Abstract
Background
Major pathologic response (MPR) is mainly focused on residual viable tumor in the tumor bed regardless of lymph node. Herein, we investigated the predictive value of MPR and node status on survival in nonsmall‐cell lung cancer (NSCLC) patients receiving neoadjuvant chemotherapy (NAC) and surgery.
Methods
A total of 194 eligible cases were included. Tumor pathologic response and node status were assessed. Based on these evaluations, patients were divided into the MPR group and the non‐MPR group, the nodal downstaging (ND) group and non‐ND group. Furthermore, patients were assigned into four subgroups (MPR + ND, MPR + non‐ND, non‐MPR + ND, and non‐MPR + non‐ND). Overall survival (OS) and disease‐free survival (DFS) were compared between groups. Multivariate analyses were performed to identify prognostic factors.
Results
MPR was identified in 32 patients and ND was present in 108 patients. OS and DFS were better in the MPR group than in the non‐MPR group, but with no statistical significance (OS, p = 0.158; DFS, p = 0.126). The ND group had better OS than the non‐ND group (p = 0.031). However, the DFS between these two groups was comparable (p = 0.103). Further analyses suggested that both OS and DFS were better in the MPR + ND group than in the non‐MPR + non‐ND group (OS, p = 0.017; DFS, p = 0.029). Multivariate analyses confirmed that MPR + ND was an independent favorable predictor.
Conclusions
MPR combined with ND could improve the predictive value on survival in NSCLC patients receiving NAC.
Keywords: major pathologic response, nodal downstaging, non small‐cell lung cancer
Pathologic response and nodal status of 194 nonsmall‐cell lung cancer patients who received neoadjuvant chemotherapy and surgery were investigated. We demonstrated that major pathologic response was not adequate to predict survival, but when combined with nodal downstaging it could improve the efficacy of predicting survival in these patients. This helped to identify the population subset with the most favorable prognosis.
INTRODUCTION
Neoadjuvant chemotherapy (NAC) has been the benchmark for the treatment of locally advanced nonsmall‐cell lung cancer (NSCLC) and improves the 5‐year overall survival (OS) rate of 5%. 1 , 2 , 3 OS has been adopted as the gold‐standard primary endpoint in primary studies evaluating the efficacy of NAC. 4 However, concerning the research duration and financial cost, it is imperative to seek other surrogate endpoints for OS to predict long‐term outcomes. 4
Major pathologic response (MPR), defined as 10% or less residual viable tumor, has recently raised interest as a promising surrogate endpoint to predict long‐term survival in NSCLC patients who received NAC 4 , 5 In clinical practice, however, it simply refers to the pathologic response in the primary tumor, and few pathologists examine the therapeutic response in the lymph node. 4 , 6 In addition, controversies regarding the prognostic value of MPR on survival also exist. 7 , 8 Nodal downstaging (ND), one of the dominant advantages of NAC, was also demonstrated as a promising predictor on long‐term outcomes in NSCLC patients receiving NAC in previous studies. 9 , 10 , 11 We therefore supposed that a combination of MPR and ND might improve the predictive value on long‐term outcomes in these patients.
Herein, we investigated the predictive value of MPR and ND on long‐term outcomes in resected NSCLC patients who received NAC. We proposed that a combination of MPR and ND might improve the efficacy of predicting both OS and disease‐free survival (DFS) in these patients, with a promising surrogate indicator to identify the population subset with the most favorable prognosis.
MATERIALS AND METHODS
Patient selection
This study was approved by the Institutional Review Board of Sun Yat‐sen University Cancer Center. A retrospective chart review was conducted on NSCLC patients treated with NAC and surgery at Sun Yat‐sen University Cancer Center from January 2001 to December 2014.
All included cases fit the following criteria: (1) primary stage I to stage III NSCLC; (2) performed NAC before surgery; (3) surgical specimens' paraffin blocks were available for reassessment of hematoxylin and eosin stains.
The exclusion criteria were (1) previous or concurrent other primary cancers and (2) perioperative death, which was defined as death within 30 days after the operation or any time after the operation if the patient did not leave the hospital alive. 12
The authenticity of the study has been validated by uploading the raw data onto the Research Data Deposit public platform (www.researchdata.org.cn), with the approval RDD number RDDA2020001437.
Chemotherapy treatment
Third‐generation platinum‐based doublet chemotherapy was hired as neoadjuvant chemotherapy, including gemcitabine/ pemetrexed/paclitaxel/vinorelbine with cisplatin or carboplatin. The specific doses are as follows: gemcitabine (1.0 g/m2, day 1, 8), pemetrexed (500 mg/m2, day 1), paclitaxel (175 mg/m2, day 1), vinorelbine (25 mg/m2, day 1, 8), carboplatin (AUC of 5.0–6.0), and cisplatin (75 mg/m2, day 1). Neoadjuvant chemotherapy was administered every 3–4 weeks as a cycle. CT scan was administered every two cycles to assess the radiological efficacy. Adverse events (AEs) were recorded according to National Cancer Institute Common Toxicity Criteria, version 2.0 (http://ctep.info.nih.gov).
