Abstract

Methods: Between January 2010 and January 2020, a total of 71 non-small cell lung cancer patients (63 males, 8 females; mean age: 57.9±9.6 years; range, 34 to 76 years) diagnosed with T4 tumors and underwent surgery were retrospectively analyzed. Of these patients, 50 underwent neoadjuvant therapy before surgical resection (Group 1), while 21 underwent surgical resection alone (Group 2). Demographic characteristics, complications, mortality and pathological examination results of the patients were recorded.

Results: The neoadjuvant therapy group exhibited a significantly lower mortality rate (odds ratio=4.3). Age and neoadjuvant treatment were the most significant factors on mortality. Overall survival was longer among patients receiving neoadjuvant chemoradiotherapy, but not statistically significant (80.5±9.9 months vs. 60.9±7.9 months, p=0.081).

Conclusion: Our study results indicated a substantial reduction in mortality rates among patients with T4 tumors who underwent concurrent neoadjuvant chemoradiotherapy. Based on these results, neoadjuvant treatment serves as a beneficial preoperative intervention for eligible patients and should be considered before surgical resection.

Non-small cell lung cancer (NSCLC) is classified as T4, if the tumor has a diameter greater than 7 cm and/or invades specific anatomical structures, including the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral corpus, or carina.[4] Additionally, the presence of nodules in the same lung, but different lobes from the primary tumor also classifies the disease as T4. No modifications are anticipated in the T stage for TNM 9.[5]

The first studies on neoadjuvant treatment dates back to 1995, when the Southwest Oncology Group conducted a study. The study reported a commendable local control rate of 90% and an overall survival (OS) time of 18 months.[6] Recent studies have consistently confirmed that neoadjuvant chemotherapy correlates with improved survival outcomes.[7]

The proven advantages of neoadjuvant treatment in operable Stage 3 NSCLC encompass early systemic control of micrometastases, the possibility of planning smaller-sized resections due to post-treatment tumor shrinkage and facilitating the achievement of R0 resection.[8]

In modern NSCLC neoadjuvant planning, tumor size and location are supplemented by biological markers such as driver mutations and programmed death-ligand 1 (PDL-1) positivity. The National Comprehensive Cancer Network (NCCN) guidelines recommend perioperative systemic therapy encompassing both preoperative and postoperative strategies for tumors >4 cm.[9] Resectable T4 tumors are treated with either primary surgery or neoadjuvant therapy, including chemoimmunotherapy or concurrent chemoradiation, based on immune checkpoint inhibitor results.[9]

It has been well established that median survival with surgery alone is limited in Stage 3 NSCLC cases. Pre- or postoperative chemotherapy has been shown to provide an OS advantage.[10] In the present study, we aimed to investigate the efficacy of preoperative chemoradiotherapy in T4 tumors representing the locally advanced stage of NSCLC.

Methods

This single-center, retrospective study was conducted at Erciyes University Faculty of Medicine, Department of Thoracic Surgery between January 2010 and January 2020. A total of 71 NSCLC patients (63 males, 8 females; mean age: 57.9±9.6 years; range, 34 to 76 years) diagnosed with T4 tumors and underwent surgery were included. Of these patients, 21 underwent neoadjuvant therapy before surgical resection (Group 1), while 50 underwent surgical resection alone (Group 2). Written informed consent was obtained from each patient. The study protocol was approved by the Erciyes University Faculty of Medicine Ethics Committee (Date: 01.03.2020, No: 2020/189). The study was conducted in accordance with the principles of the Declaration of Helsinki.

In our hospital, the decision for neoadjuvant therapy is made through a Multidisciplinary Thoracic Council, where parameters such as the patient's clinical characteristics, tumor size, mediastinal and vascular invasion, and superior sulcus involvement are thoroughly discussed. The entire neoadjuvant treatment group received concurrent chemoradiotherapy (carboplatin, pemetrexed + 50 Gy radiotherapy) as their preoperative regimen. Patients who received only chemotherapy or only radiotherapy as neoadjuvant treatment were not included in the study. The staging for the neoadjuvant treatment group considered the pre-treatment clinical T stage, while the group undergoing primary surgery was staged based on the pathological T stage. Patients with positive surgical margins postoperatively were also excluded from the study due to the potential independent effect of preoperative treatment on the survey outcomes.

