Research ArticleClinical Studies
Open Access

Adjuvant Chemotherapy in Addition to Neoadjuvant Chemotherapy for Locally Advanced Non-small Cell Lung Cancer

RYO MIYATA, MASAYA AOKI, SHOICHIRO MORIZONO, TADASHI UMEHARA, AYA HARADA-TAKEDA, GO KAMIMURA, TOSHIYUKI NAGATA and KAZUHIRO UEDA
In Vivo September 2024, 38 (5) 2515-2522; DOI: https://doi.org/10.21873/invivo.13723

Abstract

Background/Aim: The prognostic impact of adjuvant cytotoxic chemotherapy for patients with resectable locally advanced non-small cell lung cancer (NSCLC) who underwent surgery after neoadjuvant chemotherapy remains unclear. Patients and Methods: A retrospective chart review was performed to identify patients who underwent surgery following neoadjuvant therapy for clinical T3N0 or N1-N2 resectable NSCLC between 2011 and 2016 at our hospital. Survival outcomes were analyzed with the Kaplan–Meier method and a Cox proportional hazard model. Results: Thirty-eight patients were identified. The median recurrence-free survival (RFS) was 50.6 months and overall survival (OS) was 75.2 months. Patients who had undergone adjuvant chemotherapy were not associated with a favorable RFS (hazard ratio=1.01, p=0.98) or OS (hazard ratio=0.72, p=0.55), as compared with those who had not. However, subgroup analysis revealed that hazard ratio based on RFS and OS varied greatly between subgroups, suggesting that selected patients might benefit from adjuvant therapy, while others might be harmed by it. For example, in surgical-pathological stage III disease, adjuvant therapy showed a favorable RFS (HR=0.22, 95%CI=0.02-2.57, p=0.23) and OS (HR=0.36, 95%CI=0.03-4.01, p=0.40). Conversely, in surgical-pathological stage 0-II disease, adjuvant therapy showed an unfavorable RFS (HR=1.40, 95%CI=0.49-3.96, p=0.53) and OS (HR=0.95, 95%CI=0.29-3.12, p=0.93). Conclusion: Regardless of the negative findings in our overall patient cohort, our results may be beneficial in identifying patients who may likely benefit from adjuvant therapy. This contribution could assist the planning of large-scale prospective studies.

Key Words:

Perioperative chemotherapy has been shown to improve survival in patients with non-small cell lung cancer (NSCLC) (1). The 5-year overall survival (OS) rate is 92% for pathologic stage IA1 cases, but only 36% for those in pathologic stage IIIA, suggesting that the poor prognosis in advanced stage NSCLC may be due to the presence of micrometastases at the time of surgical resection (2). Based on several randomized controlled clinical trials (RCTs), adjuvant chemotherapy has become the standard perioperative chemotherapy for stage IB (≥4 cm) to IIIA NSCLC in the guidelines of the Japan Lung Cancer Society (JLCS), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) (3-5), although the 5-year OS rate shows only a modest 4-5% improvement. Neoadjuvant therapy is used to reduce tumor size, increase resectability, and eradicate micrometastases, with a significant improvement in OS observed in patients with resectable NSCLC (1). The absolute survival improvement at five years was 5% (1). Therefore, there seems to be little difference between neoadjuvant and adjuvant chemotherapy in resectable NSCLC, and there is a future need to determine whether treatment should be given in the neoadjuvant or adjuvant setting.

The role of neoadjuvant and adjuvant chemotherapy is controversial. In clinical N2-stage III NSCLC, adjuvant chemotherapy for patients who underwent surgery after neoadjuvant chemotherapy prolonged survival outcomes (6). In clinical N1 disease, adjuvant chemotherapy for patients who underwent surgery after neoadjuvant chemotherapy significantly improved OS (6-8), although each guideline has no recommendation beyond adjuvant chemotherapy followed by surgery (3-5). In clinical T1-2N1 disease, adjuvant chemotherapy for patients who underwent surgery after neoadjuvant chemotherapy appears to be unnecessary (8). In contrast, the role of postneoadjuvant adjuvant chemotherapy remains unknown in borderline resectable locally advanced NSCLC (clinical T3-4N1). Therefore, we hypothesize that adjuvant therapy after surgery following neoadjuvant therapy could be a potential management strategy.

