were no significant differences observed between the two groups in terms of the incidence of all events or adverse reactions of grade 3 or higher. In the morning group, the most common adverse reactions were bone marrow suppression and liver function decline, with bone marrow suppression primarily manifested as anemia (65.52%), leukopenia (50.00%), and neutropenia (41.38%). Liver function damage was determined by the elevation of reference indicators such as ALT and AST. In the afternoon group, the most common adverse reactions were bone marrow suppression and nutritional metabolic disorders. Patients exhibited decreased appetite (33.78%), fatigue (35.14%), and hypoalbuminemia (31.08%). It is noteworthy that there was a certain difference in the incidence of edema between the two groups, which may suggest that administering chemotherapy drugs in the afternoon could reduce the occurrence of edema, as detailed in Table 4. Discussion NSCLC, the leading malignant tumor in terms of global incidence and mortality, still primarily relies on chemotherapy for treatment in its advanced stages. However, chemotherapy is a double-edged sword [ 31 ], offering therapeutic benefits to patients while also inevitably causing adverse reactions. How to make chemotherapy more cost-effective and efficient has become a question worth contemplating. Studies have indicated that the occurrence of tumors is closely related to biological rhythms [ 32 ], with the growth of tumor cells regulated by genes associated with these rhythms. Based on this understanding, a novel therapeutic approach known as chronotherapy has been proposed. Several studies [ 28 ] have shown that chronotherapy not only has advantages in efficacy compared to traditional chemotherapy but also reduces the incidence of adverse reactions. Our research builds upon and expands our preliminary experiments, which is noteworthy as they were published in abstract form at the 2024 ASCO Annual Meeting [ 33 ]. To the best of our knowledge, this is the first study to explore the efficacy and safety of chronotherapy with AP regimen in NSCLC. In this retrospective study, we found that NSCLC patients who received chemotherapy in the morning experienced better PFS benefits compared to those treated in the afternoon. Similarly, survival benefits were observed in major subgroups such as age, smoking, and family history. In terms of the incidence of adverse reactions grade 3 or above, the morning group had a higher rate than the afternoon group (31.03%vs 21.62%), although there was no statistically significant difference between the groups. Furthermore, through univariate and multivariate variable analysis, we concluded that the timing of drug administration is an independent prognostic factor for PFS. The research conclusions we have drawn are consistent with those of other domestic and international studies on chronotherapy for tumors. This not only demonstrates that chronotherapy can bring good news to patients with NSCLC, but also suggests the potential for the widespread applicability of chronotherapy in malignant tumors. Chronotherapy may well become the mainstream direction for the treatment of malignant tumors in the future. There are still some limitations in this study. Firstly, like other retrospective studies, ours is inevitably subject to selection bias, which may impact our research findings. Consequently, further validation of our conclusions requires additional prospective randomized controlled trials. Secondly, although we have collected all available data on NSCLC, the stringent requirements for drug infusion timing in chronotherapy result in a limited sample size that meets the inclusion criteria. More data from large-sample experiments are needed to support our findings, highlighting the critical role of sample size in enhancing the reliability of research. Lastly, it is worth noting that our data originate from a single center, which limits our coverage to different regions and populations, potentially restricting the generalizability of our study's results. Conclusion Administering AP regimen chronochemotherapy in the morning significantly may enhance PFS in advanced NSCLC. However, it should be noted that this chronomodulated treatment approach did not demonstrate superior safety profiles. These results underscore the potential of CCT to enhance the therapeutic outcomes of individualized chemotherapy regimens in advanced NSCLC, particularly through temporal optimization of drug delivery. Declarations Author contributions QA Xu, as the first author, was primarily responsible for the study conception, experimental design, data collection and analysis, manuscript writing, and figure preparation. KX Xian and X Xu, as co-first authors, contributed equally to the literature search, data organization, and preliminary data interpretation. P Xie and MD Hao provided critical insights and constructive suggestions for methodology improvement. DY Zhou, WL Liu and ZY Wang actively participated in the scientific discussion and interpretation of research findings. As the co-corresponding author, XX Zeng supervised the research progress, critically revised the manuscript, and secured funding support. The corresponding author, XH Zhang, oversaw the entire research project, provided scientific guidance, and was responsible for final manuscript review and editing. All authors have thoroughly reviewed and approved the final version of the manuscript. Ethical approval Statement The conduct of this study was approved by the Medical Ethics Committee of the Second Provincial General Hospital, with the ethical approval number: 2024-KY-KZ-415. Data Availability Statement The datasets generated during the current study are available from the corresponding author on reasonable request. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This study was supported by Guangdong Medical Scientific Research (grant No. A2024619). References R S Zheng, R Chen, B F Han, et al. Cancer incidence and mortality in China, 2022. Zhonghua Zhong Liu Za Zhi. 2024. 