# Survival of clinical stage III NSCLC according to therapeutic strategy: Relevance of the tumor board decision in the era of immunotherapy

Justin Benet, Anne-Claire Toffart, Pierre-Yves Brichon, Thibaut Chollier, Stéphane Ruckly, Julie Villa, Camille Emprou, Thomas Pierret, Isabelle Dumas, Gilbert Ferretti, et al.

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Justin Benet, Anne-Claire Toffart, Pierre-Yves Brichon, Thibaut Chollier, Stéphane Ruckly, et al. Survival of clinical stage III NSCLC according to therapeutic strategy: Relevance of the tumor board decision in the era of immunotherapy. Cancer Treatment and Research Communications, 2022, 30, pp.100508. 10.1016/j.ctarc.2021.100508. inserm-05216941

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# Survival of clinical stage III NSCLC according to therapeutic strategy: Relevance of the tumor board decision in the era of immunotherapy

Justin Benet<sup>a, *</sup>, Anne-Claire Toffart<sup>a, b</sup>, Pierre-Yves Brichon<sup>a</sup>, Thibaut Chollier<sup>a</sup>, Stéphane Ruckly<sup>c</sup>, Julie Villa<sup>a</sup>, Camille Emprou<sup>a, b</sup>, Thomas Pierret<sup>a</sup>, Isabelle Dumas<sup>a</sup>, Gilbert Ferretti<sup>a, b</sup>, Denis Moro-Sibilot<sup>a, b</sup>, Matteo Giaj Levra<sup>a, b, 1</sup>

## ARTICLE INFO

### Keywords:

- Non-small-cell lung cancer

- Stage III disease

- Multidisciplinary tumor board

- Survival

## ABSTRACT

**Introduction:** Stage III NSCLC comprises a heterogeneous population. Different treatment strategies are available, including surgery, radiotherapy, and chemotherapy. The PACIFIC trial results represented a significant change and improvement in the therapeutic strategy for these patients. We aimed to compare the different treatment strategies employed in Stage III NSCLC patients within our institution.

**Methods:** All Stage III NSCLC patients discussed during the weekly thoracic oncology multidisciplinary team meetings at the University hospital Grenoble Alpes (France) between January 2010 and January 2017 were included. Patients' overall survival (OS) according to treatment strategies along with their respective changes were compared.

**Results:** Overall, 476 patients were identified. Among patients initially scheduled to receive neoadjuvant chemotherapy followed by surgery (n = 60), only 37 (62%) actually underwent surgery. Median OS of the cohort was 21.3 months [IQR 25%-75%: 9.6-48.3]. Patients who received neoadjuvant chemotherapy followed by surgery displayed better survival than those treated by CT-RT: 53.2 months [IQR 25%-75%: 16.1-87.3] versus 23.9 [IQR 25%-75%, 13.3-48.1]. Survival was slightly superior for patients treated by upfront CT-RT than for those planned for neoadjuvant chemotherapy followed by surgery who eventually converted to CT-RT (current or sequential): 23.9 months [IQR 25%-75%: 13.3-48.1] versus 20.4 [IQR 25%-75%:10.8-36], respectively.

**Conclusion:** While patients who underwent neoadjuvant chemotherapy followed by surgery displayed a better survival than those treated using CT-RT, switch from surgery to CT-RT actually shortened survival. These results stress the relevance of the tumor board in deciding which is the best therapeutic strategy for Stage III disease patients.

## 1. Introduction

Stage III non-small-cell lung cancers (NSCLCs) represent about one-third of NSCLCs, all stages included [1]. According to the 8th edition of the TNM classification for lung cancer [2], locally advanced NSCLCs represent a heterogeneous population, in which Stages IIIA, IIIB, and IIIC are distinguished depending on the loco-regional disease extension.

Different treatment strategies are available, including surgery, radiotherapy, and chemotherapy, which are mostly given in

combination, either sequentially or concurrently. Given this heterogeneity, this stage clearly requires, even more than the others, a multidisciplinary discussion and approach. This kind of approach is forcefully recommended by international guidelines [3].

