Efficacy of neoadjuvant therapy for lung squamous cell carcinoma and lung adenocarcinoma: A retrospective comparative study
- Authors:
- Published online on: November 6, 2023 https://doi.org/10.3892/ol.2023.14133
- Article Number: 546
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Copyright: © Gan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Lung cancer is the most common malignancy responsible for cancer-related death worldwide, accounts for 18% of all diagnosed cancers (1). Notably, 85% of patients with lung cancer are diagnosed with non-small cell lung cancer (NSCLC) (2). The 5-year survival rate for NSCLC varies; while patients with stage IA have a good prognosis (85%), only 6% of patients with stage IV cancer survive for 5 years (3). Surgery is currently the main treatment for early-stage NSCLC; however, for locally advanced NSCLC, preoperative platinum-based adjuvant chemotherapy improves the 5-year survival rate by only 5% compared to surgery alone (4). Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced NSCLC compared with chemotherapy alone, and patients with NSCLC who received immunotherapy combined with chemotherapy were reported to have higher pathological complete response (pCR) rates and longer event-free survival (5,6). It has been reported that the rapid development of individualized treatment for lung cancer has brought hope to patients with lung cancer. To improve the prognosis of NSCLC, it is necessary to better understand the benefit of preoperative neoadjuvant therapy in specific patient populations.
NSCLC is primarily divided into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). LUAD originates from cells that secrete surfactant components, and LUSC originates from cells lining the lung airways, the differentially expressed genes between LUAD and LUSC cause differences in the regulatory networks of DNA replication and repair and RNA splicing, and further cause differences in cell structure, which causes them to serve different roles in tumor cell proliferation and tissue invasion, so LUAD and LUSC are not only histologically distinct tumors, but also have unique biological characteristics and clinical features (7,8). Although often treated similarly, LUAD and LUSC have different prognoses and this is likely because the unique clinical characteristics and behavior of LUAD and LUSC remain largely unknown (9). There are currently no clear guidelines on the efficacy of neoadjuvant therapy for different subtypes of NSCLC (10).
The majority of previous clinical evaluations of post-neoadjuvant therapy have focused only on tumors, and there are few reports assessing pathological responses in the lymph node after neoadjuvant therapy (11). The CheckMate 816 trial was a rare exception to this practice, but it is clear that evidence for the efficacy of neoadjuvant immunotherapy in lymph nodes is insufficient (12). The main purpose of the present study was to review and analyze the clinical data from patients who had received neoadjuvant therapy for LUAD and LUSC, to preliminarily evaluate the efficacy of neoadjuvant therapy in both tumors and lymph node remission of patients with two distinct pathological subtypes, and to provide clinical treatment guidelines.
Materials and methods
Patients and methods
The clinical data of patients who underwent surgery after neoadjuvant chemotherapy or chemotherapy combined with immunotherapy at The First Affiliated Hospital, Sun Yat-sen University (Guangzhou, China) between January 2016 and August 2022 were retrospectively analyzed. Patients who had received chemotherapy combined with immunotherapy were recruited from January 2020 to August 2022. The inclusion criteria were as follows: i) Aged ≥18 years; ii) all patients with biopsy-proven NSCLC with a defined histological subtype; iii) patients with lymph node metastasis, no distant metastasis, potentially operable but not suitable for immediate resection (based on imaging information), classified according to the tumor-lymph node-metastasis (TNM) staging system of the 8th edition of the American Joint Committee on Cancer (13); iv) received chemotherapy or chemotherapy combined with immunotherapy before surgery; v) unspecified driver gene mutations, including anaplastic lymphoma kinase and epidermal growth factor receptor; vi) no history of other malignancies prior to treatment and no prior antitumor therapy; and vii) Eastern Cooperative Oncology Group (ECOG) performance status scores of 0 or 1 (14). The general information and treatment data of the patients, such as age, sex, smoking history, histopathological type, clinical TNM stage, chemotherapy regimen and frequency, imaging changes before and after treatment, and final pathological TNM stage, were recorded in detail.
Treatment
All patients received platinum-based chemotherapy or ICIs combined with chemotherapy, and were evaluated using the same procedures before and after neoadjuvant therapy. Tumor changes were assessed based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) as complete remission (CR), partial remission (PR), stable disease (SD) or progressive disease (PD) (15). Pathological response to treatment was graded; pCR was defined as the complete absence of residual tumor cells. and major pathological response (MPR) was defined as the presence of residual viable tumor cells ≤10%. Pathological stable disease (SD) is defined as the presence of >50% viable tumor cells in the resected cancer specimen; incomplete pathological response is defined as the presence of >50% viable tumor cells in the resected cancer specimen >10% viable tumor cells present (16).