Pathologic response evaluation
Histology slides were retrieved from the Department of Pathology, Sun Yat‐sen University Cancer Center. All cases were reviewed by two pathologists (Dr. Yan SM and Dr. Feng YF) under a multiheaded microscope. Assessment was performed as previously described by Pataer et al. 5 Briefly, formalin‐fixed paraffin‐embedded tissue sections (5 μm thick and at least one section per centimeter of tumor greatest diameter) of gross residual tumor with hematoxylin and eosin stains were reviewed. 5 The percentage of residual tumor was calculated by comparing the estimated cross‐sectional area of the viable tumor foci to the estimated cross‐sectional areas of necrosis, fibrosis, and inflammation on each slide. 5 Patients were considered to achieve MPR if they had 10% viable tumor or less.
Clinical staging evaluation
Nodal status before NAC and after surgery were evaluated. Nodal staging before NAC could be performed pathologically (based on endobronchial ultrasonography [EUS] or mediastinoscopy) or clinically (based on PET/CT or CT scan). For the latter, the lymph node with escalated SUV (SUVmax ≥ 2.5) in PET/CT or with the short axis more than 10 mm in the CT scan was considered malignant. 13 However, PET/CT was not mandatory in our series because it has not yet been covered by medical insurance in mainland China. 14 , 15
Statistical analysis
The OS was calculated from the date of diagnosis to the date of death from any cause or last follow‐up. The DFS was defined as the time from the date of diagnosis to the date of tumor recurrence or death from any cause. All time‐to‐event outcomes were estimated using the Kaplan–Meier method with a log‐rank test. Univariate and multivariate analyses of prognostic factors were calculated with the Cox proportional hazard regression model. Pearson's χ 2 test or Fisher's exact test was used to compare categorical variables. The Mann–Whitney U test or the Kruskal–Wallis H test was used to compare continuous distributed variables. Two‐sided p < 0.05 was considered statistically significant. All of the statistical analyses were carried out with IBM SPSS Statistics (version 25.0, IBM Corp) and Graphpad Prism 8.
RESULTS
Patient characteristics
A total of 194 NSCLC patients were included in this study, and the general clinical characteristics are summarized in Table 1. The median age of the entire cohort was 56 years old (range from 32 to 73 years old). Males (78.4%) and smokers (64.4%) accounted for most of the cases. Before treatment, clinical stage III patients accounted for the majority of the cases (83.0%); however, after surgery, the pathologic staging showed that stage III cases dropped to 44.8% of patients. For the clinical staging evaluation, a substantial proportion of cases (93.8%, 182/194) were evaluated by contrast‐enhanced CT, 4 patients by PET‐CT, and only 8 patients were pathologically diagnosed (6 patients by mediastinoscopy and 2 patients by EUS). As for RECIST CT response, two patients reached complete response (CR), 71 patients reached partial response (PR), 108 patients reached stable disease (SD), and 13 patients reached progressive disease (PD). Regarding the histology types, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were at comparable proportions (49.5% vs. 45.4%).
TABLE 1.
Clinical characteristics for the entire cohort
| Characteristic | Total (n = 194) | MPR (n = 32) | Non‐MPR (n = 162) | p | ND (n = 108) | Non‐ND (n = 86) | p |
|---|---|---|---|---|---|---|---|
| Age, median (range) | 56 (32–73) | 57 (41–73) | 56 (32–73) | 0.246 a | 56 (32–73) | 56 (33–73) | 0.883 a |
| Age, years, n (%) | 0.979 | 0.765 | |||||
| ≤60 | 133 (68.6) | 22 (68.8) | 111 (68.5) | 75 (69.4) | 58 (67.4) | ||
| >60 | 61 (31.4) | 10 (31.3) | 51 (31.5) | 33 (30.6) | 28 (32.6) | ||
| Sex, n (%) | 0.169 | 0.235 | |||||
| Female | 42 (21.6) | 4 (12.5) | 38 (23.5) | 20 (18.5) | 22 (25.6) | ||
| Male | 152 (78.4) | 28 (87.5) | 124 (76.5) | 88 (81.5) | 64 (74.4) | ||
| Smoking, n (%) | 0.172 | 0.053 | |||||
| Nonsmoker | 69 (35.6) | 8 (25.0) | 61 (37.7) | 32 (29.6) | 37 (43.0) | ||
| Smoker | 125 (64.4) | 24 (75.0) | 101 (62.3) | 76 (70.4) | 49 (57.0) | ||
| ND, n (%) | 0.215 | ||||||
| Yes | 108 (55.7) | 21 (65.6) | 87 (53.7) | ||||
| No | 86 (44.3) | 11 (34.4) | 75 (46.3) | ||||
| Pathologic response, n (%) | 0.215 | ||||||