23;46(3):221-231. Lindsey A Torre, Rebecca L Siegel, Ahmedin Jemal. Lung Cancer Statistics. Adv Exp Med Biol. 2016. 893:1-19. Yanting Zhang, Salvatore Vaccarella, Eileen Morgan, et al. Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. Lancet Oncol. 2023. 24(11):1206-1218. Aundrea L Oliver. Lung Cancer: Epidemiology and Screening. Surg Clin North Am. 2022. 102(3):335-344. Alesha A Thai, Benjamin J Solomon, Lecia V Sequist, et al. Lung cancer. Lancet. 2021. 7;398(10299):535-554. Freddie Bray, Mathieu Laversanne, Hyuna Sung. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. 74(3):229-263. Amanda Leiter, Rajwanth R Veluswamy, Juan P Wisnivesky, et al. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol. 2023. 20(9):624-639. Yaser Alduais, Haijun Zhang, Fan Fan, et al. Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment. Medicine (Baltimore). 2023.102(8):e32899. Georgios Geropoulos, Stepan M Esagian, Konstantinos Skarentzos, et al. Video-assisted thoracoscopic versus open sleeve lobectomy for non-small cell lung cancer: A systematic review and meta-analysis from six comparative studies. Asian Cardiovasc Thorac Ann. 2022. 30(8):881-893. Chi-Fu Jeffrey Yang, Arvind Kumar, Brian C Gulack, et al. Long-term outcomes after lobectomy for non-small cell lung cancer when unsuspected pN2 disease is found: A National Cancer Data Base analysis. J Thorac Cardiovasc Surg. 2016. 151(5):1380-8. Kareem Tahayneh, Mayar Idkedek, Firas Abu Akar, et al. NSCLC: Current Evidence on Its Pathogenesis, Integrated Treatment, and Future Perspectives. J Clin Med. 2025. 6;14(3):1025. Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018. 378(2):113-125. Suresh S Ramalingam, Johan Vansteenkiste, David Planchard, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020. 382(1):41-50. Martin Reck, Delvys Rodríguez-Abreu, Andrew G Robinson, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019. 37(7):537-546. Justin F Gainor, Alice T Shaw, Lecia V Sequist, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis. Clinical Cancer Research. 2016. 22(18), 4585-4593. Caitriona Holohan, Sandra Van Schaeybroeck, Daniel B Longley, et al. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013. 13(10):714-26. Roy S Herbst, Daniel Morgensztern, Chris Boshoff. The biology and management of non-small cell lung cancer. Nature. 2018. 24;553(7689):446-454. Michael A Postow, Robert Sidlow, Matthew D Hellmann. Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine. 2018. 378(2), 158-168. Daniel S Chen, Ira Mellman. Elements of cancer immunity and the cancer-immune set point. Nature. 2017. 541(7637):321-330. Qianqian Guo, Liwei Liu, Zelong Chen, et al. Current treatments for non-small cell lung cancer. Front Oncol. 2022. 12:945102. Jean-Pierre Pignon, Hélène Tribodet, Giorgio V Scagliotti, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008. 26(21):3552-9. Howard West, Michael McCleod, Maen Hussein, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019. 20(7):924-937. Joan H Schiller, David Harrington, Chandra P Belani, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002. 10;346(2):92-8. D Planchard, S Popat, K Kerr, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018. 1;29(Suppl 4):iv192-iv237. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer. JCO. 2013;31(23):2895–2902. Kevin B Koronowski, Paolo Sassone-Corsi. Communicating clocks shape circadian homeostasis. Science. 2021. 12;371(6530):eabd0951. Wei Ruan, Xiaoyi Yuan, Holger K Eltzschig. Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021. 20(4):287-307. Li J, Chen R, Ji M, Zou S, Zhu L. Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis. Cancer Chemother Pharmacol. 2015. 76(3):651–655. Li Y. The Effect of Chronochemotherapy with Gemcitabine and Cisplatin on Advanced Non-Small Cell Lung Cancer Patients and Related Indicators of Anticipatory Nausea and Vomiting. China Medical Frontier Journal (Electronic Edition). 2014. 6(05):126-129. Lawrence H Schwartz, Saskia Litière, Elisabeth de Vries, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016. 62:132-7. Giulia Meoni 1, Fabiana Letizia Cecere, Elisa Lucherini, et al. Medical treatment of advanced non-small cell lung cancer in elderly patients: a review of the role of chemotherapy and targeted agents. J Geriatr Oncol. 2013. 4(3):282-90. Fangjun Yu, Yuanyuan Liu, Rong Zhang, et al. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy. Biochem Pharmacol. 2022 Sep:203:115185. Prasanna V Ashok Kumar, Panshak P Dakup, Soumyadeep Sarkar, et al. It's About Time: Advances in Understanding the Circadian Regulation of DNA Damage and Repair in Carcinogenesis and Cancer Treatment Outcomes. Yale J Biol Med. 2019. 92(2):305-316. Sun L-Y, Xu Q-A, Xu X, et al. Efficacy and safety of time-of-day infusion of pemetrexed plus platinum and paclitaxel plus platinum for patients with advanced non-small cell lung cancer: A retrospective study. JCO. 2024;42(16_suppl):e20557–e20557. Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files file.xls Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6248417","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":451661776,"identity":"24bf7542-e470-4c05-bb86-4b64966e74a1","order_by":0,"name":"Quan-An Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDADfv7mAwc+/CBFi+SMY4kHZ/aQosXgQI7xYQ42YlTeSN4m8XOHXR7DgTMfDjPwMMjzix0g5J60MsneM8nFjM29Gw4XWDAYzpydgF8Lv0SOmQRvG3NiM8PZDYdn8DAkGNwmoIUNqEXyb1t9YhtDzoPDPGxEaAHZIs3bdjixhyGHgTgtkj3Piq1l244nzpA4ZgAMZAnCfjE4nrzx5tu26sT955sff/jww0aeX5qAFpAuZI4EQeUYWkbBKBgFo2AUYAIAbjNGh5uLMVMAAAAASUVORK5CYII=","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":true,"prefix":"","firstName":"Quan-An","middleName":"","lastName":"Xu","suffix":""},{"id":451661777,"identity":"73cfeaad-a61a-4594-8857-6bf540b581df","order_by":1,"name":"Ke-Xin Xian","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Ke-Xin","middleName":"","lastName":"Xian","suffix":""},{"id":451661778,"identity":"9f2325c9-2e18-4206-9869-b614cdb9cb21","order_by":2,"name":"Xian