Abstract
Background
Retrospective studies indicate that morning chemotherapy enhances efficacy and reduces side effects in non-small cell lung cancer (NSCLC). However, the role of infusion timing for pemetrexed plus platinum (AP) chronotherapy remains unclear. This study evaluates the impact of AP administration time on efficacy and safety in advanced NSCLC.
Methods
We retrospectively analyzed 132 advanced NSCLC patients receiving AP chemotherapy at Guangdong Second Provincial General Hospital from 2018 to 2023. Based on previous research, patients were grouped into morning (AM; infusion before 2:00 PM, n=58) and afternoon (PM; n=74) groups. 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 (AEs) were identified and graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0.
Results
The AM group showed significantly longer PFS than the PM group (24.0 vs. 14.0 months, P=0.04). 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 (TEAEs) in both AM and PM (AM 86.21% vs. PM 86.49% in AP cohort), and grade ≥3 TEAEs (AM 31.03% vs. PM 21.62% in AP cohort). The most common AEs were anemia, leukopenia, and neutropenia. Univariate and multivariate analyses indicated that the infusion time of AP chemotherapy (P=0.03) was an independent prognostic factor for NSCLC.
Conclusions
AP treatment administered in the morning may enhance PFS in advanced NSCLC. This suggests that chrono-chemotherapy (CCT) could potentially enhance the efficacy of individualized chemotherapy in advanced NSCLC.
Keywords: Time-of-day infusion, chrono-chemotherapy (CCT), circadian rhythm, non-small cell lung cancer (NSCLC), biological clock
Highlight box.
Key findings
• In advanced non-small cell lung cancer (NSCLC), morning infusion (before 2:00 PM) of pemetrexed plus platinum (AP) chemotherapy was associated with significantly longer progression-free survival (PFS) compared to afternoon infusion (24.0 vs. 14.0 months).
• Infusion time was identified as an independent prognostic factor for PFS.
• The safety profile (incidence and severity of treatment-emergent adverse events) was similar between morning and afternoon administration groups.
What is known and what is new?
• Retrospective evidence suggests that the timing of chemotherapy (chronotherapy) can influence efficacy and toxicity for some cancers and regimens.
• This study provides specific evidence that chronotherapy applies to the AP regimen in advanced NSCLC, demonstrating a significant PFS benefit for morning administration without compromising safety.
What is the implication, and what should change now?
• The timing of AP chemotherapy infusion is a modifiable factor that may improve outcomes. This supports the integration of chronotherapy principles into individualized treatment plans for advanced NSCLC.
• Clinical practice should consider scheduling AP chemotherapy for the morning to potentially enhance efficacy. These findings warrant prospective validation and investigation into chronotherapy for other chemotherapy regimens.
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, non-small cell lung cancer (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 increases 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 is only extended to 16.9 months (25). In addition, traditional chemotherapy often adversely affects patient outcomes due to its high dosage and toxicity.
Chrono-chemotherapy (CCT), 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 CCT tends to demonstrate superior efficacy and safety compared to conventional chemotherapy. A retrospective study (28) categorized patients who had undergone paclitaxel plus cisplatin (TP) regimen chemotherapy 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, in NSCLC patients undergoing first-line gemcitabine plus cisplatin (GC) chemotherapy, chronotherapy was associated with significantly higher 1- and 2-year survival rates compared to conventional chemotherapy (29). These findings provide a theoretical basis for the application of chronotherapy in NSCLC chemotherapy.
To date, the efficacy and safety of the pemetrexed plus platinum (AP) regimen CCT in advanced NSCLC remain largely uncharted territory. Consequently, this retrospective cohort study aims to investigate the survival and safety benefits of AP regimen CCT in patients with advanced NSCLC. This cohort composition is explained by the clinical context of the time. All patients lacked EGFR/ALK mutations, excluding them from targeted therapy. Furthermore, during much of the study period, immuno-chemo combinations faced limited access due to cost and reimbursement constraints, making AP a common first-line choice. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1861/rc).
Methods
Study population
The number of cases in our hospital during the study period determined the sample size. 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: (I) histologically confirmed NSCLC; (II) age ≥18 years with adequate physiological status to tolerate chemotherapy; (III) completion of at least two cycles of AP regimen chemotherapy to ensure treatment continuity and reliable efficacy evaluation; (IV) TNM stage III or IV disease, consistent with advanced NSCLC diagnosis; (V) ECOG performance status of 0-1 with expected survival ≥3 months to ensure treatment tolerance and follow-up completion; (VI) no prior systemic antitumor therapy to avoid confounding effects; (VII) adequate organ function as evidenced by ALT/AST ≤2.5×ULN, serum creatinine ≤1.5×ULN, ANC ≥1.5×109/L, and PLT ≥100×109/L. Exclusion criteria included: (I) previous antitumor treatments that might confound results; (II) concurrent secondary primary malignancies; (III) severe cardiac, hepatic, or renal dysfunction; (IV) known hypersensitivity to study drug components; (V) inability to evaluate tumor response; (VI) loss follow-up. Treatment discontinuation criteria were: (I) disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by contrast-enhanced chest computed tomography (CT); (II) occurrence of severe or life-threatening AEs (grade 4 hematological toxicity or grade ≥3 non-hematological toxicity) unresponsive to supportive care; (III) death from any cause.
