The Multidisciplinary Approach in Stage III Non-Small Cell Lung Cancer over Ten Years: From Radiation Therapy Optimisation to Innovative Systemic Treatments

Abstract

Background: About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, adequate staging, and a careful patient selection for surgery or radiation therapy integrated with systemic treatment. Methods: This is a single-center observational retrospective and prospective study including a consecutive series of stage III NSCLC patients who were referred to the Veneto Institute of Oncology and University Hospital of Padova (Italy) between 2012 and 2021. We described clinico-pathological characteristics, therapeutic pathways, and treatment responses in terms of radiological response in the entire study population and in terms of pathological response in patients who underwent surgery after induction therapy. Furthermore, we analysed survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS). Results: A total of 301 patients were included. The majority of patients received surgical multimodality treatment (n = 223, 74.1%), while the remaining patients (n = 78, 25.9%) underwent definitive CRT followed or not by durvalumab as consolidation therapy. At data cut-off, 188 patients (62.5%) relapsed and the median RFS (mRFS) of the entire population was 18.2 months (95% CI: 15.83−20.57). At the time of analyses 140 patients (46.5%) were alive and the median OS (mOS) was 44.7 months (95% CI: 38.4−51.0). A statistically significant difference both in mRFS (p = 0.002) and in mOS (p < 0.001) was observed according to the therapeutic pathway in the entire population, and selecting patients treated after 2018, a significant difference in mRFS (p = 0.006) and mOS (p < 0.001) was observed according to treatment modality. Furthermore, considering only patients diagnosed with stage IIIB-C (N = 131, 43.5%), there were significant differences both in mRFS (p = 0.047) and in mOS (p = 0.022) as per the treatment algorithm. The mRFS of the unresectable population was 16.3 months (95% CI: 11.48−21.12), with a significant difference among subgroups (p = 0.030) in favour of patients who underwent the PACIFIC-regimen; while the mOS was 46.5 months (95% CI: 26.46−66.65), with a significant difference between two subgroups (p = 0.003) in favour of consolidation immunotherapy. Conclusions: Our work provides insights into the management and the survival outcomes of stage III NSCLC over about 10 years. We found that the choice of radical treatment impacts on outcome, thus suggesting the importance of appropriate staging at diagnosis, patient selection, and of the multidisciplinary approach in the decision-making process. Our results confirmed that the PACIFIC trial and the following introduction of durvalumab as consolidation treatment may be considered as a turning point for several improvements in the diagnostic-therapeutic pathway of stage III NSCLC patients.

Keywords: PACIFIC regimen; concurrent chemo-radiation therapy; immunotherapy; multidisciplinary team; multimodality treatment; neoadjuvant therapy; radiotherapy; stage III NSCLC.

Scheme 1

Management of stage III NSCLC based on imaging, invasive lymph node staging, and multidisciplinary assessment. CT, chemotherapy; LN, lymph node; NSCLC, non-small cell lung cancer; RT, radiotherapy.

Scheme 2

Programmed cell death ligand 1.

Figure 1

Consort flow diagram.

Figure 2

Bar graphs of therapeutic pathways before and after 2018. CRT, chemo-radiation therapy.

Figure 3

Bar graphs of timing of radiotherapy before and after 2018. CRT, chemo-radiation therapy; RT, radiotherapy.

Figure 4

Kaplan–Meier curve of estimated relapse-free survival in the intention-to-treat population.

Figure 5

Kaplan–Meier curve of estimated overall survival in the intention-to-treat population.

Figure 6

Kaplan–Meier curves of estimated relapse-free survival in the intention-to-treat population as per radical treatment modality. CT-RT, chemo-radiation therapy.

Figure 7

Kaplan–Meier curves of estimated overall survival in the intention-to-treat population as per radical treatment modality. CT-RT, chemo-radiation therapy.

Figure 8

Kaplan–Meier curves of estimated relapse-free survival according to treatment modality in patients treated after 2018. CT-RT, chemo-radiation therapy.

Figure 9

Kaplan–Meier curves of estimated overall survival according to treatment modality in patients treated after 2018. CT-RT, chemo-radiation therapy.

Figure 10

Kaplan–Meier curves of estimated overall survival according to treatment modality in stage IIIA patients. CT-RT, chemo-radiation therapy.

Figure 11

Kaplan–Meier curves of estimated overall survival according to treatment modality in stage IIIA patients treated after 2018. CT-RT, chemo-radiation therapy.

Figure 12

Kaplan–Meier curves of estimated relapse-free survival according to treatment modality in stage IIIB-C patients. CT-RT, chemo-radiation therapy.

Figure 13

Kaplan–Meier curves of estimated overall survival according to treatment modality in stage IIIB-C patients. CT-RT, chemo-radiation therapy.

Figure 14

Kaplan–Meier curves of estimated relapse-free survival according to treatment modality in stage IIIB-C patients treated after 2018. CT-RT, chemo-radiation therapy.

Figure 15

Kaplan–Meier curves of estimated overall survival according to treatment modality in stage IIIB-C patients treated after 2018. CT-RT, chemo-radiation therapy.

Figure 16

Kaplan–Meier curves of estimated relapse-free survival in the entire population who underwent definitive chemo-radiation therapy according to treatment pathway. CT-RT, chemo-radiation therapy.

Figure 17

Kaplan–Meier curves of estimated overall survival in the entire population who underwent definitive chemo-radiation therapy according to treatment pathway. CT-RT, chemo-radiation therapy.

Figure 18

Kaplan–Meier curves of estimated relapse-free survival in patients treated after 2018 who underwent definitive chemo-radiation therapy according to treatment pathway. CT-RT, chemo-radiation therapy.

Figure 19

Kaplan–Meier curves of estimated overall survival in patients treated after 2018 who underwent definitive chemo-radiation therapy according to treatment pathway. CT-RT, chemo-radiation therapy.