First-site-metastasis pattern in patients with inoperable stage III NSCLC treated with concurrent chemoradiotherapy with or without immune check-point inhibition: a retrospective analysis

Purpose The aim of this study was to investigate a first-site-metastasis pattern (FSMP) in unresectable stage III NSCLC after concurrent chemoradiotherapy (cCRT) with or without immune checkpoint inhibition (ICI). Methods We defined three patient subgroups according to the year of initial multimodal treatment: A (2011–2014), B (2015–2017) and C (2018–2020). Different treatment-related parameters were analyzed. Observed outcome parameters were brain metastasis-free survival (BMFS), extracranial distant metastasis-free survival (ecDMFS) and distant metastasis-free survival (DMFS). Results 136 patients treated between 2011 and 2020 were included with ≥ 60.0 Gy total dose and concurrent chemotherapy (cCRT); thirty-six (26%) received ICI. Median follow-up was 49.7 (range:0.7–126.1), median OS 31.2 (95% CI:16.4–30.3) months (23.4 for non-ICI vs not reached for ICI patients, p = 0.001). Median BMFS/ecDMFS/DMFS in subgroups A, B and C was 14.9/16.3/14.7 months, 20.6/12.9/12.7 months and not reached (NR)/NR/36.4 months (p = 0.004/0.001/0.016). For cCRT+ICI median BMFS was 53.1 vs. 19.1 months for cCRT alone (p = 0.005). Median ecDMFS achieved 55.2 vs. 17.9 (p = 0.003) and median DMFS 29.5 (95% CI: 1.4–57.6) vs 14.93 (95% CI:10.8–19.0) months (p = 0.031), respectively. Multivariate analysis showed that age over 65 (HR:1.629; p = 0.036), GTV ≥ 78 cc (HR: 2.100; p = 0.002) and V20 ≥ 30 (HR: 2.400; p = 0.002) were negative prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS (HR: 1.739; p = 0.027). After onset of brain metastasis (BM), patients survived 13.3 (95% CI: 6.4–20.2) months and 8.6 months (95% CI: 1.6–15.5) after extracranial-distant-metastasis (ecDM). Patients with ecDM as FSMP reached significantly worse overall survival of 22.1 (range:14.4–29.8) vs. 40.1 (range:18.7–61.3) months (p = 0.034) in the rest of cohort. In contrast, BM as FSMP had no impact on OS. Conclusion This retrospective analysis of inoperable stage III NSCLC patients revealed that age over 65, V20 ≥ 30 and GTV ≥ 78 cc were prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS. ICI treatment led to a significant improvement of BMFS, ecDMFS and DMFS. ecDM as FSMP was associated with significant deterioration of OS, whereas BM as FSMP was not. Supplementary Information The online version of this article (10.1007/s00066-023-02175-6) contains supplementary material, which is available to authorized users.


Introduction
Regarding cancer-related mortality, lung cancer is the most common cause worldwide [1].Inoperable stage III NSCLC is a highly heterogeneous disease with varying macroscopic tumor extensions, and therefore, patients' prognosis depends heavily on multiple patient and treatment factors.After multimodality treatment, historically, the five-year survival rate of patients has been as low as ten to thirty percent [2][3][4].The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy [5] followed by maintenance therapy with the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab [6].The addition of immune checkpoint inhibition (ICI) to the multimodality treatment strategy has led to a significant improvement in patient outcomes, as demonstated by the unprecedented results of the PACIFIC trial [7,8].
However, distant failure remains a burden for patients with unresectable NSCLC: Over time 30% of affected patients develop brain metastases (BM) [9], but there is encouraging evidence that anti-PD-1/PD-L1 agents may have a beneficial impact on their development [10].Knowledge of the effects of chemoradioimmunotherapy on the development of distant metastases (DM) is limited.This retrospective analysis evaluates the impact of treatment patterns and patient-related factors on brain metastasis-free (BMFS), extracranial distant metastasis-free (ecDMFS), and distant metastasis-free survival (DMFS) after concurrent chemoradiotherapy (cCRT) with and without immune checkpoint inhibitors (ICI).