All enrolled patients underwent testing for common driver genetic alterations. Tumor tissue samples were analyzed by quantitative real-time polymerase chain reaction (PCR) or next-generation sequencing, covering at least EGFR, ALK, and ROS1. Specifically, EGFR mutation status was detected by PCR, while ALK and ROS1 rearrangements were confirmed by Ventana immunohistochemistry or fluorescence in situ hybridization. Only patients confirmed to be without sensitive EGFR mutations (e.g., exon 19 deletion, L858R) and ALK or ROS1 rearrangements were included in the final analysis.
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of Guangdong Second Provincial General Hospital (No. 2025-KY-KZ-413-01) and individual consent for this retrospective analysis was waived.
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. Patients received AP regimen treatment until disease progression, and no pemetrexed monotherapy was used as maintenance treatment. The median number of treatment cycles in this population was 4. To ensure patient safety and tolerance to pemetrexed-based chemotherapy, all patients received the following premedication regimen: oral folic acid supplementation (400 µg/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 (1,000 µg) 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 AEs, 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
We used a blinded independent center review to assess the tumor response. Progression-free survival (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 AEs, 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 AEs (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: (I) including age, gender, smoking status, alcohol consumption, family history, tumor stage, and survival outcomes; (II) 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 cohort 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 magnetic resonance imaging (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. 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.
Results
Patients’ characteristics
Through eligibility review, a total of 132 patients with advanced NSCLC adenocarcinoma who received first-line AP regimen chemotherapy were ultimately included in the study. Baseline characteristics and patient selection flowchart are illustrated in Table 1 and Figure 1. In the morning cohort, comprising 58 NSCLC 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.
| Characteristics | AM (n=58) | PM (n=74) | P |
|---|---|---|---|
| Gender | 0.54 | ||
| Male | 43 (74.14) | 61 (82.43) | |
| Female | 15 (25.86) | 13 (17.57) | |
| Age (years) | 61.03±9.77 | 59.03±11.33 | 0.25 |
| <65 | 37 (64.79) | 46 (62.16) | |
| ≥65 | 21 (36.21) | 28 (37.84) | |
| Smoking rate | 20 (34.48) | 23 (31.08) | 0.57 |
| Drinking rate | 7 (12.07) | 6 (8.11) | 0.33 |
| Family history | 8 (13.79) | 8 (10.81) | 0.45 |
| Disease staging | 0.46 | ||
| III | 13 (22.41) | 20 (27.03) | |
| IIIA | 2 (3.45) | 3 (4.05) | |
| IIIB | 10 (17.24) | 9 (12.16) | |
| IIIC | 1 (1.72) | 8 (10.81) | |
| IV | 45 (77.59) | 54 (72.97) | |
| Outcome | 0.52 | ||
| PR | 12 (20.69) | 20 (27.03) | |
| SD | 30 (51.72) | 29 (39.19) | |
| PD | 16 (27.59) | 25 (33.78) | |
| Follow-up time (months) | 10.84±13.96 | 7.61±8.66 | – |
Data are presented as n (%) or mean ± standard deviation. PD, progressive disease; PR, partial response; SD, stable disease.
Figure 1.
Flowchart of the patient selection process for this study. AP, pemetrexed plus platinum; NSCLC, non-small cell lung cancer.
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 Figure 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 Figure 3.
Figure 2.
Comparative Kaplan-Meier analysis of progression-free survival in NSCLC patients between the AM group and PM groups. AP, pemetrexed plus platinum; CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival; NSCLC, non-small cell lung cancer.
Figure 3.
Subgroup analysis of NSCLC patients between the AM and PM groups. CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer.
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 2. 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.
Table 2. Risk factors for progression-free survival based on univariate and multivariate analysis.
| Factors | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|
| P value | HR | 95% CI | P value | HR | 95% CI | ||
| Gender | |||||||
| Male | 0.046 | 2.642 | 1.018, 6.763 | 0.14 | 2.086 | 0.782, 5.565 | |
| Female | Reference | Reference | |||||
| Age (years) | |||||||
| <65 | 0.006 | 2.771 | 1.348, 5.696 | 0.002 | 3.305 | 1.573, 6.945 | |
| ≥65 | Reference | Reference | |||||
| Smoking | |||||||
| Yes | 0.46 | 1.331 | 0.623, 2.845 | – | – | – | |
| No | Reference | ||||||
| Drinking | |||||||
| Yes | 0.43 | 0.563 | 0.135, 2.350 | – | – | – | |
| No | Reference | ||||||
| Family history | |||||||
| Yes | 0.40 | 2.567 | 0.550, 4.463 | – | – | – | |
| No | Reference | ||||||
| Disease staging | |||||||
| III | 0.08 | 0.426 | 0.167, 1.092 | – | – | – | |
| IV | Reference | ||||||
| Group | |||||||
| AM | 0.04 | 0.507 | 0.263, 0.978 | 0.03 | 0.448 | 0.218, 0.921 | |
| PM | Reference | Reference | |||||
CI, confidence interval; HR, hazard ratio.