Statistical analysis
Statistical analysis was performed using SPSS 23.0 (IBM Corp.). Continuous variables are presented as mean ± standard deviation. Student's t-test was used to compare independent samples of normally distributed continuous variables, and the Mann-Whitney U test was used to compare non-normally distributed continuous variables. Categorical data are presented as frequencies (percentages). Comparisons of categorical variables between groups were made using Fisher's exact test or Pearson's χ2 test. Univariate logistic regressive analysis was used to evaluate the influence of certain clinical variables on pathological remission. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient characteristics
In the present study, a total of 67 cases were identified, including 36 patients with LUSC and 31 patients with LUAD. The basic information and clinical characteristics of the patients are shown in Table I. All patients underwent surgery after neoadjuvant therapy. Patients were predominantly male (79.10%), and most patients were diagnosed with stage III NSCLC (82.19%) and ipsilateral mediastinal and/or subcarinal lymph node metastasis (N2) (55.22%). No significant differences were demonstrated in patient characteristics between LUSC and LUAD except for age. However, age was not a risk factor for clinical efficacy when data were analyzed using univariate logistic regression.
Efficacy
According to RECIST 1.1 criteria, 9 (13.43%) patients achieved CR, 38 (56.72%) patients achieved PR, 18 (26.87%) patients achieved SD and 2 (2.98%) patients achieved PD. There was no significant difference in radiological response after neoadjuvant therapy between patients with LUAD or LUSC (Table II).
 | Table II.Comparison of radiological and pathological responses in patients after neoadjuvant therapy. |
Next, the pathological response of the two NSCLC subtypes were compared, 38.89% of patients with LUSC achieved pCR after surgery compared with 16.13% of patients with LUAD (Table II). Lymph node regression rates were comparable between the two groups (86.11% vs. 77.42%; Table II). LUSC appeared to be more responsive to neoadjuvant therapy, but there were no statistically significant differences in tumor regression and lymph node downstaging after neoadjuvant therapy between the LUSC and LUAD groups.
Radiological response in patients with pCR
Analysis of the concordance between two different subtypes of radiological responses and pCR was performed. The results demonstrated that among all patients who achieved pCR, 50% of patients with LUSC had radiographic CR (7/14) compared with 40% of patients with LUAD (2/5) (Fig. 1).
Regression analysis of risk factors for postoperative pathological response
Univariate logistic regression models were used to assess whether sex, age, pathological subtype, clinical stage, neoadjuvant therapy modality and number of previous neoadjuvant therapies could be risk factors for pCR and MPR events. The results demonstrated that chemotherapy combined with immunotherapy was a risk factor affecting pCR and MPR. (odds ratio 5.74; 95% confidence interval 1.93–17.01; P<0.002; Table III).
To further clarify the role of ICIs in NSCLC, the effects of neoadjuvant chemotherapy and neoadjuvant chemotherapy combined with immunotherapy on NSCLC subtypes were compared. Compared with chemotherapy alone, chemotherapy combined with immunotherapy improved the pCR and MPR rates; specifically, the pCR rate of LUAD increased from 11.76 to 21.43% (Table SIII) and that of LUSC increased from 21.05 to 58.82% (Table IV). Although LUSC had a higher pCR rate than LUAD after chemotherapy or chemotherapy combined with immunotherapy, no statistically significant difference was demonstrated between the two subtypes (chemotherapy combined with immunotherapy, pCR P=0.07; chemotherapy, pCR P=0.66; Tables SI and SII). Moreover, in LUSC, neoadjuvant chemotherapy combined with immunotherapy significantly improved the pCR rate (P=0.01; Table IV), whereas there was no significant difference in LUAD (P=0.64; Table SIII).
| Table IV.Comparison of pathological remission of neoadjuvant chemotherapy and neoadjuvant immunotherapy in LUSC. |
Discussion
Patients with locally advanced NSCLC can benefit from neoadjuvant chemotherapy, and programmed cell death 1 inhibitor combined with chemotherapy has been reported to enhance the immune response further against tumor cells (17,18). However, NSCLC is a diverse and complex disease with distinct differences in clinical, histopathological and molecular characteristics between the LUAD and LUSC subtypes (19,20). In the present study, a comprehensive analysis was performed to evaluate the clinical efficacy of neoadjuvant therapy in these two distinct NSCLC pathological types.