Xu","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Xian","middleName":"","lastName":"Xu","suffix":""},{"id":451661779,"identity":"1e3fe833-8bd5-460f-ad0e-d0c2aea52ddc","order_by":3,"name":"Pei Xie","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Pei","middleName":"","lastName":"Xie","suffix":""},{"id":451661780,"identity":"2e07d121-6b57-4ded-adf2-4b0408eaf3c9","order_by":4,"name":"Meng-Di Hao","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Meng-Di","middleName":"","lastName":"Hao","suffix":""},{"id":451661781,"identity":"ee834f05-2467-43d1-89d9-e64debcd3a09","order_by":5,"name":"Wei-Lu Liu","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Wei-Lu","middleName":"","lastName":"Liu","suffix":""},{"id":451661782,"identity":"5b4d1090-65a9-4553-adc3-d1345322e2d3","order_by":6,"name":"Dai-Yan Zhou","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dai-Yan","middleName":"","lastName":"Zhou","suffix":""},{"id":451661783,"identity":"b181f8a5-aab0-48c2-a428-15d2454f8d36","order_by":7,"name":"Zi-Yi Wang","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Zi-Yi","middleName":"","lastName":"Wang","suffix":""},{"id":451661784,"identity":"2464b6d9-a73b-46b0-abaf-0bce74a29796","order_by":8,"name":"Xin-Xin Zeng","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Xin-Xin","middleName":"","lastName":"Zeng","suffix":""},{"id":451661785,"identity":"4fd712e7-f082-4e44-b586-81a2b968dfb8","order_by":9,"name":"Xu-Hui Zhang","email":"","orcid":"","institution":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Xu-Hui","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-03-18 01:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6248417/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6248417/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82151647,"identity":"1f899153-fcb8-4508-bbfa-3206e11bacd1","added_by":"auto","created_at":"2025-05-07 07:21:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":173201,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the patient selection process for this study\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6248417/v1/f5aa89648ec0cfc897b8a445.png"},{"id":82153996,"identity":"452b084c-e399-4c0b-b943-c5db404b28ff","added_by":"auto","created_at":"2025-05-07 07:29:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79502,"visible":true,"origin":"","legend":"\u003cp\u003eComparative Kaplan-Meier Analysis of progression-free survival in NSCLC patients between the AM group and PM groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6248417/v1/562e40e163a0b0096df11659.png"},{"id":82784478,"identity":"071d8207-bfef-49ca-ad3e-8c6f024bc5b5","added_by":"auto","created_at":"2025-05-15 08:53:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":708817,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6248417/v1/b9280880-119f-4262-b13d-0e159b126d98.pdf"},{"id":82154909,"identity":"96e0f10b-a9f8-4c47-8437-16fb25ea46ae","added_by":"auto","created_at":"2025-05-07 07:37:26","extension":"xls","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":105472,"visible":true,"origin":"","legend":"","description":"","filename":"file.xls","url":"https://assets-eu.researchsquare.com/files/rs-6248417/v1/49bb4ae2b628ccf03ece01fe.xls"},{"id":82151654,"identity":"6b7480bd-6d7f-4246-949c-f32183156be1","added_by":"auto","created_at":"2025-05-07 07:21:26","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":269169,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6248417/v1/ff7ff9e4845e8654a13f91b6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of time-of-day infusion of pemetrexed plus platinum for patients with advanced non-small cell lung cancer: A retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer stands as the preeminent killer in the realm of cancer, representing the most formidable malignancy that poses the greatest threat to human health and life on a global scale [1, 2]. It imposes a substantial burden and presents significant challenges to public health systems [3, 4]. As the predominant pathological subtype, NSCLC represents the most frequently diagnosed form of lung cancer, accounting for approximately 85% of all lung cancer cases worldwide [3, 5]. This malignancy demonstrates significantly higher incidence and mortality rates compared to other pulmonary neoplasms, posing a substantial global health burden with its complex molecular pathogenesis and heterogeneous clinical manifestations [6]. According to epidemiological statistics, numerous high-risk factors have been identified for NSCLC. Among these, long-term smoking, air pollution, and environmental exposure are widely recognized as the primary contributors [7]. The therapeutic landscape of NSCLC encompasses a diverse array of modalities, including surgical intervention, chemotherapy, targeted therapy, and immunotherapy [8]. Among these approaches, surgical resection is widely regarded by both the medical community and general population as the most potentially curative treatment option when clinically indicated [9, 10]. Owing to the insidious nature of its onset, the majority of patients with NSCLC are diagnosed at an advanced stage [11], thereby missing the window for potential curative surgical intervention.