| MPR | 32 (16.5) | 21 (19.4) | 11 (12.8) | ||||
| Non‐MPR | 162 (83.5) | 87 (80.6) | 75 (87.2) | ||||
| RECIST 1.1 response, n (%) | 0.007 b | 0.026 | |||||
| CR/PR | 73 (37.6) | 20 (62.5) | 53 (32.7) | 48 (46.2) | 25 (27.8) | ||
| SD | 108 (55.7) | 11 (34.4) | 97 (59.9) | 49 (47.1) | 59 (65.6) | ||
| PD | 13 (6.7) | 1 (3.1) | 12 (7.4) | 7 (6.7) | 6 (6.7) | ||
| Histology, n (%) | 0.001 | 0.174 | |||||
| Adenocarcinoma | 96 (49.5) | 7 (21.9) | 89 (54.9) | 47 (43.5) | 49 (57.0) | ||
| Squamous cell carcinoma | 88 (45.4) | 21 (65.6) | 67 (41.4) | 55 (50.9) | 33 (38.4) | ||
| Other c | 10 (5.2) | 4 (12.5) | 6 (3.7) | 6 (5.6) | 4 (4.7) | ||
| Clinical stage, n (%) | 0.709 b | <0.001 | |||||
| I | 12 (6.2) | 1 (3.1) | 11 (6.8) | 0 (0.0) | 10 (11.6) | ||
| II | 21 (10.8) | 4 (12.5) | 17 (10.5) | 6 (5.6) | 15 (17.4) | ||
| III | 161 (83.0) | 27 (84.4) | 134 (82.7) | 102 (94.4) | 61 (70.9) | ||
| Pathological stage, n (%) | <0.001 | <0.001 | |||||
| I | 52 (26.8) | 17 (53.1) | 35 (21.6) | 44 (40.7) | 8 (9.3) | ||
| II | 55 (28.4) | 9 (28.1) | 46 (28.4) | 42 (38.9) | 13 (15.1) | ||
| III | 87 (44.8) | 6 (18.8) | 81 (50.0) | 22 (20.4) | 65 (75.6) | ||
| Cell differentiation, n (%) | 0.174 b | 0.354 | |||||
| Well | 9 (4.6) | 0 (0.0) | 9 (5.6) | 5 (4.6) | 4 (4.7) | ||
| Moderately | 64 (33.0) | 8 (25.0) | 56 (34.6) | 31 (28.7) | 33 (38.4) | ||
| Poorly/undifferentiated | 121 (62.4) | 24 (75.0) | 97 (59.9) | 72 (66.7) | 49 (57.0) | ||
| Type of resection, n (%) | 0.630 | 0.155 | |||||
| Pneumonectomy | 49 (25.3) | 7 (21.9) | 42 (25.9) | 23 (21.3) | 26 (30.2) | ||
| Nonpneumonectomy | 145 (74.7) | 25 (78.1) | 120 (74.1) | 85 (78.7) | 60 (69.8) | ||
| Margin d , n (%) | 0.602 b | 0.758 | |||||
| R0 | 187 (96.4) | 32 (100.0) | 155 (95.7) | 105 (97.2) | 82 (95.3) | ||
| R1/R2 | 7 (3.6) | 0 (0.0) | 7 (4.3) | 3 (2.8) | 4 (4.7) | ||
| Neoadjuvant chemotherapy, n (%) | 0.113 b | 0.055 b | |||||
| Gemcitabine/platinum | 19 (9.8) | 6 (18.8) | 13 (8.0) | 9 (8.3) | 10 (11.6) | ||
| Pemetrexed/platinum | 56 (28.9) | 6 (18.8) | 50 (30.9) | 29 (26.9) | 27 (31.4) | ||
| Paclitaxel/platinum | 109 (56.2) | 17 (53.1) | 92 (56.8) | 68 (63.0) | 41 (47.7) | ||
| Vinorelbine/platinum | 6 (3.1) | 1 (3.1) | 5 (3.1) | 2 (1.9) | 4 (4.7) | ||
| Other e | 4 (2.1) | 2 (6.3) | 2 (1.2) | 0 (0.0) | 4 (4.7) | ||
| EGFR mutation (n = 81) | 0.183 | 0.003 | |||||
| Positive | 14 (17.3) | 3 (33.3) | 11 (15.3) | 3 (6.5) | 11 (31.4) | ||
| Negative | 67 (82.7) | 6 (66.7) | 61 (84.7) | 43 (93.5) | 24 (68.6) | ||
Abbreviations: MPR, major pathologic response; ND, nodal downstaging; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; EGFR, epidermal growth factor receptor.
The meaning of bold values is two‐sided P < 0.05.
Mann–Whitney U test.
Fisher's exact test.
Other includes six patients diagnosed as adenosquamous carcinoma, three patients diagnosed as large cell carcinoma, one patient diagnosed as carcinoid, and one patient diagnosed as lymphoepithelioma‐like carcinoma.
R0, microscopic complete resection; R1/R2, microscopic or macroscopic incomplete resection.
Other includes etoposide‐based regimen and tegafur.
With respect to chemotherapy cycle, before operation 66.5% (129/194) of cases received two cycles, 14.4% (28/194) of cases received three cycles, and 10.8% (21/194) of cases received four cycles. After surgery, most patients did not undergo chemotherapy (52.1%, 101/194), 23.2% (45/194) received two cycles, and 11.3% (22/194) of cases received one cycle. According to National Cancer Institute Common Toxicity Criteria, version 2.0, 11 (5.7%) patients were suffered from hematologic toxicity, 16 (8.2%) patients were suffered from gastrointestinal (GI) toxicity, one patient was suffered from myalgia, one patient was suffered from neuropathy, and one patient was suffered from sensory abnormal. The chemotherapy related toxicity is recorded in Supporting Information Table S1.
MPR was observed in 16.5% of the cases in the entire cohort and was more likely to occur in SCC than in ADC (65.6% vs. 21.9%, p = 0.001). Figure 1 shows typical histopathology figures of MPR in ADC and SCC. The data suggested that ND seemed not to be associated with MPR (p = 0.215). Interestingly, our data demonstrated that epidermal growth factor receptor (EGFR) wild‐type patients were more likely to achieve ND than EGFR mutation patients (93.5% vs. 6.5%, p = 0.003).
FIGURE 1.
