Prolonged Progression-Free Survival and Overall Survival are Associated with Diabetes Mellitus but Inversely Associated with Levels of Blood Glucose in Patients with Lung Cancer
Lung cancer remains one of the leading causes of cancer-related deaths worldwide, with a persistently low 5-year survival rate despite advancements in diagnosis and treatment. The survival of lung cancer patients is influenced by various factors, including comorbidities such as diabetes mellitus (DM), which is one of the most common comorbidities in these patients. However, the relationship between DM and lung cancer survival has been a subject of conflicting evidence in previous studies. Some studies have reported increased survival in lung cancer patients with DM, while others have shown no change or even decreased survival. This study aimed to assess the impact of DM and blood glucose levels on progression-free survival (PFS) and overall survival (OS) in lung cancer patients, providing further insights into this complex relationship.
Background and Rationale
Lung cancer is a major global health concern, and its prognosis is influenced by a variety of factors, including age, sex, tumor histology, disease stage, and performance status. Among these, DM has emerged as a significant comorbidity, with studies suggesting a higher prevalence of DM in lung cancer patients. However, the impact of DM on lung cancer survival remains unclear, with conflicting results reported in the literature. Some studies have shown that lung cancer patients with DM have increased survival, while others have found no significant difference or even decreased survival. This discrepancy highlights the need for further research to clarify the relationship between DM and lung cancer survival.
In addition to DM, fluctuations in blood glucose levels are known to influence the prognosis of DM patients. In lung cancer patients, blood glucose levels can fluctuate due to various factors, including DM itself, chemotherapy, corticosteroids, surgery, and other treatments. However, the impact of blood glucose levels on the survival of lung cancer patients has not been thoroughly investigated. This study aimed to explore the association between blood glucose levels and PFS/OS in lung cancer patients, providing valuable insights into the potential prognostic value of blood glucose levels in this population.
Methods
This retrospective study analyzed data from lung cancer patients admitted to the Department of Pulmonary Medicine at Zhongshan Hospital, Fudan University, Shanghai, between January 2010 and January 2012. The follow-up period extended from January 2010 to January 2015. The data collected included patient demographics (sex, age, body mass index [BMI], smoking status), history of DM, blood glucose levels, pathological type of lung cancer, clinical stage of cancer, chemotherapy regimen, and history of anti-DM medication. The inclusion criteria were newly diagnosed lung cancer patients with a confirmed pathological type and clinical stage, pre-existing DM before the lung cancer diagnosis, completion of chemotherapy regimens, and follow-up after treatment. Patients with insufficient clinical or pathological data, incomplete follow-up records, or other concurrent comorbidities (except DM) were excluded.
The pathological types of lung cancer included squamous-cell carcinoma, adenocarcinoma, and small cell lung cancer. The clinical stage of cancer was determined according to the International Association for the Study of Lung Cancer criteria. Chemotherapy regimens included cisplatin/pemetrexed (PP), cisplatin/docetaxel (DP), cisplatin/vinorelbine (NP), cisplatin/paclitaxel (TP), and cisplatin/gemcitabine (GP). All stage I and stage II patients underwent surgical treatment before chemotherapy. Some patients received intravenous dexamethasone on the day of chemotherapy.
Pre-existing DM was diagnosed based on hospital medical records indicating a history of DM or the use of anti-diabetic medication. Blood glucose levels were monitored at each chemotherapy cycle and during the follow-up period, which lasted from 36.0 to 60.0 months. The primary endpoint was OS, defined as the time from chemotherapy initiation to the date of death from any cause or the last follow-up. PFS was defined as the time from chemotherapy initiation to disease progression or death or the last follow-up. Disease progression was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.
Statistical Analysis
Statistical analyses were performed using SPSS software (version 19.0). The chi-square test and independent-samples t-test were used to compare categorical and continuous variables, respectively. Normally distributed data were presented as mean ± standard deviation. The Kaplan-Meier method was used for survival analysis, and the Cox proportional hazard regression model was used to analyze the association between PFS/OS and various prognostic factors. The significance level was set at P < 0.05.
Results
A total of 200 lung cancer patients (138 males and 62 females, aged 29.0 to 78.0 years, mean age 60.0 ± 8.6 years) were included in the study. Among these, 31 patients had pre-existing type 2 DM. For survival analysis, patients were divided into three groups: lung cancer with DM (n = 31), lung cancer without DM but with elevated blood glucose levels (n = 40), and lung cancer without DM or elevated blood glucose levels (n = 128). One patient dropped out of the study.