All patients underwent mediastinoscopy for mediastinal staging, with those identified as N0 considered resectable. Subsequently, they were either taken directly to surgery or subjected to surgery after neoadjuvant treatment.

Following preoperative preparations, all patients underwent thoracotomy and lung resection. The extent of lymph node dissections performed was tailored to the tumor size and the potential for invasion.

The clinical characteristics, pathology, and imaging data of the patients were evaluated using the hospital database. The survival data of the patients were obtained using the hospital database and the National Death Notification System.

Statistical analysis

Statistical analysis was performed using the IBM SPSS version 26.0 software (IBM Corp., Armonk, NY, USA). Descriptive data were expressed in mean ± standard deviation (SD), median (min-max) or number and frequency, where applicable. The comparison between groups was conducted using the chi-square test for categorical variables and the log-rank test for continuous variables. Survival analysis was carried out employing the Kaplan-Meier survival curve. To determine the factors affecting patient mortality, logistic regression analysis was conducted. A p value of <0.05 was considered statistically significant.

Results

Table 1: Clinical characteristics of patients (n=71)

Comparing the clinical data of patients in Group 1 with those in Group 2, a significantly higher mortality rate was observed in Group 2 (p=0.027). No significant association was found between the type of surgery performed (lobectomy or pneumonectomy) and the administration of neoadjuvant therapy (p=0.312) (Table 2).

Table 2: Comparison of clinical data of patients

Table 3 presents a comparison of mean survival between groups. In the primary surgery group, two patients experienced mortality within 30 days postoperatively, while in the neoadjuvant group, one patient had the same outcome. This result was not found to be statistically significant. Survival analysis revealed a trend toward a longer survival for individuals undergoing neoadjuvant therapy. However, the observed difference between the two groups did not reach statistical significance. Specifically, patients who underwent neoadjuvant therapy had a mean survival of 80.5±9.9 months, whereas those exclusively undergoing surgical resection had a mean survival of 60.9±7.9 months (Table 3 and Figure 1).

Table 3: Survival analysis of patients stratified by neoadjuvant therapy before surgical resection

Figure 1: Kaplan-Meier curve for cumulative (cum) overall survival of patients.

The logistic regression analysis was carried out to identify factors influencing mortality outcomes revealed a significant association between increasing age and increases mortality (p=0.016). Accordingly, patients who underwent surgical resection without neoadjuvant therapy exhibited a statistically significant 4.3-fold increase in mortality (p=0.020). However, no significant relationships were observed between mortality and factors such as sex, type of surgery, and lymph node stage (p>0.05) (Table 4).

Table 4: Logistic regression analysis of factors potentially associated with mortality

Discussion

A study by Towe et al.[13] found that patients who underwent neoadjuvant therapy were usually younger than those in the alternative group. In contrast, Daly et al.[14] reported that age did not influence the choice of neoadjuvant therapy, although increased mortality was significantly associated with advanced age. In our study, the mean patient age was 57.9±9.6 years, with no significant age difference between those who received neoadjuvant therapy and those who did not (p=0.412). However, logistic regression analysis revealed a significant association between age and mortality (p=0.016), consistent with previous findings.

One of the main goals of neoadjuvant therapy is to reduce mortality. Early studies by Pass et al.[15] compared Stage 3 NSCLC patients undergoing primary surgery versus neoadjuvant chemotherapy followed by surgery, showing a median survival of 29 months for the neoadjuvant group versus 15.8 months for the primary surgery group.[15] A m etaanalysis by Watanabe et al.[16] found that neoadjuvant chemotherapy reduced five-year mortality from 45 to 40%, with survival rates for Stage 3 patients ranging from 17 to 56%. The 2012 CHEST trial reported a median survival of 93.6 months for pre-Stage 3 patients receiving neoadjuvant therapy, compared to 58.5 months for those without.[17] Additionally, studies on Stage 3a NSCLC patients showed that neoadjuvant chemoimmunotherapy did not increase morbidity or mortality and was safe.[18] T owe e t a l.[13] reported a median survival of 65.9 months for neoadjuvant therapy patients versus 27.5 months for primary surgery patients, highlighting its survival benefits. In our study, 29.6% of patients received neoadjuvant therapy, while 70.4% underwent primary surgery. Mortality rates were 33.3% in the neoadjuvant group versus 62% in the primary surgery group (p=0.027). Logistic regression analysis identified the absence of neoadjuvant therapy as the second strongest factor associated with mortality after age, increasing mortality risk four-fold (p=0.020). The mean survival was 80.5±9.9 months for neoadjuvant therapy patients versus 60.9±7.9 months for primary surgery patients, although this difference was not statistically significant.

