Predictors of survival and recurrence patterns following definitive chemoradiotherapy in stage III non-small cell lung cancer—a retrospective cohort study

Introduction

Background

For a long time, standard treatment of inoperable patients with stage III non-small cell lung cancer (NSCLC) has been chemoradiotherapy (CRT) (1). This includes a platinum-based doublet (2) in combination with at least 60 Gray (Gy) of radiation (3), either given sequentially or concomitantly, with a minor survival benefit for the latter (4). The most common regimen in Sweden is three cycles of chemotherapy (platinum doublet) with addition of concomitant radiotherapy (68 Gy) at cycle two. While the intent of treatment is curative, the 5-year survival rate in most studies is only about 15–25% (2,5,6), hence only marginally improved outcome compared with stage IV patients. Although most patients relapse after CRT, there are no specific protocols for salvage treatment in this situation. The choice of treatment in second-line depends mainly on recurrence patterns and patient characteristics; thus, principally, all available NSCLC treatment modalities can be considered.

In 2015, there was a major breakthrough in the treatment of NSCLC when the first checkpoint inhibitor was approved in Europe and the United States as second-line treatment of advanced stage disease (7-9). The treatment was included in clinical practice as one of the most promising candidates for salvage therapy after recurrence following CRT and in 2018, this immune modality was also approved in Europe as adjuvant treatment of stage III disease with a programmed death-ligand 1 (PD-L1) expression exceeding 1%, without progression during CRT (10).

Rational and knowledge gap

Despite modern therapeutic strategies, treatment response and survival are highly variable. Therefore, in this heterogeneous patient population, a detailed knowledge of patient characteristics, recurrence patterns, and applied salvage therapies might help to guide clinical decision making.

Objective

The aim of this study was to characterize a large cohort of real-world stage III NSCLC patients who received CRT with curative intent and to define parameters that could predict recurrence patterns, overall survival (OS) and survival time from recurrence. In addition, we analyzed if type of salvage therapy affected survival from recurrence. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-840/rc).

Methods

Study population

NSCLC patients treated with CRT ≥60 Gy 2009–2018 (n=235) were retrospectively identified from three Mid-East regions in Sweden (Uppsala, Dalarna, and Gävleborg) by using the hospital software for radiotherapy and the International Classification of Diseases, 10th Revision (ICD-10) code for lung cancer (C34). To avoid selection bias, all registered patients were included. After exclusion of subjects with stages other than III [based on the 8^th lung cancer tumor, node, metastasis (TNM) classification], non-curative treatment intent and patients with incomplete data, 193 subjects remained (Figure 1).

Figure 1 Study population. A flowchart comprising inclusion and exclusion criteria of study cohort of patients with stage III NSCLC receiving curatively intent chemoradiotherapy during the time period 2009 to 2018. fx, fraction; NSCLC, non-small cell lung cancer; RT, radiotherapy.

Data collection

Clinical parameters were retrieved from the medical records in each region and included age, sex, smoking habits, Eastern Cooperative Oncology Group (ECOG) performance status (PS), weight loss prior to diagnosis, pre-treatment blood count, TNM-stage, histology, presence of a genetic driver alteration, radiotherapy dose, chemotherapy schedule and type of drug. In addition, laboratory results related to inflammation were collected comprising C-reactive protein (CRP), white blood cell count (WBC), platelet count (PLT), and albumin (Alb). The presence of genetic driver alterations was analyzed with next-generation sequencing (NGS) from September 1, 2014, and later. In prior analyzes, only epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-testing was performed. Due to the change in test methods, this earlier data is not included in the comparison between patients with and without genetic driver alterations. OS was calculated from the time of diagnosis to the time of death or last follow-up. Time to recurrence was calculated from day 1 of radiotherapy in the CRT until date of radiologic exam with findings of recurrence. Post-recurrence survival (PRS) was calculated from the date of recurrence to death or last follow-up.

For patients with recurrence during follow-up, additional information was obtained on time point and location of recurrence and whether the recurrence was diagnosed in routine follow-up or due to disease-related symptoms. ECOG PS was re-evaluated and laboratory results at the time of recurrence were collected. For patients with no available blood tests from the date of recurrence, data was used from the most recent blood test within a period of 2 weeks before or after recurrence date prior to start of salvage treatment.

Ethics

The study was approved by the Swedish Ethical Review Authority (No. 2021-01513) and all study procedures were performed in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent has not been obtained specifically for this study. Due to the exceptionally high mortality rate of lung cancer and the retrospective design of this research project, the majority of study participants were deceased at the time of data collection. All results will be published in an anonymized form and presented at the group level.