The standard of care for patients with good Eastern Cooperative Oncology Group performance status (ECOG-PS) and unresectable Stage III NSCLC is a platinum-based doublet chemotherapy with concurrent radiotherapy (CT-RT). Indeed, concurrent CT-RT has been proven superior to the sequential approach in terms of overall survival (OS) (23.8% of patients alive at 3 years versus 18.1%, hazard ratio [HR]:

<footnote><sup>a</sup> Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, 38700 France</footnote>

<footnote><sup>b</sup> Institute for Advanced Biosciences INSERM U1209 CNRS UMR5309 Université Grenoble Alpes, Grenoble, France</footnote>

<footnote><sup>c</sup> ICUREsearch, Paris, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: jbenet@chu-grenoble.fr (J. Benet).</footnote>

<footnote n="1">¹ for the Multidisciplinary Thoracic Oncology Group Grenoble University Hospital France</footnote>
## Abbreviations

95%CI 95% confidence interval

CT-RT Chemo-radiotherapy

ECOG-PS Eastern Cooperative Oncology Group performance status

HR Hazard ratio

NSCLC, Non-small-cell lung cancer

OS Overall survival

PD-L1 Programmed cell death protein ligand-1

PFS Progression-free survival.

0.84) and progression-free survival (PFS) (HR: 0.90; 95% confidence interval [CI]: 0.79–1.01; P = 0.07) [1].

Based on a literature review, Ramnath et al. highlighted that neoadjuvant chemotherapy followed by surgery did not show any clear benefits in terms of OS compared with definitive CT-RT in this setting [4].

Despite these efforts to optimally handle Stage III disease patients, until a few years ago, these patients' prognosis was poor, with a median PFS of 8 months and only 15% of patients still alive at 5 years [1,5].

A significant change and improvement in the therapeutic strategy came along in 2017, with the publishing of the PACIFIC trial results. These data disclosed a clear benefit of adding durvalumab, an anti-programmed cell death protein ligand-1 (anti-PD-L1) agent, following concurrent CT-RT [6]. The 24-month OS rate was 66.3% (95% CI: 61.7–70.4) in the durvalumab group versus (vs.) 55.6% (95% CI: 48.9–61.8) in the placebo one (two-sided P = 0.005). The median PFS was 17.2 months in the durvalumab arm and 5.6 months in the placebo one (HR: 0.51; 95% CI: 0.41–0.63) [7]. Today, the addition of durvalumab after concurrent CT-RT has become the standard of care.

Given the recent changes and novelties in Stage III disease treatments, we decided to compare the different treatment strategies in Stage III NSCLC patients within our institution, in addition to their impact on patients' survival.

# 2. Material and methods

## 2.1. Study design and patients

This is a retrospective monocentric study. All Stage III NSCLC patients discussed during the weekly thoracic oncology multidisciplinary team meetings at the University hospital Grenoble Alpes (France) between January 2010 and January 2017 were included. The TNM stages were based on the 7th TNM classification [8], which was applied at that time. An information letter was sent to each living patient, with an exemption from the obligation to inform deceased patients guaranteed by CNIL (the French data protection agency). The primary study objective was to compare the survival of patients who received surgery after neoadjuvant chemotherapy against that of patients treated using concurrent or sequential CT-RT. Secondary objectives were to record strategy changes, assess the percentage of patients who underwent surgery after neoadjuvant chemotherapy, and compare patients' characteristics according to the treatments received.

## 2.2. Data collection

The following clinical data were collected at the time of diagnosis: gender, age, ECOG-PS [9], smoking history, and cancer characteristics consisting of histology and disease stage. The TNM stages recorded were those applied at the time of the multidisciplinary tumor board. PD-L1 expression of the patient's tumor was not available. Each treatment received, including chemotherapy, radiotherapy, and surgery, was

recorded. Follow-up was completed for all patients in January 2019.

All procedures performed in the study were in accordance with the ethical standards of the Helsinki Declaration. No Institutional Review Boards (IRB) evaluation was required due to the retrospective nature of the study. All data were anonymized and the « Commission Nationale de l'Informatique et des Libertés de France » (CNIL) declaration was provided accorded to French law.

