Assessment of surgery delay-associated risk in resectable stages I–IIIA non-small-cell lung cancer

Objective: Surgery delay is a common issue worldwide because of limited medical resources, which was further exacerbated by the COVID-19 pandemic. This study aims to assess the influence of surgery delay on the outcomes of patients with resectable stage I-IIIA non-small cell lung cancer (NSCLC). Methods: Using Surveillance, Epidemiology, and End Results Program (SEER) database, we identified 50,522 patients with stage I-IIIA NSCLC who received standard pulmonary resection. Surgery delay was defined as the time interval between diagnosis date and surgery date which was recorded by month. For example, zero month represented 0-29 days, and one month represented 30-59 days, and so on. Association between the surgery delay and survival parameters was assessed with the restricted cubic spine (RCS) curve fitted for Cox proportional hazards models in which the shortest delay of zero month served as the reference. Overall survival (OS) and lung cancer-specific survival (CSS) were evaluated by Kaplan-Meier method and compared by log-rank test. Results: The RCS curve demonstrated a non-linear association between the surgery delay and estimated survival. Both all-cause and cancer-specific mortality risks increased drastically and simultaneously within the delay range of three months (0-89 days), followed by a much slower increment after 90 days. All the included patients were classified into three groups based on the death risk stratifications of surgery delay: low-risk (delay ?29 days), intermediate-risk (30-59 days), and high-risk (?60 days). Compared with low-risk group, all-cause and cancer-specific mortality risk increased by 6.2% (95%CI: 3.0%-9.5%) and 17.6% (95%CI: 10.3%-25.5%) in the intermediate-risk group, and by 18.3% (95%CI: 14.8%-21.9%) and 40.5% (95%CI: 32.1%-49.5%) in the high-risk group, respectively. Conclusion: Only one-third of patients could receive surgery within the first month after diagnosis. Surgery delay could significantly increase all-cause and cancer-specific mortality risk even beyond only one month (?30 days). The surgery delay-related mortality risk increased the fastest within a three-month delay while the risk increased more slowly when the surgery delay ranges from four to twelve months. Controlling the surgery delay within one month is essential for resectable NSCLC patients to avoid worse outcomes


Dear Editor,
As the clinical practice published in International Journal of Surgery, surgical treatment delay occurs commonly worldwide because of limited medical resources, which has been further exacerbated by the lasting COVID-19 pandemic [1,2] .Various types of scheduled surgeries may have experienced delays, especially surgeries for early-stage tumors.Theoretically, timely interventions for resectable non-small-cell lung cancer (NSCLC) patients may maximize therapeutic potentials for decreasing recurrence and improving prognosis.Despite several studies that demonstrated some associations between delayed surgery and NSCLC patients' outcomes [3][4][5] , whether the short-term delay has a significant effect and how long it is supposed to be for safety remains unclear.Thus, the objective of this study was to assess surgery delay-associated impacts on NSCLC outcomes using the largest clinical cohort to date.
Here, we reported a population-based cohort of 50 522 adults receiving standard pulmonary resection for clinical stages I-IIIA NSCLC that were diagnosed from the Surveillance, Epidemiology, and End Results Program database between January 2004 and November 2019.Surgery delay was defined as the time interval between the diagnosis date and the surgery date, which was recorded by month.For example, 0 month represented 0-29 days, and 1 month represented 30-59 days, and so on.Exclusion criteria were patients with surgery delay longer than 12 months, receiving chemotherapy or radiotherapy and undergoing more complex surgical resection.
The restricted cubic spine (RCS) curve demonstrated a nonlinear association between the surgery delay and estimated survival (Fig. 1A).Both all-cause (Fig. 1B) and cancer-specific (Fig. 1C) mortality risks increased drastically and simultaneously within the delay range of 3 months (0-89 days), followed by a much slower increment after 90 days.Therefore, we propose classifying all patients into three groups based on death risk stratification of the surgery delay: low-risk (delay ≤ 29 days), intermediate-risk (30-59 days), and high-risk ( ≥ 60 days).Compared with low-risk group, all-cause and cancer-specific in the high-risk group, respectively (P < 0.001; Fig. 1).Using the largest cohort to date, this population-based study confirmed the associations of the surgery delay with unfavorable outcomes in patients with resectable NSCLC.This study was the first to identify that surgery delay could significantly increase allcause and cancer-specific mortality risk even beyond only 1 month ( ≥ 30 days), which may overcome limitations of previous studies attributed to small sample size and large delay cutoff [3][4][5] .
We observed that approximately only one-third of patients could receive surgical treatment within the first month after diagnosis, suggesting that most of them were exposed to increased surgery delay-associated risk.In the context of favorable prognosis among early-stage resectable NSCLC patients, it is highly recommended to minimize treatment delay by improving multifaced interventions to achieve comparable outcomes, such as the settlement of socioeconomic limitations, optimization of the diagnosis process, reasonable allocation of healthcare resources, and so on.
Surprisingly, the surgery delay-related mortality risk increased the fastest within a 3-month delay, indicating that there might be disease progression during the period in some cases that the most vulnerable to the increased risk.However, when ranging from 4 to 12 months, the risk increased more slowly.Therefore, these results further suggested the necessity for patients to receive surgical treatment within the safest period of 1 month.Moreover, we also observed synchronous changes of all-cause and cancerspecific mortality risk as the delay time increased, which might indicate a closer relationship between surgery delay and cancerspecific events instead of non-cancer ones.Overall, our findings firstly reveal that controlling the surgery delay within 1 month is essential for resectable NSCLC to avoid worse outcomes.

Figure 1 .
Figure 1.(A) Restricted cubic spline model presents the hazard ratio of surgery delay on estimated survival when compared with patients who received surgery within 29 days after diagnosis.The orange line indicates all-cause mortality risk, while the blue line indicates cancer-specific mortality risk.The 95% confidence interval of the hazard ratio is also illustrated.0 month, 0-29 days; 1 month, 30-59 days; 2 months, 60-89 days, and so on.The overall estimated survival (B) and cancer-specific estimated survival (C) of patients with resectable stages I-IIIA non-small-cell lung cancer with low-risk (delay ≤ 29 days) vs. intermediate-risk (delay between 30 and 59 days) vs. high-risk (delay ≥ 60 days).(D) Percentage of patients in different risk groups.(E) All-cause and cancer-specific risks between the lowrisk group and the intermediate-risk/high-risk groups.

Table 1
Clinical characteristics and surgery delay of NSCLC patients.