Statistical analysis

Outcome variables included OS, PRS, time to recurrence, recurrence within 1 year (early recurrence), and locoregional vs. distant recurrence. Survival differences were analyzed by univariate Cox regression. Factors significant in the univariate analysis were further explored in multivariate analysis to validate their independent prognostic effects. Hazard ratios (HRs) with a 95% confidence interval (CI) were calculated using the Cox proportional hazards regression model to express the strength of the associations. Survival analyses were visualized by Kaplan-Meier curves. Chi-squared tests were conducted when comparing categorical data. Binary outcome variables were analyzed using logistic regression. Statistical significance was defined as P<0.05. A Bonferroni correction was employed to account for multiple testing. The programs used for statistical analysis were Statistica version 13 and STATA version 14.2.

Results

Patient characteristics

The final study cohort included 193 patients with a mean age of 67.9 years (range, 42–85 years), slightly more men (56%) than women (44%). The overwhelming majority of patients were smokers (40%) or former smokers (53%), with only a few never-smokers (7%). Most patients had a good ECOG PS of 0 (51%) or 1 (42%) at the time of diagnosis. The most common stages were stage IIIA (58%) followed by stage IIIB (40%). Adenocarcinoma (52%) and squamous cell carcinoma (39%) were the predominant histologies. Sequencing data from NGS was available for 63 patients. Among these, 33% harbored a genetic driver mutation, of which Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (n=13, 20.6%) and EGFR mutations (n=3, 4.8%) were the most common (Table 1).

Survival and prognostic factors

The median follow-up was 52 months with a median OS (mOS) of 33 months (95% CI: 24.5–44.1) and a 1-, 2- and 5-year survival of 79%, 58% and 34% respectively (Figure S1). Patients presenting with an ECOG PS of 2 had a mOS of 24 months compared with 34 months for ECOG PS 0–1 (HR =1.83; 95% CI: 0.98–3.40; P=0.057). Most other pre-treatment variables did not affect OS, including age, sex, smoking status, weight loss prior to diagnosis, stage, histology, the presence of a driver mutation, concurrent vs. sequential chemotherapy, or chemotherapy protocol (weekly vs. every third week, cisplatin vs. carboplatin). Table 2 shows the associations of pre-treatment variables with OS.

For 162 patients (84%), a pre-treatment CRP value was available. Of those patients, 91 had an elevated CRP (>10 mg/L) which was significantly associated with worse OS (HR for death 1.81; 95% CI: 1.16–2.83; P=0.009) with an mOS of 21 months in the group with elevated CRP compared to 39 months in the group with normal CRP. When further explored in multivariable analysis, CRP remained independently associated with OS (HR for death 1.53; 95% CI: 1.01–2.30; P=0.045), but when adjusting for multiple testing with Bonferroni correction the association was no longer significant. An elevated leukocyte count (cut-off >10×10⁹/mL) was also significantly associated with OS in univariate analysis (HR =1.58; 95% CI: 1.08–2.31; P=0.02), but lost its significance in multivariable analysis (HR =1.28; 95% CI: 0.85–1.94; P=0.24) and Bonferroni correction. A similar but non-significant trend was observed for elevated platelet count. Pre-treatment Alb was not significantly associated with OS (Table 2).

Recurrence following CRT

Data on recurrence was available for 185 patients. Of these, 123 patients (66%) relapsed during follow-up with a median time to progression (TTP) of 9 months (range, 2–87 months). Median PRS (mPRS) was 12.1 months (range, 0.2–104 months). Close to all relapses were diagnosed within the first 3 years following CRT, within 1 year in 64%, within 2 years in 88%, and within 3 years in 96% of all patients who eventually relapsed. Isolated locoregional recurrences were observed in 60 patients (48.8%) of the recurrent patients (Table 3) and tended to occur later (median 11.5 months, range 3–87 months) compared to recurrence involving distant metastases (median 6.3 months, range 2–57 months), (HR =0.7; 95% CI: 0.5–1.0; P=0.06). In the 15 patients with mixed locoregional and distant recurrence (12.2%), the disease relapse was diagnosed after a median of 6.6 months and within one year from CRT in 14 patients (one late relapse after 57 months).

The brain was the predominant site of distant metastasis, with 22 patients (34.9%) diagnosed with brain recurrence, after a median time of 9 months.

Age (P=0.59), sex (P=0.97), smoking history (P=0.18), histology (P=0.57), NGS-status (P=0.08), cisplatin-containing treatment (P=0.38), concurrent treatment (P=0.85) or N3 disease (P=0.56) were not associated with the overall risk of recurrence.