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn recent years, with the in-depth investigation of the molecular biological mechanisms underlying NSCLC, targeted therapy and immunotherapy have emerged as prominent areas of research and clinical application [12-14]. However, the efficacy of targeted therapy is highly dependent on the tumor\u0026apos;s genetic mutation profile [15], demonstrating limited effectiveness in patients without identifiable molecular targets. Moreover, tumor cells can develop resistance through multiple mechanisms, thereby restricting the long-term utility of these therapies [16]. Immunotherapy, while promising, exhibits significant interpatient variability in treatment response and is associated with immune-related adverse events (irAEs), including pneumonitis and hepatitis [17, 18]. Additionally, the emergence of acquired resistance during immunotherapy and the incomplete understanding of its underlying mechanisms necessitate further investigation [19]. Within the current therapeutic paradigm, chemotherapy remains a cornerstone in NSCLC management [20, 21], particularly for patients who are ineligible for or refractory to targeted and immunotherapeutic approaches. Chemotherapeutic agents exert their antitumor effects by targeting and destroying cancer cells [22], effectively controlling proliferation and eliminating established micrometastases. However, chemotherapy can only modestly extend the survival of patients with advanced NSCLC. Studies [23, 24] have indicated that the introduction of platinum-based chemotherapy has increased the median survival of NSCLC patients by 6-8 months. Even with the current first-line chemotherapy regimen combining paclitaxel with platinum, the median survival has only been extended to 16.9 months [25]. Thus, it can be seen that traditional chemotherapy often adversely affects patient outcomes due to its high dosage and toxicity.\u003c/p\u003e\n\u003cp\u003eChronochemotherapy, on the other hand, involves administering chemotherapeutic drugs at appropriate stages in accordance with the body\u0026apos;s physiological rhythms [26, 27], thereby achieving the goal of high efficacy and low toxicity. Recent research has indicated that chronochemotherapy tends to demonstrate superior efficacy and safety compared to conventional chemotherapy. A retrospective study [28] categorized patients who had undergone TP regimenpaclitaxel plus cisplatinchemotherapy into a chronotherapy group and a conventional chemotherapy group. Long-term follow-up revealed that the objective response rate (ORR) in the chronotherapy group was significantly higher than that in the conventional chemotherapy group (83.66%vs.43.33%). In terms of safety, the incidence of myelosuppression and gastrointestinal reactions in the chronotherapy group was lower than that in the conventional chemotherapy group. Similarly, the advantages of chronotherapy were observed in NSCLC patients undergoing first-line GP regimengemcitabine plus cisplatinchemotherapy, with the 1-year and 2-year survival rates in the chronotherapy group being higher than those in the conventional chemotherapy group [29]. These findings provide a theoretical basis for the application of chronotherapy in NSCLC chemotherapy.\u003c/p\u003e\n\u003cp\u003eTo date, the efficacy and safety of the AP regimen chronochemotherapy in advanced NSCLC remain largely uncharted territory. Consequently, this retrospective study aims to investigate the survival and safety benefits of AP regimen chronochemotherapy in patients with advanced NSCLC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective analysis of 132 patients with advanced NSCLC who received AP regimen chemotherapy at Guangdong Second Provincial General Hospital between January 2018 and December 2023. All cases were rigorously evaluated for eligibility based on predefined inclusion and exclusion criteria. The diagnosis of NSCLC was confirmed according to either the National Comprehensive Cancer Network (NCCN) guidelines or Chinese Society of Clinical Oncology (CSCO) guidelines. The inclusion criteria were as follows: (1) histologically confirmed NSCLC; (2) age \u0026ge;18 years with adequate physiological status to tolerate chemotherapy; (3) completion of at least two cycles of AP regimen chemotherapy to ensure treatment continuity and reliable efficacy evaluation; (4) TNM stage III or IV disease, consistent with advanced NSCLC diagnosis; (5) ECOG performance status of 0-1 with expected survival \u0026ge;3 months to ensure treatment tolerance and follow-up completion; (6) no prior systemic antitumor therapy to avoid confounding effects; (7) adequate organ function as evidenced by ALT/AST \u0026le;2.5\u0026times;ULN, serum creatinine \u0026le;1.5\u0026times;ULN, ANC \u0026ge;1.5\u0026times;10^9/L, and PLT \u0026ge;100\u0026times;10^9/L; (8) provision of written informed consent. Exclusion criteria included: (1) previous antitumor treatments that might confound results; (2) concurrent secondary primary malignancies; (3) severe cardiac, hepatic, or renal dysfunction; (4) known hypersensitivity to study drug components; (5) inability to evaluate tumor response; (6) loss follow-up. Treatment discontinuation criteria were: (A) disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by contrast-enhanced chest CT; (B) occurrence of severe or life-threatening adverse events (grade 4 hematological toxicity or grade \u0026ge;3 non-hematological toxicity) unresponsive to supportive care; (C) death from any cause.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe institutional review board granted ethical approval for this retrospective study. The investigation adheres to the principles outlined in the Declaration of Helsinki. All patients included in this study provided informed consent for treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll enrolled patients received platinum-based doublet chemotherapy with the AP regimen, which consisted of pemetrexed (500 mg/m\u0026sup2;, intravenous infusion, day 1) and nedaplatin (80-100 mg/m\u0026sup2;, intravenous infusion, day 1). The treatment cycle was repeated every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity occurred. To ensure patient safety and tolerance to pemetrexed-based chemotherapy, all patients received the following premedication regimen: oral folic acid supplementation (400 ug/day) was initiated 1 week before pemetrexed administration and continued until 21 days after the last chemotherapy cycle, aiming to reduce pemetrexed-induced myelosuppression and gastrointestinal toxicity. Intramuscular vitamin B12 (1000 ug) was administered every 9 weeks to