In the current study, we compared long-term outcomes with and without adjuvant chemotherapy in patients with locally advanced resectable NSCLC. A subgroup analysis was performed to identify patients who may likely benefit from adjuvant therapy.

Patients and Methods

Subjects. The study had a retrospective, single center, observational design and was performed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology Statement (9). A retrospective chart review was performed using a hospital database to identify consecutive patients who underwent resection of NSCLC at our hospital between January 2010 and July 2021, and had surgery following neoadjuvant therapy for locally advanced NSCLC. Data were collected for patient characteristics (age, sex, smoking history, and clinical lymph nodal status); intraoperative and perioperative factors; pathological data [histology, stage, therapeutic effect, pathological lymph node stage, pathological stage, microscopic residual disease, epidermal growth factor receptor (EGFR) mutation]; and follow-up information.

The subjects comprised patients who received neoadjuvant therapy followed by surgery for clinical T3N0 or N1-N2 resectable NSCLC. The neoadjuvant and adjuvant chemotherapy regimens were determined based on histological findings and administered at the discretion of the attending physician. Cases with metachronous multiple lung cancer, sublobar resection, malignant effusion at surgery, or R2 resection were excluded. Pathological staging was based on the Union for International Cancer Control TNM Classification of Malignant Tumours, 7th Edition (10). EGFR mutation was analyzed using pathological specimens obtained during surgery.

The pathological effect of neoadjuvant therapy was classified based on JLCS criteria as: Ef0, no effect; Ef1(a), very slight effect (viable cancer cells in ≥67% of the tumor tissue); Ef1(b), slight effect (viable cancer cells in ≥33% to <67% of the tumor tissue); Ef2, moderate effect (viable cancer cells in <33% of the tumor tissue, with severe degeneration or necrosis of other cancer cells); and Ef3, strong effect (no evidence of viable cancer cells) (11).

Ethics. This study was approved by the Ethics Committee on Epidemiological and Related Studies, Sakuragaoka Campus, Kagoshima University (reference number: 200249), and conformed to the principles outlined in the Declaration of Helsinki. Research participants and their relatives could opt out by viewing the research content hosted online.

Follow-up assessment. Postoperative follow-up typically included chest computed tomography (CT) every six months after the first surgery, and brain magnetic resonance imaging (MRI) in symptomatic cases, based on the JLCS, NCCN, and ESMO guidelines (3-5). Cases with suspected recurrence underwent further examinations using positron emission tomography and brain MRI. Local recurrence was defined as disease recurrence at the surgical margin. Regional recurrence was defined as disease recurrence in the ipsilateral hemithorax or mediastinum. Distant metastasis was defined as disease recurrence in the contralateral lung or outside the hemithorax and mediastinum. Pleural dissemination was regarded as distant metastasis in the TNM classification. Recurrence-free survival (RFS) was defined as the interval from the date of surgery until the date of disease recurrence or death from any cause. OS was defined as the interval from the date of surgery until the date of death from any cause. In both analyses, cases without an event at the last clinic visit were censored.

Statistical analysis. In accordance with recommended statistical and data reporting guidelines (12), descriptive statistics are given as counts and percentages for categorical variables and as medians and interquartile ranges (IQRs) for continuous variables. Differences were compared by using the Wilcoxon test for continuous variables and the Fisher exact test and chi-square test for categorial variables, as appropriate. Survival probability was estimated using the Kaplan–Meier method. The median follow-up period was calculated using the reverse Kaplan–Meier method for potential follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) for RFS and OS were calculated using Cox proportional hazards regression models. Exploratory subgroup analyses were conducted to compare the rates and HRs of RFS and OS with and without use of adjuvant chemotherapy. These analyses were adjusted for age, sex, smoking history, combined resection, histology, therapeutic effect, downstaging of lymph node status, and surgical-pathological stage. Statistical significance was set at p<0.05. All analyses were performed using JMP 14 (SAS Institute Inc., Cary, NC, USA). All data were analyzed retrospectively as of September 2022.

