Neoadjuvant Chemoimmunotherapy in Resectable Stage IIIA/IIIB Non-Small Cell Lung Cancer

Yulong Chen; Bo Yan; Feng Xu; Zhenzhen Hui; Gang Zhao; Jie Liu; Huan Zhang; Ziqing Zeng; Ran Zhang; Mariano Provencio; Xiubao Ren; Jian You

Disclosures

Transl Lung Cancer Res. 2021;10(5):2193-2204. 

In This Article

Methods

Patients

A retrospective study of 35 patients with resectable stage IIIA and IIIB NSCLC who were treated with pembrolizumab plus chemotherapy as neoadjuvant chemoimmunotherapy in Tianjin Medical University Cancer Institute and Hospital (TJMUCH; Tianjin, China) was conducted. Clinical staging was done according to the American Joint Committee on Cancer (AJCC) 8th edition.

The therapeutic safety and feasibility were studied, together radiological and pathological responses to treatment. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Changes in the size of tumors were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.[9] All patients underwent R0 resection including lobectomy, sleeve lobectomy, complete pneumonectomy, pulmonary arterioplasty, and radical dissection of lymph nodes. Feasibility was defined as any delay in the planned surgery of <30 days. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of TJMUCH (NO.: bc2020060) and informed consent was taken from all the patients.

Immunohistochemistry

PD-L1 was analyzed by immunohistochemistry (IHC) in the Pathology Department of TJMUCH using the Monoclonal Mouse Anti-Human PD-L1 clone 22C3 (LOT10145059, Dako, Carpentaria, CA, USA). The tumor proportion score (TPS) and combined positivity score (CPS) were calculated as the percentage of at least 100 viable cells with complete or partial membrane staining. In patients with no residual tumor after the treatment, only the CPS was calculated. Interpretation of TPS and CPS of patients was provided by a pathologist at TJMUCH.

Flow Cytometry

Fresh tumor tissues obtained during surgery were mechanically and enzymatically disaggregated into a single cell suspension. CD45, CD3, CD4, CD8, CD127, and CD25 were purchased from BioLegend (San Diego, CA, USA). The following antibodies were used: FITC anti-human CD4 317408; PE anti-human CD25 302606; PE anti-human CD163 326506; PerCP/Cy5.5 anti-human CD127 (IL-7Rα) 351322; APC anti-human CD68 333810; Brilliant Violet 421 anti-human CD3 300434; and Brilliant Violet 510 anti-human CD45 304036. Cells were stained with optimal amounts of each antibody for 30 minutes at 4 °C in staining buffer, according to the manufacturer's protocol. Data (10,000 events) were acquired on a BD-Aria II flow cytometer (BD Biosciences, San Diego, CA, USA) and analyzed using FlowJo software (FlowJo LLC, Ashland, OR, USA).

Pathological Assessment

Pathological response was assessed by local pathologists, who measured the percentage of residual viable tumor in primary tumors resected from each patient during surgery using previously reported methods.[1,6,10,11] All tumor bed samples measuring less than 6 cm at their greatest diameter were submitted in their entirety. For tumor bed samples with a greatest diameter of 6 cm or more, a minimum of 1 section per cm of the greatest dimension of the tumor bed was assessed. Tumor tissue samples were sectioned, and the percentage of viable tumor tissue was recorded for each tumor slide. The average percentage of viable tumor tissue for each patient was then calculated. Tumors with <10% viable tumor cells were considered to have an MPR, and those with no viable tumor cells were deemed to be pCR.

Definition of Intracavitary and Extracavitary Tumors Type

Intracavitary and extracavitary tumors type are defined as follows. For the intracavitary type, bronchoscopy shows protrusive growth of intrabronchial masses and obstruction of the bronchus. The CT image shows distal fan-shaped atelectasis. And for the extracavitary type, bronchoscope shows bronchial mucosa redness, swelling, shrinkage, and the CT image only shows central bronchial masses (Figure S1).

Figure S1.

Representative images of bronchoscopy and CT scan of tumor intracavitary or extracavitary type. For the intracavitary type, bronchoscopy shows protrusive growth of intrabronchial masses and obstruction of the bronchus and CT images shows distal fan-shaped atelectasis. And for the extracavitary type, bronchoscope shows bronchial mucosa redness, swelling, shrinkage, and CT image shows central bronchial masses.

Statistical Analysis

The Mann-Whitney U test was used to compare pathological response between patients grouped by invasion and non-invasion status and TPS score. The independent-samples t-test was used to compare the proportions of CD4, CD8, and Tregs between genotype cohorts. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier curves and the log-rank test. Pearson's correlation coefficient was used to analyze the correlation between TPS score and pathological response. All P-values were based on a 2-sided hypothesis, and data were analyzed using SPSS 22.0 (IBM Corporation, New York, USA).

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