## 2.3. Statistical analysis

Data were expressed as number (percentage) for qualitative variables and median (interquartile range [IQR]: 25%–75%) for quantitative variables. For each treatment group, point estimates of the survival times' quartiles were computed. Survivals curves were plotted using Kaplan Meier methodology and compared via log-rank testing. T0 was defined as the treatment start. All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

# 3. Results

## 3.1. Patients' characteristics at the multidisciplinary meeting

A total number of 476 patients were identified, 411 of whom were included in the analysis (Fig. 1). Patients were classified according to the planned or performed treatment. Patients' characteristics are summarized in Table 1. Median age was 65 years [IQR 25%–75%: 58–72], with 101 (25%) being women. The majority of patients exhibited an adenocarcinoma (n = 199, 48%) or squamous cell carcinoma (n = 166, 41%).

After initial discussion, 34% (n = 141) were scheduled to undergo upfront surgery, 19% (n = 78) to be administered CT-RT (concurrent or sequential), 16% (n = 63) to receive exclusive systemic treatment (chemotherapy or targeted therapy), and 15% (n = 60) to undergo neoadjuvant chemotherapy followed by surgery. (Fig. 1)

## 3.2. Therapeutic strategies

### 3.2.1. Upfront surgery

Half of clinical Stage IIIA patients were treated using upfront surgery (n = 126, 51%), which was followed or not by adjuvant chemotherapy or adjuvant CT-RT. In Stage IIIB patients who benefited from upfront surgery, this was accounted for by the disease being clinically classified as cT4N2 or because it was down-staged after mediastinoscopy (Table 1). The pTNM classification revealed that 27 patients actually were Stage I or II (Table 2).

### 3.2.2. Neoadjuvant chemotherapy followed by surgery

For patients treated with neoadjuvant chemotherapy followed by surgery, the decision to perform neoadjuvant chemotherapy has always been made within the tumor board at the beginning of the patients' management. Most patients treated with neoadjuvant chemotherapy followed by surgery exhibited a squamous cell carcinoma (n = 21; 57%) and Stage IIIA disease (n = 25; 68%). Few Stage IIIB patients received neoadjuvant chemotherapy followed by surgery (n = 12, 7%). In these cases, either the disease had been clinically staged as cT4N2 or a downstaging occurred after the first neoadjuvant chemotherapy cycles. Among patients scheduled to receive neoadjuvant chemotherapy followed by surgery (n = 60), only 37 (62%) actually underwent surgery, while the others were switched to either CT-RT (n = 13) or exclusive chemotherapy (n = 10) (Fig. 1). Among patients initially scheduled for neoadjuvant chemotherapy and finally switched to sequential or concurrent CT-RT (n = 13), in 9 cases of them, the switch was due to unresectable disease (6 stable and 3 progressive diseases after initial chemotherapy). For the last 4 patients, the treatment strategy was changed due to clinical condition worsening, rendering them ineligible for surgery. Among patients shifted for exclusive chemotherapy (n = 10), three displayed PS worsening, 3 progressive diseases after
<figure><img src="image_5.png" /><figcaption>Fig. 1. Planned and received treatments.NSCLC, non-small-cell lung cancer; RT-CT, radio-chemotherapy.</figcaption></figure>

chemotherapy, and four died prematurely.

### 3.2.3. Chemo-radiotherapy

Patients treated using CT-RT (n = 69) were mostly Stage IIIB (n = 46, 66%), with adenocarcinomas (n = 39, 57%). Those treated by concurrent CT-RT included more N3 (n = 13, 50%) involvement than those treated using sequential CT-RT (n = 17, 40%).

After CT-RT, 4 patients finally underwent surgery. Including patients scheduled for neoadjuvant chemotherapy, overall, 86 were treated using

CT-RT, notably 21% of all Stages III and 32% of Stages III who did not benefit upfront from surgery upfront. Thirty-two (37%) patients benefited from concurrent CT-RT. Among patients scheduled for CT-RT, 5 did not receive radiotherapy due to worsening clinical conditions that contraindicated RT.