Results

Patient characteristics. A total of 38 eligible patients (33 males, 5 females) were identified in the database. The background of the patients, pathological characteristics, and perioperative information are summarized in Table I. The median age was 61 years (IQR=52.8-64.3), 8 patients (21.1%) had no viable cancer cells (Ef3), 11 (28.9%) had pathological downstaging of lymph node status, and 19 (50.0%) received adjuvant chemotherapy. There was no therapy-related death. Adjuvant chemotherapy was administered significantly more often in patients with clinical N2 disease, but no difference was observed in pathological N2 disease. There was no difference in the site of initial postoperative recurrence between patients who did and did not receive adjuvant chemotherapy. The neoadjuvant and adjuvant chemotherapy regimens are shown in Table II. The same regimen was used for both therapies in nine cases.

View this table:
Table I.

Characteristics of patients who did and did not receive adjuvant chemotherapy.

View this table:
Table II.

Regimens of neoadjuvant and adjuvant therapy.

Survival outcomes. The total numbers of events were 18 for RFS and 14 for OS. The median follow-up period was 55.1 months based on RFS events and 60.1 months based on OS events. The median RFS was 50.6 months (95%CI=12.7 months–not reached) and the median OS was 75.2 months (95%CI=50.6 months–not reached). The 5-year RFS and OS rates were 45.1% (Figure 1A) and 57.2% (Figure 1B), respectively.

Figure 1.
Figure 1.

Kaplan–Meier curves for (A) recurrence-free survival and (B) overall survival in the whole cohort, and for (C) recurrence-free survival and (D) overall survival in patients who did and did not receive adjuvant therapy.

Effects of adjuvant chemotherapy. The numbers of events in patients treated with and without adjuvant chemotherapy were 10 and 8 for RFS, and 7 and 7 for OS, respectively. A comparison of patients who did (N=19) and did not (N=19) receive adjuvant chemotherapy showed that adjuvant chemotherapy was not associated with favorable RFS (HR=1.01, 95%CI=0.40-2.59, p=0.98) or OS (HR=0.72, 95%CI=0.25-2.08, p=0.55). The 5-year RFS rates (Figure 1C) were 45.3% and 41.5%, and the 5-year OS rates (Figure 1D) were 55.8% and 60.1% in the respective groups.

Exploratory subgroup analyses in cases that did and did not receive adjuvant chemotherapy. Forest plots of HRs for RFS and OS are shown in Figure 2 and Figure 3, respectively. For RFS, HRs ranged from 0.22 to 2.57, with the lowest HR (0.22, 95%CI=0.02-2.57, p=0.23) in cases in surgical-pathological stage III. For OS, HRs ranged from 0.24 to 2.26, with the lowest HR (0.24, 95%CI=0.05-1.13, p=0.07) in cases without combined resection at surgery.

Figure 2.
Figure 2.

Forest plot of hazard ratios for recurrence-free survival. The area shaded gray represents the insignificant zone for the overall treatment effect. HR: Hazard ratio; CI: confidence interval; ADC: adenocarcinoma; SCC: squamous cell carcinoma.

Figure 3.
Figure 3.

Forest plot of hazard ratios for overall survival. The area shaded gray represents the insignificant zone for the overall treatment effect. HR: Hazard ratio; CI: confidence interval; ADC: adenocarcinoma; SCC: squamous cell carcinoma.