Salvage therapy

The most common salvage treatment at the time of recurrence was chemotherapy (43%), followed by radiotherapy (16%) and immune checkpoint inhibitors (ICIs; 13%); 12.2% of the patients with recurrent disease did not receive any salvage treatment (Table 3 and Figure S2). Patients ever treated with ICI had significantly longer mPRS (25.1 months) compared to patients who never received ICI (median 9.0 months; HR =0.28; 95% CI: 0.16–0.50; P<0.001) (Figure 2). For 12 of the recurrent patients, salvage therapy was planned with curative intent. The mPRS for this group was 12.8 (range, 7.6–104) months and not significantly different from patients with palliative intended salvage treatment [12.1 months (95% CI: 0.20–65.2; P=0.14)]. Three of these 12 patients (2.4% of all recurrent patients) treated with curative intent were still alive at the last follow-up, after a median follow-up time of 35 months.

Figure 2 Kaplan-Meier distribution for PRS in months after recurrence of patients ever treated with immunotherapy (EveIO =1) and patients who never received immunotherapy (EveIO =0). PRS is defined as time from relapse to death from any cause. CI, confidence interval; Immuno, immunotherapy; mPRS, median post-recurrence survival.

Predictors of distant or locoregional recurrence

Available clinicopathologic parameters were analyzed for associations with locoregional or distant recurrence, respectively (Tables 4,5).

When analyzing predictors of locoregional relapse, none of the factors examined were significant in the univariate analysis. However, histology and smoking status reached borderline significance with odds ratio (OR) =0.33; 95% CI: 0.10–1.12; P=0.06 and OR =0.59; 95% CI: 0.33–1.07; P=0.08, respectively. In the subsequent multivariate analysis, adenocarcinoma and never smoking were associated with a lower risk of locoregional relapse with borderline significance with OR =0.55; 95% CI: 0.30–1.00; P=0.050 and OR =0.30; 95% CI: 0.09–1.02; P=0.055, respectively. None of the factors were significant after Bonferroni correction (Table 4).

Regarding the risk of distant relapses, presence of a molecular driver and N3 disease were both strong independent risk factors in the multivariate analysis (OR =13.03, 95% CI: 4.20–40.42, P<0.001; OR =6.51, 95% CI: 1.91–22.19, P=0.003). Cisplatin showed a protective effect in univariate analysis (OR =0.49; 95% CI: 0.26–0.92; P=0.03), but was not significantly associated with distant relapse in multivariate analysis (OR =0.54; 95% CI: 0.20–1.47; P=0.23). After Bonferroni correction, only the presence of a molecular driver remained significantly associated with an elevated risk of distant relapse (Table 5).

Clinical outcome of patients after recurrence

For patients with recurrence after CRT, ECOG PS at time of relapse was predictive of PRS with a mPRS of 3.3 months for patients with ECOG 2–4 compared to 16.5 months for those with ECOG PS 0–1 (HR =4.2; 95% CI: 2.7–6.5; P<0.001) (Figure 3). Sex, age, smoking or histology were not associated with survival after recurrence. Symptomatic recurrences had a worse prognosis compared to recurrences diagnosed as part of routine radiological follow-up (HR =2.2; 95% CI: 1.5–3.2; P<0.001) (Figure 4 and Table 6).

Figure 3 Kaplan-Meier distribution for PRS in months after recurrence at ECOG PS 0–1 (ECOG2 =0) and ECOG PS ≥2 (ECOG2 =1). PRS is defined as time from relapse to death from any cause. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; mPRS, median post-recurrence survival; PS, performance status.

Figure 4 Kaplan-Meier distribution for PRS in months after recurrence of patients with recurrence detected due to symptoms (Rsymt =1) or in routine imaging (Rsymt =0). PRS is defined as time from relapse to death from any cause. CI, confidence interval; mPRS, median post-recurrence survival.

Inflammatory markers and survival

Among the patients with available data from blood test drawn at time of recurrence, anemia was significantly associated with shorter mOS, 4 months compared to 16 months for those with a B-hemoglobin >120 g/L (HR =2.6; 95% CI: 1.6–4.0; P<0.001). A similar result was seen in the group of patients with elevated platelet count (>350×10⁹/L) (mOS 7 vs. 13 months; HR =1.8; 95% CI: 1.1–2.8; P=0.01). In addition, patients with hypoalbuminemia, elevated leucocytes and high CRP, had a dismal prognosis in the univariate analysis. Both anemia and elevated platelets at the time of recurrence remained independently associated with PRS in multivariable analysis (HR =1.81, 95% CI: 1.10–2.99, P=0.02; HR =2.40, 95% CI: 1.42–4.05, P=0.001) (Table 6). It should be noted, that because of statistical considerations regarding overfitting not all parameters could be included in multivariate analysis, for example only one inflammatory marker, elevated platelets, was analyzed and only one marker for time to relapse (within 12 months).