Kaplan-Meier survival analysis showed that lung cancer patients with DM had significantly increased PFS and OS compared to those without DM (log-rank, P < 0.05 for PFS and P < 0.01 for OS). The median PFS in lung cancer patients with DM was 12.0 months (95% confidence interval [CI], 4.0–16.0) compared to 6.0 months in those without DM (95% CI, 5.8–6.3). The median OS in lung cancer patients with DM was 37.0 months (95% CI, 29.0–46.6) compared to 12.0 months in those without DM (95% CI, 10.9–13.1). Among the two groups of patients without DM, those with elevated blood glucose levels tended to have shorter PFS and OS compared to those without elevated blood glucose levels.
Cox proportional hazard regression analysis revealed that PFS was favorably associated with the use of anti-DM drugs (hazard ratio [HR] = 0.126, P < 0.05), BMI (HR = 0.882, P < 0.05), clinical stage of cancer (HR = 0.174, P < 0.05), and chemotherapy regimen (HR = 0.188, P < 0.05). However, PFS was inversely associated with blood glucose levels (HR = 1.363, P < 0.05). OS was favorably associated with BMI (HR = 0.860, P < 0.05), clinical stage of cancer (HR = 0.292, P < 0.001), and the use of dexamethasone (HR = 1.954, P < 0.05). Blood glucose levels showed a weak inverse association with OS (HR = 1.346, P = 0.094).
Logistic regression analysis showed that sex, smoking status, pathological type, clinical stage of cancer, and the use of dexamethasone did not significantly influence blood glucose levels. However, a history of DM (odds ratio [OR] = 7.32, P < 0.05), BMI (OR = 1.04, P < 0.05), age (OR = 1.02, P < 0.05), and the use of DP chemotherapy regimens (OR = 1.84, P < 0.05) significantly influenced blood glucose levels.
Discussion
This study found that lung cancer patients with DM had significantly prolonged PFS and OS compared to those without DM. The median PFS in patients with DM was 12.0 months compared to 6.0 months in those without DM, and the median OS was 37.0 months compared to 12.0 months in those without DM. These results are consistent with previous studies, such as the HUNT and PEG study, which also reported increased OS in lung cancer patients with DM. However, this study goes further by demonstrating that PFS is also prolonged in lung cancer patients with DM, suggesting that PFS may be a meaningful intermediate endpoint for OS in lung cancer patients with comorbidities.
The underlying mechanisms for the survival benefit in lung cancer patients with DM are not fully understood. One possible explanation is that DM may reduce the frequency of metastasis, as most lung cancer patients die from metastasis rather than the primary tumor. Microvascular changes caused by DM may play a protective role against the metastasis of lung cancer cells. Additionally, the frequent and regular consultations required for DM management may lead to earlier diagnosis and treatment of comorbidities, contributing to improved survival.
Another important finding of this study is the inverse association between blood glucose levels and PFS in lung cancer patients. Cox regression analysis showed that PFS was inversely associated with blood glucose levels, and Kaplan-Meier analysis revealed a trend of shorter PFS and OS in patients with elevated blood glucose levels compared to those without elevated blood glucose levels. This suggests that fluctuations in blood glucose levels may negatively impact the prognosis of lung cancer patients. Logistic regression analysis showed that a history of DM, BMI, age, and the use of DP chemotherapy regimens significantly influenced blood glucose levels, providing some insight into the factors that may contribute to these fluctuations.
Limitations
This study has several limitations, including its retrospective nature and small sample size, which may introduce selection bias. However, the use of standardized data collection templates, a consistent follow-up period of 60 months, and appropriate statistical methods helped to mitigate these limitations. Despite these limitations, this study provides valuable evidence for the association between DM, blood glucose levels, and survival in lung cancer patients.
Conclusion
In conclusion, this study demonstrates that lung cancer patients with DM have prolonged PFS and OS compared to those without DM. Additionally, blood glucose levels were inversely associated with PFS, suggesting that blood glucose fluctuations may negatively impact the prognosis of lung cancer patients. These findings indicate that PFS may be a meaningful intermediate endpoint for OS in lung cancer patients with comorbidities and that blood glucose levels may serve as a prognostic factor for survival in this population. Further research is needed to confirm these findings and explore the underlying mechanisms.
doi.org/10.1097/CM9.0000000000000739
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