Discussion

In clinical practice, adjuvant chemotherapy is used in patients judged to be at high risk of recurrence after surgical resection following neoadjuvant therapy, although it is uncertain if this improves long-term outcomes. In this study, the effect of adjuvant chemotherapy after surgery following neoadjuvant therapy in patients with clinical T3N0 or N1-N2 resectable NSCLC was not associated with favorable RFS (HR=1.01, 95%CI=0.40-2.59, p=0.98) or OS (HR=0.72, 95%CI=0.25-2.08, p=0.55). The median follow-up periods were 55.1 and 60.1 months based on RFS and OS events, respectively, which appear to be sufficient to evaluate long-term outcomes, and the patterns of initial recurrence were almost the same. In subgroup analyses, adjuvant chemotherapy after surgery following neoadjuvant therapy in patients with surgical-pathological stage III showed a trend toward favorable RFS (HR=0.22, 95%CI=0.02-2.57, p=0.23) and OS (HR=0.36, 95%CI=0.03-4.01, p=0.40), and in clinical N0 cases showed a trend toward unfavorable RFS (HR=3.12, 95%CI=0.88-11.0, p=0.08) and OS (HR=3.00, 95%CI=0.67-13.7, p=0.16).

The current study suggests that routine adjuvant cytotoxic chemotherapy should not be used in patients receiving surgery after neoadjuvant therapy. This finding provides a basis for a discussion on the appropriate use of perioperative therapy. There is still room for improvement in the survival outcomes of patients undergoing surgery following perioperative chemotherapy for resectable NSCLC. The ADAURA trial showed a survival benefit with adjuvant platinum-based chemotherapy followed by 3-year osimertinib treatment in patients with resectable NSCLC harboring common EGFR mutations (13, 14). For patients with EGFR wild-type and PD-L1 expression in ≥1% of tumor cells, the Impower010 trial showed a disease-free survival (DFS) benefit with adjuvant platinum-based chemotherapy followed by up to 1 year of atezolizumab treatment (15, 16). In the neoadjuvant setting, platinum-based chemotherapy and immunotherapy gave significantly longer event-free survival (EFS) in the CheckMate816 trial (17) and AEGEAN trial (18). Neoadjuvant platinum-based chemotherapy and an immune checkpoint inhibitor (ICI) followed by surgery and adjuvant immunotherapy also resulted in significantly longer EFS in the KEYNOTE671 trial (19). Almost all of our patients who were tested for EGFR mutation were negative. Furthermore, in the study period, targeted therapy or immunotherapy were not available as adjuvant therapy. Thus, it is difficult to explain the finding that adjuvant chemotherapy was not associated with more favorable long-term survival outcomes after surgery following neoadjuvant therapy.

Adjuvant chemotherapy after surgery following neoadjuvant therapy could be a potential therapeutic option in pathological stage III cases. To the best of our knowledge, three retrospective studies have examined the effect of adjuvant chemotherapy in patients treated with surgery after neoadjuvant chemotherapy (6, 20, 21). In these studies, White et al. found that adjuvant therapy had a favorable effect on DFS and OS in 209 patients with pathological N2 NSCLC (21), whereas Spaggiari et al. suggested that adjuvant treatment did not prolong survival in 55 patients with pathological N2 NSCLC (20). Atay et al. reported that adjuvant chemotherapy for patients who underwent surgery after neoadjuvant chemotherapy prolonged OS in 780 patients with clinical N2-stage III NSCLC (6). Although adjuvant chemotherapy was administered significantly more frequently to patients with clinical N2 disease, our exploratory subgroup analysis suggested that adjuvant chemotherapy in patients undergoing surgery following neoadjuvant therapy showed a trend towards improved RFS and OS in seven cases of pathological stage III NSCLC. With reference to ongoing and published clinical trials, perioperative cytotoxic chemotherapy with immunotherapy may have an additional role in patients undergoing surgical resection for stage III NSCLC, compared to adjuvant cytotoxic chemotherapy without immunotherapy (17-19).