Patients and methods
A total of 189 consecutive patients with stage III NSCLC were assessed for eligibility in 2021.The retrospective study and analysis of individual patient data were approved by the local ethics committee (reference number: 17-230).Informed consent to the treatment and data collection for research purposes was obtained from all patients.
Out of the 189 patients treated between February 2011 and November 2020, 136 (71.9%) were included.All selected patients had been diagnosed with unresectable stage III A-C (UICC 8th edition) NSCLC.They received concurrent cCRT with and without ICI.This included either simultaneous and maintenance treatment with the PD-1 inhibitor nivolumab as part of the phase II ETOP 6-14 NICOLAS study [11,12], or maintenance treatment with the PD-L1 inhibitor durvalumab in accordance with the PACIFIC trial [7].
The cCRT consisted of conventional fractionated thoracic radiotherapy (TRT) with a total dose of ≥ 60 Gy and platinum-based chemotherapy (cisplatin/carboplatin in combination with vinorelbine/pemetrexed).To assess improvements over time, three subgroups of patients were classified according to the year of the first TRT: Subgroup A (2011-2014), Subgroup B (2015-2017), and Subgroup C (2018-2020).
All survival parameters were calculated from the last day of TRT only considering the first site of failure (FSMP), including brain metastasis-free survival (BMFS), extracranial distant metastasis-free survival (ecDMFS) and distant metastasis-free survival (DMFS).Patients with local recurrence prior to distant failure or with simultaneous multifocal progression were not included in the BM, ecDM or DM subgroup, Patient and treatment-related characteristics are displayed in Table 1.
Baseline positron emission tomography (PET) and computed tomography (CT) staging were performed in 133 (97.8%) patients before initiation of multimodality treatment to improve contouring quality [13,14] and cranial contrast-enhanced MRI was acquired in 88 (64.7%) patients, while all other patients obtained cranial contrastenhanced CT.
cCRT was recommended in a multidisciplinary tumor board for each patient.An Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate lung function (diffusing capacity of the lung for carbon monoxide corrected for hemoglobin (DLCO) ≥ 40%, forced expiratory volume in 1 s (FEV1) ≥ 1 L) were required.
Patients were positioned supine with their arms held overhead by WingSTEP™ (Innovative Technologie Voelp, Innsbruck, Austria).Target volumes were defined according to an internal protocol closely following the later published guidelines of the European Society for Radiotherapy and Oncology-Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) [15] and based conventional planning CT and PET-CT.
Gross tumor volume (GTV) and planning target volume (PTV) were transcribed from the original treatment plans.To differentiate small vs. large volumes, we chose median dichotomization for GTV (78.0 cc) and split PTV in < vs ≥ 700 cc based on literature research of previously published data [16][17][18][19].
Prior to the introduction of intensity-modulated radiation therapy (IMRT), TRT with 50 Gy in 2 Gy single-dose fractions, followed by a sequential 16-Gy boost, was used.After implementation of IMRT, TRT consisted of 30 fractions with simultaneous integrated boost (SIB) of 2.0/2.12Gy to the lymph nodes (LN)/GTV of the primary tumor (PT) with a total dose of 60.0/63.6Gy.
Follow-up was performed every three months for the first two years after treatment, every six months for the next two years, and annually thereafter.Routine blood tests, pulmonary function tests, clinical examinations, and imaging such as PET-CT or CT scans were analyzed, response was assessed according to RECIST 1.1.Additional diagnostic measures such as contrast-enhanced magnetic resonance imaging (MRI) and bone scintigraphy, were performed when deemed necessary.Brain metastases (BM), extracranial distant metastases (ecDM) and distant metastases (DM) were documented with PET-CT, CT or MRI scans.Histological confirmation of progressive disease was not obligatory.
The impact of each parameter on BMFS, ecDMFS and DMFS was analyzed by means of Kaplan-Meier analysis using the log-rank test.Multivariable Cox-regression analysis was performed with all parameters which had shown to be significant (p < 0.05) in univariate analysis.All analyses including univariate and multivariate analysis were performed using SPSS version 28 (IBM; Armonk, New York, USA).

Results
A total of 136 consecutive patients with unresectable stage IIIA-C NSCLC (UICC 8th edition) received initial treatment between 2011 and 2020 and were eligible for this analysis.A summary of patient-and tumor-characteristics is shown in Table 1.
In the entire cohort, the median follow-up was 49.7 (range: 0.7-126.1)months.Seventy-eight (57%) patients were older than 65 years and the mean age was 66.9 (range 33.6-82.5)years.Table 2 shows OS, BMFS, ecDMFS and DMFS for the entire cohort and each subgroup.
Both, patients treated with simultaneous + maintenance nivolumab and patients treated with maintenance durvalumab were included in this retrospective cohort.We found no significant differences for OS (p = 0.841), PFS (p = 0.764), DMFS (p = 0.919), ecDMFS (p = 0.628) and BMFS (p = 0.668) between these subgroups.Therefore, we pooled them as an ICI cohort versus patients treated without ICI.
Patients who had a cMRI scan prior to treatment showed no significant difference in DMFS (p = 0.295) or BMFS (p = 0.189).