### 3.2.4. Systemic treatments and radiotherapy

Systemic treatments are reported in Table 3. Neoadjuvant treatment was preferentially a platinum-/taxane-based chemotherapy. In
<table><caption>**Table 1**

Patient characteristics according to performed treatment.</caption><thead><tr><th></th><th>Total<br>(N = 411)</th><th>Concurrent chemo-<br>radiotherapy upfront (N = 26)</th><th>Sequential chemo-<br>radiotherapyupfront (N = 43)</th><th>Neoadjuvant chemotherapy<br>followed by surgery (N = 37)</th><th>Surgery upfront<br>(N = 141)</th></tr></thead><tbody><tr><td>Female</td><td>101 (25)</td><td>5 (19)</td><td>12 (28)</td><td>8 (22)</td><td>41 (29)</td></tr><tr><td>Age</td><td>65 [58; 72]</td><td>58 [55; 62]</td><td>65 [59; 75]</td><td>59 [53; 65]</td><td>64 [58; 71]</td></tr><tr><td>Number of<br>comorbidities</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0-1</td><td>183 (45)</td><td>14 (54)</td><td>22 (51)</td><td>27 (73)</td><td>63 (45)</td></tr><tr><td>2-3</td><td>157 (38)</td><td>8 (31)</td><td>16 (37)</td><td>7 (19)</td><td>54 (38)</td></tr><tr><td>4-5</td><td>71 (17)</td><td>4 (15)</td><td>5 (12)</td><td>3 (8)</td><td>24 (17)</td></tr><tr><td>Histology</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>-Adenocarcinoma</td><td>199 (48)</td><td>14 (54)</td><td>25 (58)</td><td>13 (35)</td><td>80 (57)</td></tr><tr><td>-Squamous cell<br>carcinoma</td><td>166 (41)</td><td>10 (38)</td><td>13 (30)</td><td>21 (57)</td><td>53 (38)</td></tr><tr><td>-Other NSCLC</td><td>46 (11)</td><td>2 (8)</td><td>5 (12)</td><td>3 (8)</td><td>8 (6)</td></tr><tr><td>ECOG-PS (miss,<br>n = 18)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>-0</td><td>48 (11)</td><td>2 (8)</td><td>3 (9)</td><td>2 (5)</td><td>24 (18)</td></tr><tr><td>-1</td><td>222 (54)</td><td>18 (69)</td><td>28 (73)</td><td>25 (68)</td><td>82 (63)</td></tr><tr><td>-2</td><td>89 (22)</td><td>4 (16)</td><td>7 (18)</td><td>10 (27)</td><td>23 (18)</td></tr><tr><td>-3/4</td><td>34 (8)</td><td>1 (7)</td><td>0 (0)</td><td>0 (0)</td><td>2 (2)</td></tr><tr><td>-Stage IIIA</td><td>249 (61)</td><td>5 (19)</td><td>18 (42)</td><td>25 (68)</td><td>126 (89)</td></tr><tr><td>N0</td><td>42 (17)</td><td>0 (0)</td><td>3 (17)</td><td>2 (8)</td><td>21 (15)</td></tr><tr><td>N1</td><td>33 (13)</td><td>4 (80)</td><td>1 (6)</td><td>2 (8)</td><td>16 (11)</td></tr><tr><td>N2</td><td>174 (70)</td><td>1 (20)</td><td>14 (77)</td><td>21 (84)</td><td>72 (51)</td></tr><tr><td>-Stage IIIB</td><td>162 (39)</td><td>21 (81)</td><td>25 (58)</td><td>12 (32)*</td><td>15 (11)**</td></tr><tr><td>N2</td><td>58 (33)</td><td>8 (38)</td><td>8 (32)</td><td>8 (67)</td><td>5 (4)</td></tr><tr><td>N3</td><td>104 (64)</td><td>13 (62)</td><td>17 (68)</td><td>4 (33)</td><td>10 (7)</td></tr></tbody></table>

Data are expressed as median [IQR] for quantitative variables and as number (percentage) for qualitative variables; NSCLC, non-small-cell lung carcinoma; PS, performance status.