Histopathology of tumors with MPR to NAC. (a) Squamous cell carcinoma and (b) adenocarcinoma. The arrows point to the typical areas of viable tumor, necrosis, stromal tissue, and inflammatory cells. MPR, major pathologic response; NAC, neoadjuvant chemotherapy
Gender, together with age, smoking status, cell differentiation, type of resection, resection margin, and NAC regimens were not associated with MPR or ND (Table 1).
Survival
The median follow‐up time was 43.5 months, ranging from 2.8 to 180.9 months. The detailed survival data are listed in Supporting Information Tables S2 and S3. The long‐term survival of the MPR group was superior to that of the non‐MPR group (5‐year OS rate 64.7% vs. 48.3%; median survival time 55.5 months vs. 41.6 months; Supporting Information Table S2; OS curves, Figure 2(a)), although the differences were not statistically significant (5‐year OS rate p = 0.233; median survival time p = 0.165). However, the 5‐year OS rate and median survival time for the ND group were much better than those of the non‐ND group (5‐year OS rate 58.5% vs. 41.2%, p = 0.013; median survival time 52.4 months vs. 38.1 months, p = 0.016; Supporting Information Table S2; OS curves, Figure 2(b)). When combining pathologic response with lymph node status, the survival curves suggested good discrimination among the MPR + ND group, non‐MPR + ND group, non‐MPR + non‐ND group, and MPR + non‐ND group (the MPR + ND group vs. the non‐MPR + non‐ND group, p = 0.017; Figure 2(c)).
FIGURE 2.
Kaplan–Meier estimate of overall survival in the full analysis set: (a) the MPR group vs. the non‐MPR group, (b) the ND group vs. the non‐ND group, and (c) the MPR + ND group vs. the MPR + non‐ND group vs. the non‐MPR + ND group vs. the non‐MPR + non‐ND group. MPR, major pathologic response; ND, nodal downstaging
The DFS was also comparable between the MPR group and the non‐MPR group (5‐year DFS rate: 51.8% vs. 38.4%, p = 0.254; Supporting Information Table S2; DFS curves, Figure 3(a)). Compared with the non‐ND group, the ND group showed a tendency for improved DFS (5‐year DFS rate 46.7% vs. 32.2%; Supporting Information Table S2; DFS curves, Figure 3(b)), but with no statistical significance (p = 0.121). Similar to the OS curves, DFS curves separated better among the MPR + ND group, non‐MPR + ND group, non‐MPR + non‐ND group, and MPR + non‐ND group (the MPR + ND group vs. the non‐MPR + non‐ND group, p = 0.029; Figure 3(c)).
FIGURE 3.
Kaplan–Meier estimate of disease‐free survival in the full analysis set: (a) the MPR group vs. the non‐MPR group, (b) the ND group vs. the non‐ND group, and (c) the MPR + ND group vs. the MPR + non‐ND group vs. the non‐MPR + ND group vs. the non‐MPR + non‐ND group. MPR, major pathologic response; ND, nodal downstaging
Cox regression analysis
A univariate Cox analysis revealed that ND, MPR + ND, earlier pathologic nodal staging, pneumonectomy, and gemcitabine/platinum as the NAC regimen were prognostic factors favoring OS (Table 2). In further analyses, multivariate Cox analysis confirmed that pneumonectomy and MPR + ND were independent factors favoring OS (Table 2).
TABLE 2.
Univariate and multivariate COX proportional hazard model analysis for overall survival
| Risk factor for overall survival | Univariate analysis | Multivariate analysis a | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| Age, years | 0.234 | |||||
| ≤60 | Ref | – | ||||
| >60 | 1.295 | 0.846–1.980 | ||||
| Sex | 0.771 | |||||
| Female | Ref | – | ||||
| Male | 1.076 | 0.656–1.766 | ||||
| Pathologic response | 0.162 | |||||
| MPR | Ref | – | ||||
| Non‐MPR | 1.542 | 0.841–2.829 | ||||
| ND | 0.033 | |||||
| Yes | Ref | – | ||||
| No | 1.558 | 1.037–2.342 | ||||
| Pathologic response + nodal status | 0.045 | 0.044 | ||||
| MPR + ND | Ref | – | Ref | – | ||
| Other b | 2.332 | 1.019‐5.337 | 2.371 | 1.023–5.497 | ||
| RECIST 1.1 response | 0.362 | |||||
| CR/PR | Ref | |||||
| SD | 1.279 | 0.825–1.985 | ||||
| PD | 1.630 | 0.751–3.540 | ||||
| Smoking | 0.585 | |||||
| Nonsmoker | Ref | – | ||||
| Smoker | 1.128 | 0.733–1.736 | ||||
| Histology | 0.465 | |||||
| Adenocarcinoma | Ref | – | ||||
| Squamous cell carcinoma | 0.863 | 0.569–1.308 | ||||
| Other c | 0.513 | 0.160‐1.645 | ||||
| Cell differentiation | 0.349 | |||||
| Well | Ref | – | ||||
| Moderately | 1.594 | 0.236–11.645 | ||||
| Poorly/undifferentiated | 2.244 | 0.415–16.694 | ||||
| Pathological T stage | 0.091 | |||||
| T1 | Ref | – | ||||
| T2 | 0.990 | 0.589–1.665 | ||||
| T3 | 1.481 | 0.846–2.591 | ||||
| T4 | 1.983 | 1.043–3.771 | ||||
| Pathological N stage | 0.011 | |||||
| N0 | Ref | – | ||||
| N1 | 1.624 | 0.936–2.817 | ||||
| N2 | 2.029 | 1.273–3.236 | ||||
| Type of resection | 0.008 | 0.007 | ||||
| Pneumonectomy | Ref | – | Ref | – | ||
| Nonpneumonectomy | 1.792 | 1.166–2.754 | 1.843 | 1.179–2.882 | ||
| Margin d | 0.413 | |||||
| R0 | Ref | – | ||||
| R1/R2 | 1.522 | 0.557–4.162 | ||||
| Neoadjuvant chemotherapy | 0.032 | 0.109 | ||||
| Gemcitabine/platinum | Ref | – | Ref | – | ||
| Pemetrexed/platinum | 2.558 | 0.986–6.637 | 2.678 | 1.030–6.965 | ||
| Paclitaxel/platinum | 1.900 | 0.759–4.754 | 2.087 | 0.832–5.236 | ||
| Vinorelbine/platinum | 6.287 | 1.802–21.938 | 4.645 | 1.314–16.423 | ||
| Other e | 3.581 | 0.692‐18.526 | 4.097 | 0.786–21.369 | ||
Abbreviations: HR, hazard ratio; CI, confidence interval; MPR, major pathologic response; ND, nodal downstaging; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
The meaning of bold values is two‐sided P < 0.05.