prevent megaloblastic anemia associated with pemetrexed. Oral dexamethasone (4 mg twice daily) was administered from the day before to 2 days after pemetrexed infusion to minimize cutaneous reactions and hypersensitivity. Treatment modifications or dose adjustments were implemented based on individual patient tolerance and disease progression. For instance, dose reduction of pemetrexed or platinum agents was considered for patients experiencing severe myelosuppression. Second-line therapy was initiated upon withdrawal of consent, occurrence of intolerable adverse events, or disease progression, with treatment selection guided by patient-specific factors and current clinical guidelines. Patients were stratified into morning and afternoon groups based on pemetrexed infusion timing, with the cutoff set at 14:00. Platinum-based agents were administered 30 minutes after pemetrexed infusion in both groups to optimize drug synergy. Treatment efficacy was evaluated radiologically after every two chemotherapy cycles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival outcomes and tumor response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePFS, serving as the primary endpoint, was defined as the duration from treatment initiation to either disease progression (characterized by tumor growth or emergence of new lesions) or death from any cause. Treatment efficacy was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST 1.1) [30], categorizing responses into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). These classifications not only facilitate the quantification of short-term therapeutic outcomes but also provide critical guidance for subsequent treatment decisions. To ensure the objectivity and accuracy of efficacy assessments, two experienced radiologists independently evaluated chest CT images. Radiographic assessments were conducted after every two treatment cycles to monitor disease evolution. Interobserver agreement was statistically analyzed, and any discrepancies were resolved through adjudication by a third senior radiologist, thereby ensuring the reliability of the final assessment. The secondary endpoint focused on adverse events, which were systematically documented and evaluated using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Comprehensive safety assessments, including hematological, hepatic, renal, and gastrointestinal evaluations, were regularly performed throughout the treatment period. All AEs were meticulously recorded and graded according to CTCAE v5.0 criteria. Particular attention was given to serious adverse events (grade\u0026nbsp;\u0026ge;3 or those leading to treatment discontinuation), with detailed documentation of their clinical course and outcomes. This systematic AE monitoring and evaluation protocol was designed to thoroughly characterize the safety profile of the treatment regimen and provide robust safety data for future clinical applications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and follow-up protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline clinical characteristics evaluated in this study encompassed: (1) including age, gender, smoking status, alcohol consumption, family history, tumor stage, and survival outcomes; (2) laboratory parameters, specifically hemoglobin, white blood cell count, neutrophil count, lymphocyte count, platelet count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN), uric acid, serum albumin, potassium, triglycerides, and sodium levels. This retrospective study included NSCLC patients who received AP regimen chemotherapy at Guangdong Second Provincial General Hospital between January 2018 and December 2023. The follow-up period commenced on the date of initial AP chemotherapy administration and concluded at the date of death, disease progression, or last follow-up. Follow-up assessments were conducted by two independent radiologists who evaluated chest CT and abdominal MRI scans. During the treatment phase, serological tests were performed every treatment cycle, while imaging studies were conducted every two cycles. Post-treatment surveillance involved imaging evaluations every 3 months during the first year, followed by semi-annual assessments thereafter. Additional diagnostic procedures, including bone scans, cranial CT, and comprehensive systemic examinations, were performed when metastatic progression was suspected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe statistical analysis was conducted using GraphPad (version 8.0) and SPSS (version 13.0) software. Quantitative data with normal distribution were expressed as the mean \u0026plusmn; standard deviation (x\u0026plusmn;S). Intergroup comparisons for continuous variables were performed using the Student\u0026apos;s t-test or the Welch\u0026apos;s t\u0026apos; test, as appropriate. Categorical data were compared using Fisher\u0026apos;s exact test, and ordinal data were analyzed using the Mann-Whitney U test. The Kaplan-Meier method was employed to estimate the PFS curves for the overall cohort and the matched groups. To identify independent risk factors associated with PFS, we utilized the Cox proportional hazards regression model. Statistical significance was determined using a two-tailed p-value of less than 0.05.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cstrong\u003ePatients characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThrough eligibility review, a total of 132 patients with advanced NSCL adenocarcinoma who received first-line AP regimen chemotherapy were ultimately included in the study. Baseline characteristics and patient selection fowchart are illustrated in Table.\u0026nbsp;1 and Fig.\u0026nbsp;1. In the morning cohort, comprising 58 non-small cell lung cancer patients, the median age was 61 years, with 43 males (74.1%), 20 smokers (34.5%), and 45 cases (77.6%) with distant metastasis. In contrast, the afternoon cohort consisted of 74 patients with a median age of 59 years, 61 males (82.4%), 23 smokers (31.1%), and 54 cases (73.0%) with distant metastasis.