*Ct4N2: N = 8; Ct2-3N3: down staging after the firsts cycles of chemotherapy allowing surgery: N = 4.

**Ct4N2: N = 5; CT1-2-3N3: down staging after mediastinoscopy N = 6 or new TDM N = 2; Ct3-4N3 without downstaging: N = 2.

<table><caption>**Table 2**

Patients treated using upfront surgery.</caption><thead><tr><th>Total</th><th>cTNM141</th><th>pTNM141</th></tr></thead><tbody><tr><td>-Stage IIIA</td><td>126 (89)</td><td>105 (74)</td></tr><tr><td>N0</td><td>21 (15)</td><td>21 (15)</td></tr><tr><td>N1</td><td>16 (11)</td><td>16 (11)</td></tr><tr><td>N2</td><td>72 (51)</td><td>51 (36)</td></tr><tr><td>-Stage IIIB</td><td>15 (11)</td><td>9 (6)</td></tr><tr><td>N2</td><td>5 (4)</td><td>5 (4)</td></tr><tr><td>N3</td><td>10 (7)</td><td>4 (2)</td></tr><tr><td>Stage I or II</td><td>0 (0)</td><td>27 (20)</td></tr><tr><td>Adjuvant radiotherapy</td><td>0 (0)</td><td>12 (9)</td></tr></tbody></table>

cTNM, clinical TNM classification; pTNM, pathological TNM classification.

concurrent CT-RT cases, the preferred choice was a platinum doublet with vinorelbine [1]. Concerning radiotherapy, the great majority of patients treated using CT-RT received 66 gray in 33 fractions.

### 3.3. Survival of patients

Median follow up was 14.6 months [IQR 25%–75%, 7.0 – 25.5] for deceased patients and 39.5 months [IQR 25%–75%, 23.6 – 57.7] for survivors, with a median OS of 21.3 months [IQR 25%–75%: 9.6–48.3] (Table 4). Patients treated by upfront surgery exhibited a survival of 40.2 months (IQR 25%–75%: 21.7–98.6). Patients scheduled for neoadjuvant chemotherapy followed by surgery displayed better survival than those planned for CT-RT upfront, with a median OS of 53.2 months [IQR 25%–75%: 16.1–87.3] and 23.9 months [IQR 25%–75%: 13.3–48.1], respectively. Survival was slightly superior for patients treated using upfront CT-RT than for those planned for neoadjuvant chemotherapy followed by surgery, who eventually switched to concurrent or sequential CT-RT, with a median OS of 23.9 months [IQR 25%–75%: 13.3–48.1] and 20.4 months [IQR 25%–75%: 10.8–36], respectively (Fig. 2). The 4 patients (5%) who underwent surgery after CT-RT exhibited a survival of 13.8 months [IQR 25%–75%: 9.6–not

reached]. These patients quickly suffered from complications. Of these, three patients developed early brain metastasis (median time to progression: 4.3 months ± 1), while the remaining patient died from a post-operative complication consisting of hemorrhagic shock.

### 4. Discussion

This large cohort in real-life settings evaluated the therapeutic landscape used to treat Stage III NSCLC patients. Only 12% (n = 32) of patients who did not benefit from upfront surgery were treated using concurrent CT-RT. Stage III patients who could benefit from surgery displayed a better survival: 40 months in the case of upfront surgery or 53 months in the case of surgery conducted after neoadjuvant chemotherapy. Patients treated using CT-RT demonstrated an acceptable survival regardless of whether they were initially scheduled for either neoadjuvant chemotherapy (20 months) or CT-RT (24 months). In our cohort, patients who benefited from lung surgery displayed a better survival, which clearly confirms that surgical treatment, whenever possible, remains the sole curative therapy in NSCLC.