Variables with p value less than 0.05 were included in the multivariate analysis; ND and pathological N stage were not included in the multivariate analysis due to highly correlated with MPR + ND.
Other includes the MPR + non‐ND group, non‐MPR + ND group, and non‐MPR + non‐ND group.
Other includes six patients diagnosed as adenosquamous carcinoma, three patients diagnosed as large cell carcinoma, one patient diagnosed as carcinoid, and one patient diagnosed as lymphoepithelioma‐like carcinoma.
R0, microscopic complete resection; R1/R2, microscopic or macroscopic incomplete resection.6
Other includes etoposide‐based regimen and tegafur.
Univariate analysis of DFS demonstrated that MPR + ND, earlier pathological nodal staging, pneumonectomy, and gemcitabine/platinum as the NAC regimen were prognostic factors (Table 3). Multivariate analysis also confirmed that pneumonectomy and MPR + ND were favorable prognostic factors for DFS (Table 3).
TABLE 3.
Univariate and multivariate COX proportional hazard model analysis for disease‐free survival
| Risk factor for disease‐free survival | Univariate analysis | Multivariate analysis a | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| Age, years | 0.912 | |||||
| ≤60 | Ref | – | ||||
| >60 | 0.978 | 0.659–1.452 | ||||
| Sex | 0.393 | |||||
| Female | Ref | – | ||||
| Male | 0.830 | 0.542–1.272 | ||||
| Pathologic response | 0.129 | |||||
| MPR | Ref | – | ||||
| Non‐MPR | 1.524 | 0.885–2.624 | ||||
| ND | 0.105 | |||||
| Yes | Ref | – | ||||
| No | 1.356 | 0.938–1.961 | ||||
| Pathologic response + nodal status | 0.046 | 0.043 | ||||
| MPR + ND | Ref | – | Ref | – | ||
| Other b | 2.078 | 1.012‐4.265 | 2.127 | 1.335–2.973 | ||
| RECIST 1.1 response | 0.746 | |||||
| CR/PR | Ref | |||||
| SD | 1.158 | 0.783–1.712 | ||||
| PD | 1.184 | 0.555–2528 | ||||
| Smoking | 0.989 | |||||
| Nonsmoker | Ref | – | ||||
| Smoker | 1.003 | 0.684–1.471 | ||||
| Histology | 0.511 | |||||
| Adenocarcinoma | Ref | – | ||||
| Squamous cell carcinoma | 0.802 | 0.549–1.171 | ||||
| Other c | 0.830 | 0.333–2.069 | ||||
| Cell differentiation | 0.507 | |||||
| Well | Ref | – | ||||
| Moderately | 2.016 | 0.414–12.354 | ||||
| Poorly/undifferentiated | 2.987 | 0.494–20.524 | ||||
| Pathological T stage | 0.494 | |||||
| T1 | Ref | – | ||||
| T2 | 0.919 | 0.584–1.445 | ||||
| T3 | 1.227 | 0.736–2.047 | ||||
| T4 | 1.373 | 0.755–2.498 | ||||
| Pathological N stage | 0.010 | |||||
| N0 | Ref | – | ||||
| N1 | 1.172 | 0.701–1.959 | ||||
| N2 | 1.862 | 1.233–2.812 | ||||
| Type of resection | 0.001 | 0.001 | ||||
| Pneumonectomy | Ref | – | Ref | – | ||
| Nonpneumonectomy | 1.946 | 1.320–2.869 | 1.992 | 1.335–2.973 | ||
| Margin d | 0.059 | |||||
| R0 | Ref | – | ||||
| R1/R2 | 2.214 | 0.969–5.057 | ||||
| Neoadjuvant chemotherapy | 0.014 | 0.057 | ||||
| Gemcitabine/platinum | Ref | – | Ref | – | ||
| Pemetrexed/platinum | 3.117 | 1.312–7.403 | 3.128 | 1.317–7.433 | ||
| Paclitaxel/platinum | 2.064 | 0.893–4.770 | 2.206 | 0.953–5.106 | ||
| Vinorelbine/platinum | 5.427 | 1.736–16.961 | 3.914 | 1.238–12.368 | ||
| Other e | 3.351 | 0.675‐16.641 | 3.791 | 1.238–12.368 | ||
Abbreviations: HR, hazard ratio; CI, confidence interval; MPR, major pathologic response; ND, nodal downstaging; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
The meaning of bold values is two‐sided P < 0.05.