In clinical trials, MPR and pCR are currently the most common modalities for assessing pathological responses to neoadjuvant immunotherapy and are also used for assessing survival (21). Several previous studies have reported an association between pCR status and survival in NSCLC (22,23). Neoadjuvant immunotherapy can reduce the primary tumor volume and enable radical resection (24). It exerts its antitumor effects by inducing antigens that trigger a durable and powerful T-cell immune response (25,26). In the CheckMate 816 study, squamous and non-squamous NSCLC were reported to have similar pCR rates to immunotherapy combined with chemotherapy with 25.3% for squamous and 22.8% for non-squamous NSCLC (11). In the present study, although there was no significant difference in the pCR rate between LUAD and LUSC after neoadjuvant chemotherapy combined with immunotherapy, the pCR rate of LUSC was higher than that of LUAD.
The pCR and MPR rates in response to neoadjuvant chemotherapy and neoadjuvant immune-combined chemotherapy in different pathological subtypes were compared. It was demonstrated that, compared with chemotherapy alone, the pCR and MPR of both pathological subtypes were increased and the pCR of LUSC was significantly improved after combined immunotherapy. Furthermore, the radiological CR in LUSC was closer to pathological pCR. A previous study reported that a higher primary pathological response was observed after neoadjuvant chemotherapy in patients with squamous cell carcinoma (26%) compared with that in patients with adenocarcinoma (12%), possibly because of greater necrosis of the initial tumor tissue in squamous cell carcinoma (27). Moreover, compared with adenocarcinoma, programmed cell death 1 ligand 1 expression is more extensive in squamous cell carcinoma and the infiltration of immune cells such as macrophages is more obvious, thus the response to tumors is more thorough, which may be responsible for the difference in the responses of squamous cell carcinoma and adenocarcinoma to immunotherapy (28).
At present, pCR and MPR only assess primary tumors and exclude lymph nodes (29). Although lymph node involvement is often one of the key prognostic factors in lung cancer, there are few studies which have evaluated lymph nodes after neoadjuvant therapy. In recent years, researchers have emphasized the significance of lymph node changes following adjuvant therapy (30). The aim of the present study was to evaluate the effect of neoadjuvant therapy on lymph nodes. However, no significant changes in lymph nodes were identified regardless of subtype or treatment regimen.
There are certain limitations to the present study. First, as it is a retrospective study, estimation of diagnostic efficacy, as well as differences in scanner and image acquisition parameters, could potentially lead to bias. Consequently, each sample was re-evaluated for pathology and radiological response, as part of the present study, to minimize bias. Secondly, the study was limited by the relatively small sample size and there may be unavoidable confounding factors; therefore, future studies with larger sample sizes are needed to confirm these findings. Third, the observation period was relatively short and the long-term overall survival rate was not analyzed, as although the data collected in this retrospective study are from January 2016 to August 2022, the data for chemotherapy combined with immunotherapy are from January 2021 to August 2022. Thus, the observation period was relatively short and complete survival data were not collected; therefore, subsequent long-term follow-up and more mature data are necessary. Despite these limitations, the findings of the present study demonstrated the difference in sensitivity to neoadjuvant therapy between pathological subtypes of NSCLC.
In conclusion, it was found that of the two major subtypes of NSCLC, LUSC was more sensitive to immunotherapy and had better clinical outcomes compared with LUAD.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
YG and HSZ were responsible for study conception and design; HSZ provided administrative support; YG, HSZ, ZHL, XJY, ZWT and BZ contributed to the collection of patient data; ZHL, XJY and ZWT collected and assembled the data; and YG and BZ performed data analysis and interpretation. All authors read and approved the final manuscript. YG and HSZ confirm the authenticity of all the raw data.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Thai AA, Solomon BJ, Sequist LV, Gainor JF and Heist RS: Lung cancer. Lancet. 398:535–554. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Ahmad A and Gadgeel SM: Lung cancer and personalized medicine: Novel therapies and clinical management. Adv Exp Med Biol. 890:v–vi. 2016.PubMed/NCBI | |
|
NSCLC Meta-analysis Collaborative Group, . Preoperative chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual participant data. Lancet. 383:1561–1571. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Spicer J, Wang C, Tanaka F, Saylors GB, Chen KN, Liberman M, Vokes E, Girard N, Lu S, Provencio M, et al: Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 39 (Suppl 15):S85032021. View Article : Google Scholar | |
|
Wakelee HA, Altorki NK, Zhou C, Csőszi T, Vynnychenko IO, Goloborodko O, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, et al: IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 39 (Suppl 15):S85002021. View Article : Google Scholar | |