Surgical resection alone is the standard therapy for patients with T3N0M0 NSCLC involving the chest wall. For patients with superior sulcus involvement, neoadjuvant therapy is being considered, and two clinical trials have evaluated neoadjuvant therapy and surgical resection for superior sulcus NSCLC. Kunitoh et al. showed the efficacy of neoadjuvant chemoradiotherapy followed by surgical resection without adjuvant chemotherapy in patients with superior sulcus NSCLC, with a 5-year OS rate of 56% (22). Rusch et al. reported the feasibility of neoadjuvant chemoradiotherapy and surgery followed by two planned cycles of chemotherapy for superior sulcus NSCLC (23). At five years, the OS rate for all patients and those who underwent complete resection was 44%, whereas those who underwent complete resection had an OS rate of 54% (23). Only 45% of patients received adjuvant chemotherapy (23) and the prognostic impact of this treatment could not be determined. The subgroup analyses in the current study suggested that adjuvant chemotherapy after surgery following neoadjuvant therapy resulted in unfavorable RFS or OS in clinical N0 cases, whereas similar treatment in patients without combined resection, such as the parietal pleura or chest wall, had favorable OS. Therefore, adjuvant chemotherapy may not be recommended for patients with T3N0 NSCLC who have undergone neoadjuvant therapy followed by surgery.

To date, there has been no study of the effect of age on the survival benefit of adjuvant chemotherapy in patients treated with surgery after neoadjuvant therapy for locally advanced NSCLC. In our subgroup analysis, adjuvant chemotherapy was associated with favorable RFS (HR=0.41, 95%CI=0.10-1.75, p=0.23) and OS (HR=0.26, 95%CI=0.05-1.33, p=0.10) in younger patients (age ≤60 years). Surgery has the potential to decrease activities of daily living (ADL) in the general population. In a study of the association of performance status (PS) after lobectomy with prognosis in elderly patients with NSCLC, Kawaguchi et al. concluded that a decrease in PS after lobectomy indicated an extremely poor prognosis in these patients (24). In contrast, younger patients may maintain PS after lobectomy and this may result in a good prognosis; however, adjuvant chemotherapy should not be withheld from elderly patients. In a surveillance, epidemiology, and end results (SEER) Medicare database analysis of 3,759 patients aged >65 years, Wisnivesky et al. found that patients receiving adjuvant chemotherapy had significantly better survival than those treated without adjuvant chemotherapy: OS (HR=0.80; 95%CI=0.72-0.89) and 5-year adjusted survival [35% (95%CI=32-39%) vs. 27% (95%CI=25-29%)] (25). Zhai et al. studied 865 patients with stage IB to IIIA NSCLC who underwent radical resection to investigate the effect of age on the survival benefit of postoperative chemotherapy using the Kaplan–Meier method and propensity score matching, and found a similar benefit for DFS regardless of age (26). Thus, it is important to make the decision to perform adjuvant chemotherapy in patients treated with surgery after neoadjuvant therapy for locally advanced NSCLC based on ADL status.

Study limitations. It was a retrospective study with a limited sample size conducted at a single hospital. In addition, the advent of multiplex genetic testing has transformed the landscape of modern clinical practice (27, 28), however, information on driver gene mutations and PD-L1 expression was not available for most patients. In contrast to clinical trials, the study did not include patients who did not undergo surgery following neoadjuvant therapy. Thus, there is selection bias between patients who did and did not receive adjuvant chemotherapy.

Conclusion

Regardless of the negative findings in our overall patient cohort, our results may be beneficial in identifying patients who may likely benefit from adjuvant therapy, which contribute to planning large-scale prospective studies.

Acknowledgements

An outline of this study was presented at the 40th Meeting of the Japanese Association for Chest Surgery, Niigata, Japan, June 14, 2023.

Footnotes

  • Authors’ Contributions

    RM: Conceptualization, Data curation, Statistical analysis, Writing – original draft. MA: Writing – review & editing. SM: Data curation. TU: Data curation. AHT: Data curation. GK: Data curation. TN: Data curation. KU: Project administration, Writing – review & editing.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Funding

    This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

  • Received June 7, 2024.
  • Revision received July 4, 2024.
  • Accepted July 5, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Adjuvant Chemotherapy in Addition to Neoadjuvant Chemotherapy for Locally Advanced Non-small Cell Lung Cancer
RYO MIYATA, MASAYA AOKI, SHOICHIRO MORIZONO, TADASHI UMEHARA, AYA HARADA-TAKEDA, GO KAMIMURA, TOSHIYUKI NAGATA, KAZUHIRO UEDA
In Vivo Sep 2024, 38 (5) 2515-2522; DOI: 10.21873/invivo.13723
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