Variables with p value less than 0.05 were included in the multivariate analysis; pathological N stage was not included in the multivariate analysis due to highly correlated with MPR + ND.
Other includes the MPR + non‐ND group, non‐MPR + ND group, and non‐MPR + non‐ND group.
Other includes six patients diagnosed as adenosquamous carcinoma, three patients diagnosed as large cell carcinoma, one patient diagnosed as carcinoid, and one patient diagnosed as lymphoepithelioma‐like carcinoma.
R0, microscopic complete resection; R1/R2, microscopic or macroscopic incomplete resection.
Other includes etoposide‐based regimen and tegafur.
DISCUSSION
In this study, the response efficacy of NAC on NSCLC and the prognostic factors that may impact long‐term survival outcomes were investigated. The data demonstrated that MPR was not a independent prognostic factor for OS and DFS. However, when combining MPR with ND as one variable, it was predictive of prolonged OS and DFS. Multivariate analysis also confirmed that MPR + ND independently favored long‐term survival. Based on these findings, we proposed that a combination of MPR and ND could improve the efficacy of predicting long‐term survival in resected NSCLC with NAC, and this may help us to select the patient subset with the most favorable prognosis.
The definition of pathologic response after NAC in resected NSCLC has shifted from pathologic complete response (pCR) to MPR in recent years. MPR, defined as 10% or less residual viable tumor, has been considered a promising surrogate endpoint to predict long‐term outcomes in NSCLC patients who received NAC. 4 , 5 Pataer et al. performed a comprehensive analysis of 192 resected stage I‐III NSCLC patients treated with NAC and demonstrated that 10% or fewer of viable tumors were significantly associated with a reduced hazard of overall death, compared with more than 10% of viable tumors. 5 In a prospective trial of NAC with bevacizumab in patients with nonsquamous NSCLC, the association between MPR and long‐term outcomes was again demonstrated. 16 Based on these results, MPR was proposed as a potential surrogate endpoint for survival in NSCLC patients treated with NAC. 4 However, discrepancies also existed in the prediction of MPR for survival in this population. In the study by Qu et al., 7 the authors revealed that MPR was not significantly associated with better survival in the ADC subset. In addition, Thomas et al. also presented a relatively large study of 524 patients with stage IIIA/IIIB NSCLCs who received neoadjuvant chemotherapy alone or chemoradiotherapy prior to surgical resection and suggested that less than 10% viable tumor cell was not correlated with survival. 8
In this study, the occurrence of MPR was 16.5% in the entire cohort, which was similar to previous studies. 7 , 11 , 17 Although the 5‐year OS and DFS were better in the MPR group than in the non‐MPR group in this study, the survival difference was not statistically significant. Two possible reasons may explain this result. First, this may be due to the small sample size of the MPR group (32 cases). Second, the impact of MPR on long‐term survival was not strong enough to reach a statistically significant difference. We therefore proposed that a combination of MPR with other prognostic variables may enable us to improve the predictive efficacy of patients' prognosis. In further analyses, we identified that SCC was associated with a higher probability of MPR occurrence, which could help us to select candidates that might benefit from NAC.
As noted by Travis et al., 18 the response to neoadjuvant treatment may vary between the primary tumor and the metastases of lymph nodes. In some cases, the primary tumor reached MPR after NAC because there was little viable tumor in the primary tumor bed, but there were still substantial viable metastatic tumor cells in the lymph nodes. It is therefore quite challenging to define the effect of NAC just by primary tumor response to treatment. We therefore hypothesized that a combination of MPR and ND may improve the efficacy in identifying the most favorable prognosis patient subset. It is not surprising that patients who achieved both MPR and ND had the best survival outcomes, followed by those with only ND but not MPR. These findings confirmed our hypothesis that a combination of MPR and ND did work better to predict long‐term survival and could help to select the patients who enjoy higher levels of survival.
In recent years, immune check‐point inhibitors have revolutionized the treatment strategy of advanced NSCLC and made the long‐term survival of metastatic NSCLC patients to become a reality. 19 , 20 , 21 , 22 , 23 These promising achievements have further ignited interests in the field of neoadjuvant treatment in resectable NSCLC. PD‐1/PD‐L1 blockade, alone or combined with chemotherapy or anti‐CTLA4 inhibitor, have proved the feasibility and safety as neoadjuvant treatment in resectable NSCLC. More importantly, very promising efficacy (both radiological and pathological) has been presented, with MPR rates of 19–85%. 19 , 21 , 24 , 25 Several neoadjuvant trials have set the MPR rate as the primary endpoint, 19 , 21 and controversy arises in terms of the replacement of MPR for survival in resectable NSCLC patients. Our data demonstrated that the prognosis predictive value of MPR + ND was superior than that of MPR alone. We hope that some future perspective studies could verify our assumption and furthermore integrate into neoadjuvant immunotherapy trials which select MPR other than survival as the primary endpoint.
Our study also had limitations. First, the case number of patients with MPR was small, so data from other centers are warranted to verify our results. Second, the study period was between 2001 and 2014, and EUS or mediastinoscopy was not routinely administered to every patient during this period in our center. Some patients' nodal categories were therefore determined only by imaging but not pathological evaluations. Stage migration may therefore exist in this series. In clinical practice to date, however, patients who received invasive mediastinal lymph node staging before treatments are still in the minority. 26 , 27 , 28 , 29 , 30 , 31 Herein, we proposed that pathological evaluations for nodal staging should be mandatorily performed before treatment for patients who are scheduled to receive neoadjuvant treatment.