In summary, factors associated with worse survival following recurrence were PS 3–4, symptomatically detected relapses, anemia, elevated platelets and relapse detected within 12 months. Of these all but elevated platelets remained significant after Bonferroni correction (Table 6).

Discussion

The group of patients with stage III NSCLC is heterogeneous and decision making for optimal therapy is challenging. The choice between surgery and CRT is considered as crucial, although both options are performed with curative intent. Indeed, most clinical studies of CRT modalities suggest 5-year survival rates of 15–25% (2,5,6). Our study provides some indication how these trial results translate into clinical reality. We evaluated a population-based cohort of this patient group after a median follow-up of 52 months, providing a detailed overview over treatment modalities, salvage therapy and treatment outcome in the real-world lung cancer setting in Sweden.

Key findings

The main findings of our study were (I) the relatively long mOS in this group without surgical treatment, (II) the predisposition for distant progression among patients with N3 disease or driver mutations, and (III) the substantial effect of immunotherapy as salvage treatment.

Strengths and limitations

The main strength of this study is the characterization of an unselected and consecutive, real-world cohort that reflects the stage III lung cancer patients seen in daily clinical practice. The main weakness of our study is the retrospective nature and that the patients were treated before the entry of post-CRT immunotherapy (11). We confirmed that this treatment option is effective, but some of our results may not be generalizable to current treatment algorithms for inoperable stage III patients. Nevertheless, we believe that many observations are useful also in the present clinical setting. Furthermore, from a global perspective a substantial proportion of stage III NSCLC worldwide still receive CRT without maintenance immunotherapy as the primary treatment regime. These findings also extend to patients with PD-L1 expression below 1%, who are currently not considered for adjuvant immunotherapy despite evidence of its clinical benefit (12). Although we included consecutive patients over 10 years, the total number is still limited for more focused statistical analysis. Also, the information on driver mutation status is only available for a subset of patients due to changes in clinical practice. The small number of patients is a general problem of single center studies in a group of patients (stage III) that only represent a minority of all diagnosed NSCLC cases.

Comparison with similar research

Our survival rates, with a mOS of 33 months and a 5-year OS rate of 34%, are substantially longer than in most previous clinical trials, including randomized trials studying different CRT modalities (10,13-20). Notably, this includes also the control arm of the Pacific trial analyzing maintenance durvalumab after successful CRT, reporting a median survival of 29 months (21).

In line with observations for NSCLC patients with other stages and differently treated (22-27), we identified elevated inflammatory markers at the time of diagnosis as an unfavorable prognostic factor; for example, elevated CRP levels nearly halved the expected survival time. While this effect did not remain significant after Bonferroni correction, it still suggests an important trend. Not surprisingly, we saw a similar pattern among patients who had blood tests drawn at the time of recurrence: this association was stronger and remained significant following Bonferroni correction. In the latter group, PS was also significantly associated with survival. Clinicians may already intuitively consider these simple parameters; however, a more standardized approach would give additional guidance to the individual prognosis.

Explanation of findings

One possible explanation for the long survival time is that a minor subset of patients (n=16; 8%) in our cohort received immunotherapy at some point with a measurable survival benefit. The clinical outcomes could also be affected by the advancements in radiotherapy with improved dose planning and the introduction of intensity-modulated radiation therapy/volumetric modulated arc therapy (IMRT/VMAT) technology. Additionally, the use of fluorodeoxyglucose positron emission tomography (PET) likely impacts outcomes by enhancing lymph node staging and enabling more precise targeting (28,29). Furthermore, staging methods, patient selection, and local policies for operability could influence the results. Interestingly, although median survival was longer, the proportion of patients with progression was similar to a previous report by Grass et al. (30). Keeping in mind that inoperable patients have an inferior prognosis in the first place and considering the survival rates for stage III patients after surgery (31), the CRT option should at least be regarded as a noninferior option for stage III patients in the real-world setting.