\u003c/p\u003e\n\u003cp\u003eTable 1. Baseline characteristics of enrolled patients in the entire cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparison of survival outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the mRECIST 1.1 criteria, no patients in either treatment group achieved CR. In the morning group, 12 patients achieved PR, 30 were assessed as SD, and 16 exhibited PD. In the afternoon group, 20 patients achieving PR, 29 as SD, and 25 with PD. In terms of overall treatment response, the morning group fared better than the afternoon group. Compared to the afternoon groups median PFS of 14 months, the morning group achieved a better survival outcome,with a median PFS of 24 months, as illustrated in Fig. 2. The hazard ratio (HR) between the two groups was 0.50, with a 95% confidence interval (CI) of 0.26-0.99, and a p-value of 0.037, indicating a significant 50% reduction in the risk of disease progression and death for the morning group. In subgroup analyses, the treatment effect on PFS was consistently more favorable for the morning group across all major subgroups, with particularly pronounced advantages observed in subgroups of patients under 65 years old, non-smokers, and those without a family history of cancer, as detailed in Table 2.\u003c/p\u003e\n\u003cp\u003eTable 2. Subgroup analysis of NSCLC patients between the AM group and PM groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFactors contributing to survival outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe employed the Cox proportional hazards regression model to analyze both univariate and multivariate factors. The univariate and multivariate factors influencing the PFS of patients NSCLC are presented in Table 3. Factors with a p-value less than 0.05 in the univariate analysis, including age, gender, and the time of drug infusion, were incorporated into the multivariate analysis. Ultimately, the multivariate analysis identified age and the time of drug infusion as independent prognostic factors affecting PFS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted an analysis of the incidence of adverse reactions in the morning and afternoon groups, which included blood routine, liver and kidney function, metabolic status, and gastrointestinal reactions. There were no significant differences observed between the two groups in terms of the incidence of all events or adverse reactions of grade 3 or higher. In the morning group, the most common adverse reactions were bone marrow suppression and liver function decline, with bone marrow suppression primarily manifested as anemia (65.52%), leukopenia (50.00%), and neutropenia (41.38%). Liver function damage was determined by the elevation of reference indicators such as ALT and AST. In the afternoon group, the most common adverse reactions were bone marrow suppression and nutritional metabolic disorders. Patients exhibited decreased appetite (33.78%), fatigue (35.14%), and hypoalbuminemia (31.08%). It is noteworthy that there was a certain difference in the incidence of edema between the two groups, which may suggest that administering chemotherapy drugs in the afternoon could reduce the occurrence of edema, as detailed in Table 4.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNSCLC, the leading malignant tumor in terms of global incidence and mortality, still primarily relies on chemotherapy for treatment in its advanced stages. However, chemotherapy is a double-edged sword [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], offering therapeutic benefits to patients while also inevitably causing adverse reactions. How to make chemotherapy more cost-effective and efficient has become a question worth contemplating. Studies have indicated that the occurrence of tumors is closely related to biological rhythms [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], with the growth of tumor cells regulated by genes associated with these rhythms. Based on this understanding, a novel therapeutic approach known as chronotherapy has been proposed. Several studies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] have shown that chronotherapy not only has advantages in efficacy compared to traditional chemotherapy but also reduces the incidence of adverse reactions. Our research builds upon and expands our preliminary experiments, which is noteworthy as they were published in abstract form at the 2024 ASCO Annual Meeting [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first study to explore the efficacy and safety of chronotherapy with AP regimen in NSCLC. In this retrospective study, we found that NSCLC patients who received chemotherapy in the morning experienced better PFS benefits compared to those treated in the afternoon. Similarly, survival benefits were observed in major subgroups such as age, smoking, and family history. In terms of the incidence of adverse reactions grade 3 or above, the morning group had a higher rate than the afternoon group (31.03%vs 21.62%), although there was no statistically significant difference between the groups. Furthermore, through univariate and multivariate variable analysis, we concluded that the timing of drug administration is an independent prognostic factor for PFS. The research conclusions we have drawn are consistent with those of other domestic and international studies on chronotherapy for tumors. This not only demonstrates that chronotherapy can bring good news to patients with NSCLC, but also suggests the potential for the widespread applicability of chronotherapy in malignant tumors. Chronotherapy may well become the mainstream direction for the treatment of malignant tumors in the future.