Discussion
In the past decade, important advances have been achieved in the multimodal treatment of inoperable stage III NSCLC.The introduction of VMAT has decreased the toxicity of TRT [20][21][22] and routine concurrent chemo-radiotherapy has constantly been improved [23].The PACIFIC trial has changed the landscape of thoracic oncology with unprecedented improvements in OS and PFS [7,8,24].In this comprehensive analysis of patients treated in the past decade we depict patterns of first distant failure after cCRT for Stage III NSCLC.We identified factors during initial treatment that predict patients' risk for later onset of metastasis and analyzed impact of metastasis on OS of affected patients.
We observed no significant differences for OS, PFS, DMFS, ecDMFS and BMFS between patients treated with durvalumab vs. those treated with nivolumab, therefore we decided pool both cohorts together against patients treated without ICI to raise patient numbers.
In our cohort the median DMFS for patients treated with CRT+ICI was 29.5 months vs 14.93 months (p = 0.031) for those treated with CRT alone.This is in close accordance with the data of the PACIFIC-trial, were the median time to death or distant metastasis was reported as 28.3 months for patients treated with durvalumab vs.16.2 months for patients in the placebo arm [25].In the LUN 14-179 trial, a time to metastatic disease or death of 30.7 months (95% CI: 18.7 to NR) was reported for patients receiving pembrolizumab after cCRT [26].In contrast to Kishi et al., we did not observe female sex as a negative prognosticator for the onset of DM [27].
BMFS and ecDMFS had a significant negative correlation with larger GTV, PTV (≥ 700 cc) and with total lung V20 ≥ 30%.This suggests that patients with initially larger initial tumor burden are more likely to experience distant failure after cCRT.The association of larger PTVs with diminished regional control has been reported frequently re-K ported in literature [18,19,34,35].However, the impact of initial GTV and its' shrinkage during CRT in patients that afterwards receive IO maintenance is currently unknown and should be considered for future investigations [36,37].Also, underdosage of large tumours or reduced margins at the discretion of the performing physicians could be an explanation of this strong negative correlation.
The study split patients into three subgroups (A 2011-2014, B 2015-2017 and C 2018-2020) and showed constant improvements of DMFS, BMFS and ecDMFS over the years, especially in subgroup C, which coincided with the implementation of ICItreatment Interestingly, the study also observed numerical improvements in post-DM-survival from 7.2 months in subgroup A to 15.1 months in subgroup B to 18.5 in subgroup C.Although these numerical benefits were not statistically significant, they hint towards improved post-progression therapy and we are planning further analyses on this subject [4,38].
Patients treated with cCRT alone, who initially presented with PD-L1 expressing (≥ 1%) tumors had significantly worse DMFS in univariate analysis (p = 0.033) and showed a clear negative trend in multivariate analysis (HR: 1.666; p = 0.091).This indicates a vast improvement in outcomes for those patients after implementation of durvalumab maintenance, considering IO was almost exclusively administered in patients with PD-L1 on ≥ 1% of tumor cells due to regulations by the European medicines agency (EMA).
The importance of post progression survival (PPS) has been highlighted by Imai et al. [39].In this study's patients initially treated with cCRT+ICI showed numerically improved post-DM-survival compared to those who were initially treated with cCRT alone.Interestingly, BM as FSMP did not significantly impact survival, whereas ecDM lead to impaired OS.Also PPS after BM as FSMP was significantly longer than after the onset of ecDM.This could be due to the highly efficient treatment options of BM via stereotactic radiosurgery (SRS) [40].Overall the median post progression survival achieved in our cohort (13.3 months) is 2.7 months longer compared to the 10.6 months reported by Delasos et al., but nevertheless unsatisfying [41].It is of utmost interest to further improve treatment for patients with progression after cCRT (+/-) ICI for stage III NSCLC, especially those with ecDM as FSMP.Further trials are needed to tailor post progression therapy aiming to improve PPS.
We are planning to analyse factors for PPS, like second line TKI-therapy, ICI-therapy or chemotherapy in the near future.
Given the limitations of this retrospective study we want to acknowledge the low number of patients with PD-L1 assessment prior to treatment, lack of Next Generation Sequencing and subtotal MRI staging prior to treatment.These points should be included in all prospective trials concerning lung cancer.

Conclusion
In conclusion, this retrospective analysis of unresectable stage III NSCLC patients identified V20 ≥ 30%, GTV ≥ 78 cc, and age over 65 as strong prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS.Additionally, T-stage, V20 ≥ 30 and GTV ≥ were found to be prognosticators for DMFS.Implementation of ICI treatment resulted in a significant improvement of BMFS, ecDMFS, and DMFS.Patients with ecDM had shorter overall survival, while BM did not impact survival of affected patients compared to the entire cohort.

Fig. 1
Fig. 1 Kaplan-Meier curves of overall survival for all patients with and without extracranial metastasis (ecDM) (a) vs. with and without brain metastasis (BM) (b)

Table 1
Patient characteristics

Table 2
Survival parameters

Table 3
Univariate analysis