Another interesting observation was that patients with EGFR and KRAS driver mutations were much more likely to develop distant relapse (62%) after CRT than mutation-negative patients (26%). These results possibly reflect previous reports of metastatic patterns in KRAS and EGFR-positive patients, both showing more frequent central nervous system (CNS) metastases at diagnosis (32-35). This finding, and the fact that immunotherapy in EGFR-positive NSCLC has inferior efficacy, emphasizes the need for tailored adjuvant treatment in these patients. Adjuvant EGFR inhibition after surgery is already included in clinical practice after positive trials (36-38), and data from the LAURA trial also show that adjuvant treatment with EGFR tyrosine kinase inhibitor offers a clear benefit to placebo. The HR for disease progression or death was 0.16 (95% CI: 0.10–0.24, P<0.001), suggesting that this approach will soon be adapted in clinical practice as well (39).

Implications and action needed

Besides providing additional insights on prognosis based on clinical parameters, our finding provides guidance for post-CRT monitoring decisions. Current European Society for Medical Oncology (ESMO) guidelines recommend radiographic monitoring only in patients deemed suitable for salvage therapy and suggest a minimum interval of computed tomography (CT)-scans twice yearly (1). In Sweden, the present guideline for monitoring patients with stage IIB–III NSCLC who have received treatment with curative intent is CT scans of the thorax and abdomen three times annually for the initial 2 years, followed by semiannual scans up until 5 years post-diagnosis.

Our findings suggest that the current standards can be adapted to improve the chances of discovering recurrence in time for effective treatment. Firstly, patients with N3 disease or driver mutations are more prone to develop distant metastases upon recurrence and are likely to benefit from extended radiology, including the brain. Secondly, 96% of all recurrences occurred within 3 years after the start of treatment. Thus, an optimized surveillance strategy would involve more intensive monitoring in the earlier follow-up and fewer controls in the later phase. Another promising monitoring option currently under extensive investigation, and likely to be used in the near future, is the use of liquid biopsies for circulating tumour DNA as a complement to radiological imaging.

Our study does not provide enough information as to whether an earlier detection of recurrence will lead to improved survival although the improved OS for patients with recurrent disease detected at routine scans compared to symptomatic recurrences would support this hypothesis. Few patients were identified in time to be considered for treatment with curative intent. Notably, other studies have demonstrated that treatment for local relapse with surgery is beneficial for selected patients (40) and that the use of stereotactic body radiotherapy (SBRT) is an option not only at distant relapse but also possible in some instances in local recurrence despite previous radiotherapy treatment (41,42).

Conclusions

Despite the clear benefits of CRT for some patients, the majority will relapse within 3 years after treatment, most of them without the chance of cure. Thus, prognostic markers for early progression would be highly clinically relevant to further optimize therapy. Our study reinforces that readily available parameters from routine diagnostics can be used to predict survival, as well as time to and site of recurrence in individual patients receiving CRT with curative intent. This may provide a rational for more individualized patient monitoring, possibly improving the chances of detecting residual or metastatic disease while curative salvage therapies still remain an option. Further, the introduction of immunotherapy had a profound impact on survival in this real-world patient cohort, supporting that this option should be offered to all eligible patients in any line of therapy.

Acknowledgments

We thank the Research and Development Unit of the Pathology Department of the University Hospital Uppsala for their continuous support as well as the Uppsala Biobank.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-840/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-840/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-840/prf

Funding: This study was partly supported by the Sjöberg Foundation, Sweden; the Swedish Cancer Society, the Lions Cancer Foundation Uppsala, Sweden; and the Swedish Government Grant for Clinical Research.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-840/coif). J.I. reports participation in advisory board and lectures on the topic of stage III NSCLC for AstraZeneca. T.H. received payment for lecture from AstraZeneca and for participating in expert panel from Daiichi. T.H. received payment for lecture from AstraZeneca and for participating in an expert panel from Daiichi. T.H. is a member of the national group of oncologists, pulmonary medicine, thoracic surgeons, pathologists and radiologist that update the national Swedish guidelines for lung cancer. No support from the industry is given for this work. The group is supported by the Swedish Cancer Society. G.H. has received payments from Roche for tutoring during lung cancer educational sessions during 2023–2024. J.B. received research grants from Amgen and Bristol-Myers Squibb; and lecture honoraria from Astra Zeneca, MSD, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Illumina, GSK, Lilly, Amgen, Incyte, Daiichi and Sanofi. M.L. reports research grant from Ipsen, paid to Karolinska Institutet; and participation in advisory boards of MSD, Ipsen and BMS. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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. The study was approved by the Swedish Ethical Review Authority (No. 2021-01513) and all study procedures were performed in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent has not been obtained specifically for this study. Due to the exceptionally high mortality rate of lung cancer and the retrospective design of this research project, the majority of study participants were deceased at the time of data collection. All results will be published in an anonymized form and presented at the group level.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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