|
Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Relli V, Trerotola M, Guerra E and Alberti S: Abandoning the notion of non-small cell lung cancer. Trends Mol Med. 25:585–594. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Kawase A, Yoshida J, Ishii G, Nakao M, Aokage K, Hishida T, Nishimura M and Nagai K: Differences between squamous cell carcinoma and adenocarcinoma of the lung: are adenocarcinoma and squamous cell carcinoma prognostically equal? Jpn J Clin Oncol. 42:189–195. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Detterbeck FC, Socinski MA, Gralla RJ, Edelman MJ, Jahan TM, Loesch DM, Limentani SA, Govindan R, Zaman MB, Ye Z, et al: Neoadjuvant chemotherapy with gemcitabine-containing regimens in patients with early-stage non-small cell lung cancer. J Thorac Oncol. 3:37–45. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Pataer A, Weissferdt A, Vaporciyan AA, Correa AM, Sepesi B, Wistuba II, Heymach JV, Cascone T and Swisher SG: Evaluation of pathologic response in lymph nodes of patients with lung cancer receiving neoadjuvant chemotherapy. J Thorac Oncol. 16:1289–1297. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 386:1973–1985. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V, et al: The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 11:39–51. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Azam F, Latif MF, Farooq A, Tirmazy SH, AlShahrani S, Bashir S and Bukhari N: Performance status assessment by using ECOG (eastern cooperative oncology group) score for cancer patients by oncology healthcare professionals. Case Rep Oncol. 12:728–736. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Pataer A, Kalhor N, Correa AM, Raso MG, Erasmus JJ, Kim ES, Behrens C, Lee JJ, Roth JA, Stewart DJ, et al: Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol. 7:825–832. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Emens LA and Middleton G: The interplay of immunotherapy and chemotherapy: Harnessing potential synergies. Cancer Immunol Res. 3:436–443. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Provencio M, Nadal E, Insa A, García-Campelo MR, Casal-Rubio J, Dómine M, Majem M, Rodríguez-Abreu D, Martínez-Martí A, De Castro Carpeño J, et al: Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 21:1413–1422. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Z, Fillmore CM, Hammerman PS, Kim CF and Wong KK: Non-small-cell lung cancers: A heterogeneous set of diseases. Nat Rev Cancer. 14:535–546. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Wang BY, Huang JY, Chen HC, Lin CH, Lin SH, Hung WH and Cheng YF: The comparison between adenocarcinoma and squamous cell carcinoma in lung cancer patients. J Cancer Res Clin Oncol. 146:43–52. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Junker K, Thomas M, Schulmann K, Klinke F, Bosse U and Müller KM: Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol. 123:469–477. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Waser N, Adam A, Schweikert B, Vo L, McKenna M, Breckenridge M, Penrod JR and Goring S: 1243P Pathologic response as early endpoint for survival following neoadjuvant therapy (NEO-AT) in resectable non-small cell lung cancer (rNSCLC): Systematic literature review and meta-analysis. Ann Oncol. 31 (Suppl 4):S8062020. View Article : Google Scholar | |
|
Rosner S, Liu C, Forde PM and Hu C: Association of pathologic complete response and long-term survival outcomes among patients treated with neoadjuvant chemotherapy or chemoradiotherapy for NSCLC: A meta-analysis. JTO Clin Res Rep. 3:1003842022.PubMed/NCBI | |
|
Forde PM, Chaft JE and Pardoll DM: Neoadjuvant PD-1 blockade in resectable lung cancer. N Eng J Med. 379:e142018. View Article : Google Scholar : PubMed/NCBI | |
|
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Eng J Med. 378:2078–2092. 2018. View Article : Google Scholar | |
|
Reck M, Shankar G, Lee A, Coleman S, McCleland M, Papadimitrakopoulou VA, Socinski MA and Sandler A: Atezolizumab in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, including patients with EGFR mutations. Exp Rev Respir Med. 14:125–136. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Qu Y, Emoto K, Eguchi T, Aly RG, Zheng H, Chaft JE, Tan KS, Jones DR, Kris MG, Adusumilli PS and Travis WD: Pathologic assessment after neoadjuvant chemotherapy for NSCLC: Importance and implications of distinguishing adenocarcinoma from squamous cell carcinoma. J Thorac Oncol. 14:482–493. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Q, Fu YY, Yue QN, Wu Q, Tang Y, Wang WY, Wang YS and Jiang LL: Distribution of PD-L1 expression and its relationship with clinicopathological variables: an audit from 1071 cases of surgically resected non-small cell lung cancer. Int J Clin Exp Pathol. 12:774–786. 2019.PubMed/NCBI | |
|
Choi NC, Carey RW, Daly W, Mathisen D, Wain J, Wright C, Lynch T, Grossbard M and Grillo H: Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol. 15:712–722. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Travis WD, Dacic S, Wistuba I, Sholl L, Adusumilli P, Bubendorf L, Bunn P, Cascone T, Chaft J, Chen G, et al: IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. J Thorac Oncol. 15:709–740. 2020. View Article : Google Scholar : PubMed/NCBI |