In conclusion, our data suggested that a combination of MPR and ND could improve the efficacy of predicting OS and DFS in operable NSCLC patients who received NAC, which could help clinicians identify the patient subset with the most favorable prognosis, and this may shed light on personal surveillance and treatment.
CONFLICT OF INTEREST
The authors have no conflict of interest to disclose.
Supporting information
Supporting Information Table S1 Neoadjuvant chemotherapy‐related toxicity
Supporting Information Table S2 The median survival time, 5‐year OS rate, and 5‐year DFS rate of the MPR group and the non‐MPR group, the ND group and the non‐ND group.
Supporting Information Table S3 The median survival time, 5‐year OS rate, and 5‐year DFS rate of the MPR + ND group, MPR + non‐ND group, non‐MPR + ND group and non‐MPR + non‐ND group
ACKNOWLEDGMENTS
We thank Elsevier (http://cn.webshop.elsevier.com) for its language editing assistance. This work was supported by the Sun Yat‐sen University Clinical Research 5010 Program (2019012, ChiCTR2000034737), the Natural Science Foundation of Guangdong Province (2018A030313410, 2020A151501311), the National Natural Science Foundation of China (82072572), the Sun Yat‐sen University Young Teacher Plan (19ykpy179), and the Guangzhou Science and Technology Program (202002020074).
Cai J‐S, Li S, Yan S‐M, et al. Is major pathologic response sufficient to predict survival in resectable nonsmall‐cell lung cancer patients receiving neoadjuvant chemotherapy? Thorac Cancer. 2021;12:1336–1346. 10.1111/1759-7714.13903
[Correction added on 31 March 2021, after first online publication: the symbol ‘†’ has been added to Jing‐Sheng Cai, Shuo Li, and Shu‐Mei Yan to indicate that they contributed equally to this paper.]
Funding information the National Natural Science Foundation of China, Grant/Award Number: 82072572; the Guangzhou Science and Technology Program, Grant/Award Number: 202002020074; the Natural Science Foundation of Guangdong Province, Grant/Award Numbers: 2018A030313410, 2020A151501311; the Sun Yat‐sen University Clinical Research 5010 Program, Grant/Award Numbers: 2019012, ChiCTR2000034737; the Sun Yat‐sen University Young Teacher Plan, Grant/Award Number: 19ykpy179
Contributor Information
Hao‐Xian Yang, Email: yanghx@sysucc.org.cn.
Xue Hou, Email: houxue@sysucc.org.cn.
REFERENCES
- 1. Song WA, Zhou NK, Wang W, Chu XY, Liang CY, Tian XD, et al. Survival benefit of neoadjuvant chemotherapy in non‐small cell lung cancer: An updated meta‐analysis of 13 randomized control trials. J Thorac Oncol. 2010;5:510–6. [DOI] [PubMed] [Google Scholar]
- 2. Burdett S, Stewart LA, Rydzewska L. A systematic review and meta‐analysis of the literature: Chemotherapy and surgery versus surgery alone in non‐small cell lung cancer. J Thorac Oncol. 2006;1:611–21. [PubMed] [Google Scholar]
- 3. Berghmans T, Paesmans M, Meert AP, Mascaux C, Lothaire P, Lafitte JJ, et al. Survival improvement in resectable non‐small cell lung cancer with (neo)adjuvant chemotherapy: Results of a meta‐analysis of the literature. Lung Cancer. 2005;49:13–23. [DOI] [PubMed] [Google Scholar]
- 4. Hellmann MD, Chaft JE, William WN Jr, Rusch V, Pisters KM, Kalhor N, et al. Pathological response after neoadjuvant chemotherapy in resectable non‐small‐cell lung cancers: Proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol. 2014;15:e42–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Pataer A, Kalhor N, Correa AM, Raso MG, Erasmus JJ, Kim ES, et al. Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol. 2012;7:825–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Corsini EM, Weissferdt A, Pataer A, Zhou N, Antonoff MB, Hofstetter WL, et al. Pathological nodal disease defines survival outcomes in patients with lung cancer with tumour major pathological response following neoadjuvant chemotherapy. Eur J Cardiothorac Surg. 2021;59:100–108. [DOI] [PubMed] [Google Scholar]
- 7. Qu Y, Emoto K, Eguchi T, Aly RG, Zheng H, Chaft JE, et al. Pathologic assessment after neoadjuvant chemotherapy for NSCLC: Importance and implications of distinguishing adenocarcinoma from squamous cell carcinoma. J Thorac Oncol. 2019;14:482–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Thomas M, Rube C, Hoffknecht P, Macha HN, Freitag L, Linder A, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: A randomised trial in stage III non‐small‐cell lung cancer. Lancet Oncol. 2008;9:636–48. [DOI] [PubMed] [Google Scholar]
- 9. van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA‐N2 non‐small‐cell lung cancer. J Natl Cancer Inst. 2007;99:442–50. [DOI] [PubMed] [Google Scholar]
- 10. Jaklitsch MT, Herndon JE 2nd, DeCamp MM Jr, Richards WG, Kumar P, Krasna MJ, et al. Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non‐small cell lung cancer in CALGB protocol #8935. J Surg Oncol. 2006;94:599–606. [DOI] [PubMed] [Google Scholar]
- 11. Betticher DC, Hsu Schmitz SF, Totsch M, Hansen E, Joss C, Von Briel C, et al. Mediastinal lymph node clearance after docetaxel‐cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non‐small‐cell lung cancer: A multicenter phase II trial. J Clin Oncol. 2003;21:1752–9. [DOI] [PubMed] [Google Scholar]