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 3.
Table 3. Treatment-related adverse events.
| System organ class preferred team | AM (n=58), % | PM (n=74), % | P value | |||||
|---|---|---|---|---|---|---|---|---|
| All grades | Grades ≥3 | All grades | Grades ≥3 | All grades | Grade ≥3 | |||
| Any TEAEs | 86.21 | 31.03 | 86.49 | 21.62 | 0.96 | 0.22 | ||
| Blood and lymphatic system disorders | ||||||||
| Anemia | 65.52 | 15.52 | 58.11 | 10.81 | 0.39 | 0.43 | ||
| Leukopenia | 50.00 | 12.07 | 43.24 | 8.11 | 0.44 | 0.45 | ||
| Neutropenia | 41.38 | 12.07 | 40.54 | 8.11 | 0.92 | 0.45 | ||
| Thrombocytopenia | 29.31 | 6.90 | 27.03 | 6.76 | 0.77 | 0.98 | ||
| Lymphopenia | 24.14 | 6.90 | 29.73 | 2.70 | 0.48 | 0.25 | ||
| Hepatorenal toxicity | ||||||||
| ALT increased | 31.03 | 0 | 18.92 | 2.70 | 0.11 | 0.21 | ||
| AST increased | 22.41 | 0 | 14.86 | 2.70 | 0.27 | 0.21 | ||
| Creatinine increased | 17.24 | 0 | 9.46 | 0 | 0.19 | – | ||
| Urea nitrogen increased | 6.90 | 0 | 9.46 | 0 | 0.60 | – | ||
| Uric acid increased | 17.24 | 0 | 14.86 | 0 | 0.71 | – | ||
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 20.69 | 0 | 33.78 | 0 | 0.10 | – | ||
| Hypoalbuminemia | 34.48 | 0 | 31.08 | 0 | 0.68 | – | ||
| Hypokalemia | 25.86 | 0 | 16.22 | 0 | 0.18 | – | ||
| Hypertriglyceridemia | 27.59 | 0 | 17.57 | 0 | 0.17 | – | ||
| Hyponatremia | 10.34 | 0 | 8.11 | 0 | 0.66 | – | ||
| GI disorders | ||||||||
| Nausea | 18.97 | 0 | 27.03 | 0 | 0.28 | – | ||
| Constipation | 3.45 | 0 | 4.05 | 0 | 0.86 | – | ||
| Vomiting | 17.24 | 0 | 13.56 | 0 | 0.19- | – | ||
| Diarrhea | 12.07 | 0 | 27.03 | 0 | 0.45 | – | ||
| General disorders | ||||||||
| Fatigue | 25.86 | 0 | 35.14 | 0 | 0.26 | – | ||
| Fever | 5.17 | 0 | 4.05 | 0 | 0.76 | – | ||
| Edema | 8.62 | 0 | 1.35 | 0 | 0.05 | – | ||
| Skin and subcutaneous tissue disorders | ||||||||
| Rash | 6.90 | 0 | 6.76 | 0 | 0.98 | – | ||
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal; TEAEs, treatment-emergent adverse events.
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 (28,33) 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 American Society of Clinical Oncology (ASCO) Annual Meeting (34).
Our study observed a remarkably prolonged median PFS in patients receiving morning infusions of AP, a result that substantially exceeds the PFS typically reported with this regimen in Western populations and even rivals the overall survival achieved with modern chemoimmunotherapy combinations. We hypothesize that this superior efficacy primarily stems from a “chronotherapy” effect. The antitumor activity of pemetrexed, which targets folate metabolism and DNA synthesis, may be optimized by morning administration—synchronizing with peak circadian rhythms in cellular metabolism and proliferation. However, our findings must be interpreted with caution. As a single-center, retrospective analysis, the study is susceptible to selection bias. Furthermore, known differences in tumor biology, drug metabolism, and subsequent therapies between Eastern and Western populations may also influence outcomes.
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 cohort 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.
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.
Conclusions
Administering AP regimen CCT in the morning may significantly 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.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of Guangdong Second Provincial General Hospital (No. 2025-KY-KZ-413-01) and individual consent for this retrospective analysis was waived.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1861/rc
Funding: This study was supported by the Guangdong Yiyang Healthcare Charity Foundation and Beijing Kanghe Foundation.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1861/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1861/dss
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