The strength of our study is the wide variety of data recorded, including ECOG PS at the time of tumor board, planned treatment strategies, as well as treatments actually delivered. Moreover, the reasons for treatment changes were similarly reported. Finally, the size of the whole cohort appears substantial, in spite of this single center experience. During the 7 years of inclusion of the patients, we could observe a certain stability of the therapeutic strategies over time. The only thing that could be different is the improvement of mediastinal staging by EBUS. However, almost no patient benefited from endoscopic management during the inclusion period in our cohort. This point gives our study a certain constancy in the selection of patients and in the choice of different treatments. The study weaknesses include the low number of patients in each subgroup and single center nature of this study, which do not enable us to compare different habits in regard to the therapeutic disease approach, thereby limiting the results' generalizability. The absence of PD-L1 expression can also be considered
<table><caption>**Table 3**
Systemic treatment received.</caption><thead><tr><th rowspan="2">Type of chemotherapy</th><th colspan="2">Treatment strategies</th><th rowspan="2">Neoadjuvant chemotherapy</th><th rowspan="2">Sequential chemo-radiotherapy</th><th rowspan="2">Concurrent chemo-radiotherapy</th></tr><tr><th>Exclusive systemic treatment</th><th>Exclusive systemic treatment</th></tr></thead><tbody><tr><td>Platinum doublet with paclitaxel</td><td>25 (37%)</td><td>6 (10%)</td><td>16 (37%)</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Platinum doublet with pemetrexed</td><td>13 (19%)</td><td>4 (6%)</td><td>10 (23%)</td><td>2 (8%)</td><td>2 (8%)</td></tr><tr><td>Platinum doublet with etoposide</td><td>3 (4%)</td><td>1 (2%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Platinum doublet with vinorelbine</td><td>3 (4%)</td><td>9 (15%)</td><td>11 (26%)</td><td>24 (92%)</td><td>0 (0%)</td></tr><tr><td>Platinum doublet with gemcitabine</td><td>8 (12%)</td><td>9 (15%)</td><td>2 (5%)</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Platinum doublet with docetaxel</td><td>12 (18%)</td><td>31 (52%)</td><td>4 (9%)</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Targeted therapies</td><td>4 (6%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td></tr></tbody></table>

Data were expressed as n (%).

a weakness. Yet, until the PACIFIC study was published, the PD-L1 status played no role in the therapeutic choices. Moreover, in the 4-year survival study with durvalumab published by C. Faivre-Finn, patient enrolment was not restricted to PD-L1 expression either [10]. Finally, in our study, it is impossible to separate the role of baseline prognosis and the role of treatment in determining overall survival. Thus, all comparisons are descriptive and exploratory.

Our population exhibits quite similar characteristics in terms of median age, gender ratio, and Stage IIIA and IIIB numbers in comparison with those reported in the PACIFIC study and other published series, as well [6,11]. Among all patients, 82 (20%) were treated using CT-RT, with 32 (8%) receiving concurrent and 50 (12%) sequential treatments. These data are comparable with those of a study published by Yusuf et al. [11] describing the treatments received in a NSCLC Stage III population, showing that only 11.6% of all patients received concurrent CT-RT.

The median survival of patients scheduled for CT-RT was slightly higher versus that of those who were scheduled for neoadjuvant chemotherapy followed by surgery, yet finally switched to CT-RT. Although large tumors without mediastinal nodes are usually operated on, the precise role of surgery in the treatment of Stage IIIA disease patients with mediastinal involvement (T1–3N2M0) is a continuous topic of discussion, with contradictory study results. When comparing

surgery with CT-RT for Stage IIIA-N2, such randomized controlled trials have usually revealed no significant differences in terms of OS. In a recent cumulative meta-analysis, Pöttgen et al. [12] overall evaluated surgery within multimodality treatment settings vs. CT-RT in Stage III NSCLC patients. This paper included 6 trials in addition to the ESPATUE [13] study, which also included Stage IIIA (N2) and Stage IIIB (N3) patients. In this study, no OS difference was found between the 2 arms (HR: 0.92 [95% CI: 0.82–1.04], *p* = 0.19). Albain et al. [14] reported a significant improvement in PFS when using surgery (median 12.8 months vs. 10.5, HR: 0.77), whereas OS was not significantly improved in the surgical arm (median 23.6 months vs. 22.2, HR: 0.87). In a recent Canadian study [15], the performance of surgery and CT-RT appears similar. Indeed, median OS was 28.6 months for surgery vs. 27 for CT-RT. Looking at the updated PACIFIC trial results [16] (36-month OS of 55% in the durvalumab arm vs. 44% in the placebo arm), it appears crucial for patients not to miss the opportunity to benefit from durvalumab after CT-RT, should surgery be contraindicated. Furthermore, as survival in our surgically-treated patients was slightly higher than 36 months, the question could be raised if CT-RT followed by durvalumab would be better than surgery for Stage III patients who are not immediately operable. This is even more likely to be true given that survival of patients who underwent upfront surgery was probably overestimated in our study, on account of many pathological Stage I or II (27/141) cases being present after surgery (Table 2).