- 12. Yang HX, Woo KM, Sima CS, Bains MS, Adusumilli PS, Huang J, et al. Long‐term survival based on the surgical approach to lobectomy for clinical stage I nonsmall cell lung cancer: Comparison of robotic, video‐assisted thoracic surgery, and thoracotomy lobectomy. Ann Surg. 2017;265:431–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. [DOI] [PubMed] [Google Scholar]
- 14. Yang MZ, Hou X, Li JB, Cai JS, Yang J, Li S, et al. Impact of L4 lymph node dissection on long‐term survival in left‐side operable non‐small‐cell lung cancer: A propensity score matching study. Eur J Cardiothorac Surg. 2020;57:1181–8. [DOI] [PubMed] [Google Scholar]
- 15. Yang HX, Hou X, Lin P, Rong TH, Yang H, Fu JH. Survival and risk factors of surgically treated mediastinal invasion T4 non‐small cell lung cancer. Ann Thorac Surg. 2009;88:372–8. [DOI] [PubMed] [Google Scholar]
- 16. Murakami S, Saito H, Kondo T, Oshita F, Yamada K. Phase II study of bevacizumab, cisplatin, and pemetrexed in advanced non‐squamous non‐small cell lung cancer (NS‐NSCLC) with EGFR wild‐type. J Exp Ther Oncol. 2019;13:131–8. [PubMed] [Google Scholar]
- 17. Chaft JE, Rusch V, Ginsberg MS, Paik PK, Finley DJ, Kris MG, et al. Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non‐small‐cell lung cancers. J Thorac Oncol. 2013;8:1084–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Travis WD, Dacic S, Wistuba I, Sholl L, Adusumilli P, Bubendorf L, et al. IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. J Thorac Oncol. 2020;15:709–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Shu CA, Gainor JF, Awad MM, Chiuzan C, Grigg CM, Pabani A, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non‐small‐cell lung cancer: An open‐label, multicentre, single‐arm, phase 2 trial. Lancet Oncol. 2020;21:786–95. [DOI] [PubMed] [Google Scholar]
- 20. Reck M, Rodriguez‐Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Updated analysis of KEYNOTE‐024: Pembrolizumab versus platinum‐based chemotherapy for advanced non‐small‐cell lung cancer with PD‐L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37:537–46. [DOI] [PubMed] [Google Scholar]
- 21. Cascone T, William WN, Weissferdt A, Lin HY, Leung CH, Carter BW, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non‐small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol. 2019;37:2. [Google Scholar]
- 22. Paz‐Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non‐small‐cell lung cancer. N Engl J Med. 2018;379:2040–51. [DOI] [PubMed] [Google Scholar]
- 23. Gandhi L, Rodriguez‐Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non‐small‐cell lung cancer. N Engl J Med. 2018;378:2078–92. [DOI] [PubMed] [Google Scholar]
- 24. Provencio M, Nadal E, Insa A, García‐Campelo MR, Casal‐Rubio J, Dómine M, 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. 2020;21:1413–22. [DOI] [PubMed] [Google Scholar]
- 25. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Neoadjuvant PD‐1 blockade in resectable lung cancer. N Engl J Med. 2018;378:1976–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Haager B, Wiesemann S, Passlick B, Schmid S. Prognostic value of lymph node ratio after induction therapy in stage IIIA/N2 non‐small cell lung cancer: A monocentric clinical study. J Thorac Dis. 2018;10:3225–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Remark R, Lupo A, Alifano M, Biton J, Ouakrim H, Stefani A, et al. Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients. Onco Targets Ther. 2016;5:e1255394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Renaud S, Falcoz PE, Olland A, Reeb J, Santelmo N, Massard G. Mediastinal downstaging after induction treatment is not a significant prognostic factor to select patients who would benefit from surgery: The clinical value of the lymph node ratio. Interact Cardiovasc Thorac Surg. 2015;20:222–7. [DOI] [PubMed] [Google Scholar]
- 29. Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non‐small‐cell lung cancer: A phase 3 randomised trial. Lancet. 2015;386:1049–56. [DOI] [PubMed] [Google Scholar]
- 30. Marulli G, Verderi E, Zuin A, Schiavon M, Battistella L, Perissinotto E, et al. Outcomes and prognostic factors of non‐small‐cell lung cancer with lymph node involvement treated with induction treatment and surgical resection. Interact Cardiovasc Thorac Surg. 2014;19:256–62; discussion 62. [DOI] [PubMed] [Google Scholar]
- 31. Katakami N, Tada H, Mitsudomi T, Kudoh S, Senba H, Matsui K, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer. 2012;118:6126–35. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information Table S1 Neoadjuvant chemotherapy‐related toxicity
Supporting Information Table S2 The median survival time, 5‐year OS rate, and 5‐year DFS rate of the MPR group and the non‐MPR group, the ND group and the non‐ND group.
Supporting Information Table S3 The median survival time, 5‐year OS rate, and 5‐year DFS rate of the MPR + ND group, MPR + non‐ND group, non‐MPR + ND group and non‐MPR + non‐ND group