\u003c/p\u003e \u003cp\u003eThere are still some limitations in this study. Firstly, like other retrospective studies, ours is inevitably subject to selection bias, which may impact our research findings. Consequently, further validation of our conclusions requires additional prospective randomized controlled trials. Secondly, although we have collected all available data on NSCLC, the stringent requirements for drug infusion timing in chronotherapy result in a limited sample size that meets the inclusion criteria. More data from large-sample experiments are needed to support our findings, highlighting the critical role of sample size in enhancing the reliability of research. Lastly, it is worth noting that our data originate from a single center, which limits our coverage to different regions and populations, potentially restricting the generalizability of our study's results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAdministering AP regimen chronochemotherapy in the morning significantly may enhance PFS in advanced NSCLC. However, it should be noted that this chronomodulated treatment approach did not demonstrate superior safety profiles. These results underscore the potential of CCT to enhance the therapeutic outcomes of individualized chemotherapy regimens in advanced NSCLC, particularly through temporal optimization of drug delivery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQA Xu, as the first author, was primarily responsible for the study conception, experimental design, data collection and analysis, manuscript writing, and figure preparation. KX Xian and X Xu, as co-first authors, contributed equally to the literature search, data organization, and preliminary data interpretation. P Xie and MD Hao provided critical insights and constructive suggestions for methodology improvement. DY Zhou, WL Liu and ZY Wang actively participated in the scientific discussion and interpretation of research findings. As the co-corresponding author, XX Zeng supervised the research progress, critically revised the manuscript, and secured funding support. The corresponding author, XH Zhang, oversaw the entire research project, provided scientific guidance, and was responsible for final manuscript review and editing. All authors have thoroughly reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe conduct of this study was approved by the Medical Ethics Committee of the\u0026nbsp;Second Provincial General Hospital, with the ethical approval number: 2024-KY-KZ-415.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Guangdong Medical Scientific Research (grant No. A2024619).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eR S Zheng, R Chen, B F Han, et al. Cancer incidence and mortality in China, 2022. Zhonghua Zhong Liu Za Zhi. 2024. 23;46(3):221-231.\u003c/li\u003e\n \u003cli\u003eLindsey A Torre, Rebecca L Siegel, Ahmedin Jemal. Lung Cancer Statistics. Adv Exp Med Biol. 2016. 893:1-19.\u003c/li\u003e\n \u003cli\u003eYanting Zhang, Salvatore Vaccarella, Eileen Morgan, et al. Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. Lancet Oncol. 2023. 24(11):1206-1218.\u003c/li\u003e\n \u003cli\u003eAundrea L Oliver. Lung Cancer: Epidemiology and Screening. Surg Clin North Am. 2022. 102(3):335-344.\u003c/li\u003e\n \u003cli\u003eAlesha A Thai, Benjamin J Solomon, Lecia V Sequist, et al. Lung cancer. Lancet. 2021. 7;398(10299):535-554.\u003c/li\u003e\n \u003cli\u003eFreddie Bray, Mathieu Laversanne, Hyuna Sung. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. 74(3):229-263.\u003c/li\u003e\n \u003cli\u003eAmanda Leiter, Rajwanth R Veluswamy, Juan P Wisnivesky, et al. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol. 2023. 20(9):624-639.\u003c/li\u003e\n \u003cli\u003eYaser Alduais, Haijun Zhang, Fan Fan, et al. Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment. Medicine (Baltimore). 2023.102(8):e32899.\u003c/li\u003e\n \u003cli\u003eGeorgios Geropoulos, Stepan M Esagian, Konstantinos Skarentzos, et al. Video-assisted thoracoscopic versus open sleeve lobectomy for non-small cell lung cancer: A systematic review and meta-analysis from six comparative studies. Asian Cardiovasc Thorac Ann. 2022. 30(8):881-893.\u003c/li\u003e\n \u003cli\u003eChi-Fu Jeffrey Yang, Arvind Kumar, Brian C Gulack, et al. Long-term outcomes after lobectomy for non-small cell lung cancer when unsuspected pN2 disease is found: A National Cancer Data Base analysis. J Thorac Cardiovasc Surg. 2016. 151(5):1380-8.\u003c/li\u003e\n \u003cli\u003eKareem Tahayneh, Mayar Idkedek, Firas Abu Akar, et al. NSCLC: Current Evidence on Its Pathogenesis, Integrated Treatment, and Future Perspectives. J Clin Med. 2025. 6;14(3):1025.\u003c/li\u003e\n \u003cli\u003eJean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018. 378(2):113-125.\u003c/li\u003e\n \u003cli\u003eSuresh S Ramalingam, Johan Vansteenkiste, David Planchard, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020. 382(1):41-50.\u003c/li\u003e\n \u003cli\u003eMartin Reck, Delvys Rodr\u0026iacute;guez-Abreu, Andrew G Robinson, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019. 37(7):537-546.\u003c/li\u003e\n \u003cli\u003eJustin F Gainor, Alice T Shaw, Lecia V Sequist, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis. Clinical Cancer Research. 2016. 22(18), 4585-4593.\u003c/li\u003e\n \u003cli\u003eCaitriona Holohan, Sandra Van Schaeybroeck, Daniel B Longley, et al. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013. 13(10):714-26.\u003c/li\u003e\n \u003cli\u003eRoy S Herbst, Daniel Morgensztern, Chris Boshoff. The biology and management of non-small cell lung cancer. Nature. 2018. 24;553(7689):446-454.\u003c/li\u003e\n \u003cli\u003eMichael A Postow, Robert Sidlow, Matthew D Hellmann. Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine. 2018. 378(2), 158-168.\u003c/li\u003e\n \u003cli\u003eDaniel S Chen, Ira Mellman. Elements of cancer immunity and the cancer-immune set point. Nature. 2017. 541(7637):321-330.\u003c/li\u003e\n \u003cli\u003eQianqian Guo, Liwei Liu, Zelong Chen, et al. Current treatments for non-small cell lung cancer. Front Oncol. 2022. 12:945102.