The relevance of an early restaging, be it clinical or eventually pathological, along with a multidisciplinary discussion held before, in the course of, and after neoadjuvant treatment in Stage III NSCLC patients is clearly confirmed by our study results. Survival of patients treated using neoadjuvant chemotherapy followed by surgery appears to be better than that of those treated using either sequential or concurrent CT-RT. As expected, lymph node status appears highly relevant when selecting the treatment strategy, and it is very relevant in terms of patient survival, as well. Thus, if the therapeutic strategy needs to be optimized, lymph node status remains the primary prognostic factor. Other trials conducted in the 2000's described different survival rates depending on nodal involvement. Andre et al. [17] identified homogeneous N2 NSCLC prognostic subgroups, with 4 patient groups assembled in his publication consisting of 2 patient groups with clinical N2 (cN2) and 2 others with minimal N2 (mN2), with disease preoperatively detected and not detected upon computed tomographic scan, respectively. Using this classification, the authors put forward different therapeutic approaches depending on the subgroup. Consequently, these different subgroups may help choose the best treatment option.

The advent of immunotherapy has revolutionized the therapeutic strategy for unresectable Stage III disease patients, but new scenarios are likely to emerge in the coming years, especially considering immunotherapy administration in the adjuvant and neoadjuvant settings, with immunotherapy being proposed in combination with chemotherapy in the neoadjuvant setting. These wide treatment choices clearly require

<table><caption>**Table 4**
Treatment received and survival.</caption><thead><tr><th></th><th>N = 411</th><th>Death</th><th>Median OS (months)</th></tr></thead><tbody><tr><td>Total</td><td>411</td><td>294 (71)</td><td>21.3 [9.6–48.3]</td></tr><tr><td>Upfront surgery</td><td>141 (34)</td><td>77 (55)</td><td>40.2 [21.7–98.6]</td></tr><tr><td>Upfront chemo-radiotherapy</td><td>73 (17)</td><td>60 (82)</td><td>23.9 [13.3–48.1]</td></tr><tr><td>-Concurrent</td><td>26 (35)</td><td>20 (80)</td><td>19.8 [12.7–48.1]</td></tr><tr><td>- Sequential</td><td>43 (60)</td><td>36 (84)</td><td>25.2 [14.3–50.6]</td></tr><tr><td>- Followed by surgery</td><td>4 (5)</td><td>3 (75)</td><td>13.8 [9.6–NR]</td></tr><tr><td>Planned for neoadjuvant chemotherapy followed by surgery</td><td>60 (15)</td><td>39 (65)</td><td>23 [13.2–87.4]</td></tr><tr><td>- Neoadjuvant chemotherapy followed by surgery</td><td>37 (62)</td><td>19 (51)</td><td>53.3 [16.1–87.3]</td></tr><tr><td>1.%2 -Switched to chemo-radiotherapy (concurrent/sequential)</td><td>1.%2 13 (22) (6/7)</td><td>1.%2 10 (83)</td><td>1.%2 [10.8–36]</td></tr><tr><td>-Switched to exclusive chemotherapy</td><td>10 (16)</td><td>9 (90)</td><td>9.7 [6.2–16.4]</td></tr><tr><td>Exclusive radiotherapy</td><td>24 (6)</td><td>22 (92)</td><td>12.8 [5.7–21.7]</td></tr><tr><td>Exclusive systemic treatment (chemotherapy or targeted therapy)</td><td>68 (17)</td><td>59 (87)</td><td>11.6 [7.2–21.1]</td></tr><tr><td>Exclusive palliative care</td><td>45 (11)</td><td>37 (82)</td><td>4.5 [1.6–9.7]</td></tr></tbody></table>

NR, not reached; OS, overall survival.
Kaplan-Meier Plot

<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Survival curve according to treatment received.RCT, radio-chemotherapy.</figcaption></figure>

careful patient selection, especially concerning Stage III patients.