Over the past three decades, neoadjuvant therapy has become a preferred approach for advancedstage patients, particularly those with T4 disease, due to its ability to improve negative resection margins by up to five-fold.[13] W hile o ur s tudy confirmed reduced mortality with neoadjuvant therapy, it did not significantly impact OS duration, consistent with existing literature. Another goal of neoadjuvant therapy is to reduce tumor size, enabling patients initially planned for pneumonectomy to undergo lobectomy instead. Kumar et al.[19] r eported t hat 2 5% o f patients underwent pneumonectomy, while 75% had lobectomy. Similarly, Towe et al.[13] found that T4 NSCLC patients receiving neoadjuvant therapy had a lower pneumonectomy rate (25%) compared to those undergoing primary surgery (35%). In our study, 52.1% of the 71 patients underwent pneumonectomy, and 47.9% had lobectomy. The pneumonectomy rate was 42.9% in the neoadjuvant group versus 56% in the primary surgery group, although this difference was not statistically significant (p=0.312). While pneumonectomy was more common in patients who died, logistic regression analysis showed no significant link between surgery type and mortality.

In a study comparing neoadjuvant treatment modalities applied to patients with NSCLC, concurrent chemoradiotherapy (based on cisplatin) was compared with isolated chemotherapy (cisplatin- docetaxel), and the group receiving concurrent radiotherapy was found to be associated with better disease-free survival despite similar mortality.[20] I n o ur s tudy, a ll p atients r eceived cisplatin-based neoadjuvant chemoradiotherapy, and mortality was found to be significantly lower compared to the group that did not receive treatment.

In a study evaluating intra- and postoperative complications in patients undergoing lung resection following neoadjuvant therapy, the complication rate was reported as 37.8% in the neoadjuvant immunotherapy group, 10.8% in the direct surgery group, and 16.2% in the neoadjuvant chemoradiotherapy group. The authors reported that neoadjuvant therapy was associated with increased adhesions during surgery compared to the direct surgery group, making lymph node dissection more challenging. However, no significant difference in 30-day postoperative mortality was observed among the groups.[21] Similarly, in our study, no significant difference in early postoperative mortality was found, although we do not have sufficient data regarding adhesions and the difficulty of surgery. Nonetheless, our study has certain limitations, including its single-center design, reliance on retrospective patient analysis, and the absence of an assessment of patients' pain states and psychological effects through quality-of-life surveys. Another limitation is that sufficient data for complication comparisons could not be obtained from the hospital database. Despite these limitations, one of the notable strengths of our study lies in its comprehensive inclusion of all patients undergoing surgery at our center over a period of 10 years, coupled with the evaluation of long-term follow-up data.

In conclusion, our study highlights the role of neoadjuvant chemoradiotherapy in reducing mortality for T4 non-small cell lung cancer patients. Although the extension of follow-up periods did not reach statistical significance, the observed reduction in mortality and prolonged survival suggests a beneficial impact of neoadjuvant therapy. Future indications for neoadjuvant therapy may expand, making it applicable to a broader patient population. Notably, tumor type and lymph node stage did not significantly affect mortality, but age was a critical factor, underscoring its importance in treatment decisions. Current literature comparing survival between primary surgery and neoadjuvant chemoradiation in T4 non-small cell lung cancer patients remains limited. To validate our findings, further multi-center, large-scale, randomizedcontrolled studies, supported by quality-of-life assessments, are recommended. Taken together, our study results establish that neoadjuvant concurrent chemoradiotherapy contributes to a reduction in mortality for T4 non-small cell lung cancer. These results suggest the utilization of neoadjuvant therapy before surgical resection, particularly in the appropriate patient group. To enhance the robustness and validity of these results, additional extensive randomized-controlled studies supported by comprehensive quality-of-life surveys are warranted.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Conceptualization, formal analysis, writing-original draft: O.T.; Conceptualization, formal analysis, writing-original draft: L.H.; Formal analysis, writing-review & editing: S.A.; Writing-review & editing: Ö.F.D., Ö.Ö., C.E.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

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