\u003c/li\u003e\n \u003cli\u003eJean-Pierre Pignon, H\u0026eacute;l\u0026egrave;ne Tribodet, Giorgio V Scagliotti, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008. 26(21):3552-9.\u003c/li\u003e\n \u003cli\u003eHoward West, Michael McCleod, Maen Hussein, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019. 20(7):924-937.\u003c/li\u003e\n \u003cli\u003eJoan H Schiller, David Harrington, Chandra P Belani, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002. 10;346(2):92-8.\u003c/li\u003e\n \u003cli\u003eD Planchard, S Popat, K Kerr, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018. 1;29(Suppl 4):iv192-iv237.\u003c/li\u003e\n \u003cli\u003ePaz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non\u0026ndash;Small-Cell Lung Cancer. JCO. 2013;31(23):2895\u0026ndash;2902.\u003c/li\u003e\n \u003cli\u003eKevin B Koronowski, Paolo Sassone-Corsi. Communicating clocks shape circadian homeostasis. Science. 2021. 12;371(6530):eabd0951.\u003c/li\u003e\n \u003cli\u003eWei Ruan, Xiaoyi Yuan, Holger K Eltzschig. Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021. 20(4):287-307.\u003c/li\u003e\n \u003cli\u003eLi J, Chen R, Ji M, Zou S, Zhu L. Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis. Cancer Chemother Pharmacol. 2015. 76(3):651\u0026ndash;655.\u003c/li\u003e\n \u003cli\u003eLi Y. The Effect of Chronochemotherapy with Gemcitabine and Cisplatin on Advanced Non-Small Cell Lung Cancer Patients and Related Indicators of Anticipatory Nausea and Vomiting. China Medical Frontier Journal (Electronic Edition). 2014. 6(05):126-129.\u003c/li\u003e\n \u003cli\u003eLawrence H Schwartz, Saskia Liti\u0026egrave;re, Elisabeth de Vries, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016. 62:132-7.\u003c/li\u003e\n \u003cli\u003eGiulia Meoni 1, Fabiana Letizia Cecere, Elisa Lucherini, et al. Medical treatment of advanced non-small cell lung cancer in elderly patients: a review of the role of chemotherapy and targeted agents. J Geriatr Oncol. 2013. 4(3):282-90.\u003c/li\u003e\n \u003cli\u003eFangjun Yu, Yuanyuan Liu, Rong Zhang, et al. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy. Biochem Pharmacol. 2022 Sep:203:115185.\u003c/li\u003e\n \u003cli\u003ePrasanna V Ashok Kumar, Panshak P Dakup, Soumyadeep Sarkar, et al. It\u0026apos;s About Time: Advances in Understanding the Circadian Regulation of DNA Damage and Repair in Carcinogenesis and Cancer Treatment Outcomes. Yale J Biol Med. 2019. 92(2):305-316.\u003c/li\u003e\n \u003cli\u003eSun L-Y, Xu Q-A, Xu X, et al. Efficacy and safety of time-of-day infusion of pemetrexed plus platinum and paclitaxel plus platinum for patients with advanced non-small cell lung cancer: A retrospective study. JCO. 2024;42(16_suppl):e20557\u0026ndash;e20557.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Time-of-day infusion, Chronochemotherapy, Circadian rhythm, Non-small cell lung cance, biological clock, chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-6248417/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6248417/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Retrospective studies suggest that administering chemotherapy infusions in the morning can enhance treatment efficacy and mitigate side effects in non-small cell lung cancer (NSCLC) patients. However, the effectiveness of chronotherapy using pemetrexed plus platinum (AP) in advanced NSCLC chemotherapy remains unexplored. This study aims to evaluate the impact of AP chrono-chemotherapy (CCT) on treatment response and adverse events in advanced NSCLC patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod: \u003c/strong\u003eWe retrospectively analyzed 132 advanced NSCLC patients treated with AP at Guangdong Second Provincial General Hospital from 2018 to 2023. Based on previous research, we classified patients who received chemotherapy infusions before 2:00 PM as the morning (AM) group, while the rest were categorized as the afternoon (PM) group. Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors Criteria V.1.1. The primary endpoint was progression-free survival (PFS), with safety profile serving as the secondary endpoint. All adverse events were identified and graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult: \u003c/strong\u003eIn the AP cohort, the AM group exhibited a longer PFS compared to the PM group (AM vs. PM, n = 58 vs. n = 74, 24.0 vs. 14.0 months, p = 0.037). Subsequent subgroup analysis in the AP cohort favored the AM group across all major subgroups for PFS treatment effect. Furthermore, the analysis of adverse reactions revealed similar incidences of any treatment emergent adverse events (TEAE) in both AM and PM (AM vs. PM, 86.21% vs. 86.49% in AP cohort), and grade 3 TEAEs (AM vs. PM, 31.03% vs. 21.62% in AP cohort). The most common adverse events were anemia, leukopenia, and Neutropenia. Univariate and multivariate analyses indicated that the infusion time of AP chemotherapy (p = 0.029) was an independent prognostic factor for NSCLC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eAP treatment administered in the morning may enhance PFS in advanced NSCLC. This suggests that CCT could potentially enhance the efficacy of individualized chemotherapy in advanced NSCLC.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of time-of-day infusion of pemetrexed plus platinum for patients with advanced non-small cell lung cancer: A retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 07:21:21","doi":"10.21203/rs.3.rs-6248417/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"48c13520-5fa7-48ea-b97f-c7f2b76a3a5d","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48042234,"name":"Biological sciences/Cancer/Cancer therapy"},{"id":48042235,"name":"Biological sciences/Cancer/Lung cancer"}],"tags":[],"updatedAt":"2025-05-15T08:53:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 07:21:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6248417","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6248417","identity":"rs-6248417","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}