All these discussions highlight the multidisciplinary board's outmost
relevance. In our study we couldn't evaluate the impact of the tumor
board on the patient's stage III NSCLC OS. However, Friedman et al.
showed that multidisciplinary team discussions for Stage III NSCLC do
improve patient outcomes compared to those who are not discussed
within such a meeting. This superiority was shown in terms of more
efficient care coordination, better pre-treatment evaluation, and supe-
rior therapy [18]. If a multidisciplinary discussion has already shown its
relevance in terms of OS for the treatment decision concerning all stages
[19-22], such a multidisciplinary discussion appears even more funda-
mental for Stage III disease patients. Therefore, coordination between
the various professions involved, including oncologist, pulmonologists
by using EBUS, radiotherapists, and thoracic surgeons, is highly
important and this particularly in regard to borderline patients who
need early re-evaluation, so that optimized treatment strategies can be
proposed.

5. Conclusions

In our cohort, 12% (32/270) of patients who did not benefit from upfront surgery eventually received concurrent CT-RT. There is a survival benefit for patients treated with surgery following neoadjuvant chemotherapy compared with those who received CT-RT. However, those patients to whom neoadjuvant chemotherapy was offered before surgery and who eventually received CT-RT displayed a slightly lower survival than those to whom CT-RT was offered initially.

If nodal involvement remains a major prognostic factor, an early
multidisciplinary discussion for patients who cannot be operated on
appears essential in order to offer them the most appropriate care plan.
It is important to consider the possibility of using durvalumab after CT-
RT, which significantly improves patient survival. Upcoming studies
comparing neoadjuvant chemotherapy followed by surgery versus CT-
RT followed by immunotherapy are likely to be most interesting.
## Funding statement

This research received a specific grant of 10,000 € from AstraZeneca

## CRediT authorship contribution statement

Justin Benet, Anne-Claire Toffart, Matteo Giaj Levra: Conceived and designed the analysis, analyzed and interpreted the data, and wrote the paper. Stéphane Ruckly: Conceived the analysis, interpreted the data, and critically appraised the paper. Pierre-Yves Brichon, Thibaut Chollier, Julie Villa, Camille Emprou, Thomas Pierret, Isabelle Dumas, Gilbert Ferretti, Denis Moro-Sibilot: Interpreted the data and critically appraised the paper. All authors also approved the final version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

## Declaration of Competing Interest

Dr. BENET has nothing to disclose. Dr. TOFFART reports grants and personal fees from AstraZeneca, personal fees and non-financial support from BMS Bristol Myers Squibb France, personal fees and non-financial support from MSD France, personal fees and non-financial support from Roche FranceAmgen France, personal fees and non-financial support from Amgen, grants from Pfizer, grants from Sanofi, grants from Takeda, payment for lectures from Nutricia. Dr. BRICHON has nothing to disclose. Dr. CHOLLIER has nothing to disclose. Dr. RUCKLY has nothing to disclose. Dr. VILLA has nothing to disclose. Dr. EMPROU has nothing to disclose. Dr. PIERRET has nothing to disclose. Dr. DUMAS has nothing to disclose. Dr. FERRETTI reports payment for lectures from BMS, payment for lectures from MSD. Dr. MORO-SIBILOT reports grants, personal fees and travel support from BMS France, grants, personal fees and travel support from MSD France, personal fees and travel support from Roche, grants and personal fees from AstraZeneca. Dr. GIAJ LEVRA reports payment for lectures and participation on a data safety monitoring board from AstraZeneca.

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