Effect of stage shift and immunotherapy treatment on lung cancer survival outcomes

Abstract

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OBJECTIVES

Non-small-cell lung cancer mortality has declined at a faster rate than incidence due to multiple factors, including changes in smoking behaviour, early detection which shifts diagnosis, and novel therapies. Limited resources require that we quantify the contribution of early detection versus novel therapies in improving lung cancer survival outcomes.

METHODS

Non-small-cell lung cancer patients from the Surveillance, Epidemiology, and End Results-Medicare data were queried and divided into: (i) stage IV diagnosed in 2015 (n = 3774) and (ii) stage I–III diagnosed in 2010–2012 (n = 15 817). Multivariable Cox-proportional hazards models were performed to assess the independent association of immunotherapy or diagnosis at stage I/II versus III with survival.

RESULTS

Patients treated with immunotherapy had significantly better survival than those who did not (HR_adj: 0.49, 95% confidence interval: 0.43–0.56), as did those diagnosed at stage I/II versus stage III (HR_adj: 0.36, 95% confidence interval: 0.35–0.37). Patients on immunotherapy had a 10.7-month longer survival than those who were not. Stage I/II patients had an average survival benefit of 34 months, compared to stage III. If 25%% of stage IV patients not on immunotherapy received it, there would be a gain of 22 292 person-years survival per 100 000 diagnoses. A switch of only 25% from stage III to stage I/II would correspond to 70 833 person-years survival per 100 000 diagnoses.

CONCLUSIONS

In this cohort study, earlier stage at diagnosis contributed to life expectancy by almost 3 years, while gains from immunotherapy would contribute ½ year of survival. Given the relative affordability of early detection, risk reduction through increased screening should be optimized.

INTRODUCTION

Lung cancer (LC) remains the second most common cancer in both males and females and continues to be the leading cause of death in Western societies [1]. Over the years, LC mortality has been steadily declining at a pace that is faster than the decline in LC incidence [1]. The improved outcomes are the result of a multifactorial approach including early detection, shifts in histological types, changes in smoking behaviour, targeted therapies, oncogene tumour profiling, and more advanced surgical and radiological approaches [2–5].

Early detection is a significant contributor to improved survival in non-small-cell lung cancer (NSCLC). Several landmark studies have shown that low-dose computed tomography (CT) screening can identify early-stage disease in nearly 4 of 5 patients unknowingly harbouring it, with nearly 70–92% of patients with stage I surviving at 5 years after diagnosis [6–10]. More recently, we identified stage shift due to early detection—whether intentional or non-intentional—as a relevant factor in NSCLC survival [4]. This shift corresponded to a decrease in mortality with median survival for stage I/II being 57 months compared to only 7 months for stage III/IV disease [4].

Despite these findings, we cannot overlook the paradigm shift in the treatment of NSCLC that has occurred over the past decade [11]. The approval of targeted therapies starting in 2013 among patients harbouring driver mutations in oncogenes, such as epidermal growth factor receptor and anaplastic lymphoma kinase, has provided a significant survival benefit [11]. Moreover, immunotherapies, in particular programmed cell death protein 1–programmed death ligand 1 (PD-1/PD-L1) inhibitors have substantially improved survival among patients with NSCLC independently from the presence of driver mutations in oncogenes [11–16]. Howlader et al. [5] examined the impact of targeted and immunotherapies on LC mortality from 2001 to 2016. They observed that since the approval of targeted and immunotherapies starting in 2013, the incidence-based mortality for men diagnosed with NSCLC declined at a sharper rate of 6.3% per year compared to prior years when the rate of decline was only 3.2% per year [5]. Similar results were also observed for women diagnosed with NSCLC [5].

These findings suggest that the observed decrease in population mortality from NSCLC is likely due to a combination of both early detection and advents in novel therapeutics. Because of limited resources, it is important to weigh the relative contribution of early detection versus immunotherapies on survival. This step will inform how to better allocate efforts towards early detection through screening or advanced, novel immunotherapy development and testing in randomized clinical trials. We present here the analysis of a large population-based dataset with the aim to quantify how much of the observed decline in population mortality could be attributed to early detection, and the consequent stage shift, or to better immunotherapies against PD-1/PD-L1.

METHODS

Ethics statement

The Institutional Review Board at the Icahn School of Medicine at Mount Sinai deemed this study as exempt research, as this dataset is de-identified. Patient written consent for the publication of the study was not required. Data were acquired from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.

Data source and selection criteria

Data were extracted from the SEER-Medicare-linked database. SEER includes 31 population-based cancer registries in the USA, covering ∼35% of the population, and provides information on demographics and tumour characteristics [17]. Medicare insures ∼96% of all US citizens >65 years and provides information on treatment and comorbidities [18]. Patients were included if they had microscopically confirmed first or only primary LC from 1992 to 2015 (n = 489 920). Comorbidities were defined from claims in the year prior to diagnosis, while treatments in the year after diagnosis; thus, patients were excluded if they were <66 years at diagnosis, lacked continuous Parts A and B coverage or had Part C coverage, in the year prior to and post-diagnosis (n = 251 123). The sample was limited to NSCLC (n = 208 514).

Two groups of patients were selected: the first group included stage IV patients diagnosed in 2015 (n = 9282) – the latest available year in the dataset and based on U.S. Food and Drug Administration (FDA) approval of immunotherapy for stage IV LC in 2013 (cohort 1). Sensitivity analyses were conducted on those who received either immunotherapy or chemotherapy (n = 1499; 377 immunotherapy, 1122 chemotherapy). A second group (cohort 2) included cases diagnosed in 2010–2012 (n = 29 948) and limited to stage I–III (n = 15 817). This sample was selected to allow for 5-year follow-up and to identify cases diagnosed before 2013 – the introduction of approved targeted therapies.

The primary outcome was overall survival (OS). For cohort 1, claims in the year after diagnosis were queried for immunotherapy and/or chemotherapy HCPCS codes. Immunotherapy included approved PD-1/PD-L1 inhibitors available in 2015 (Supplementary Material, Table S1). Survival was complete through December 31, 2017; follow-up was limited to 2 years, as this is the most clinically relevant information for stage IV NSCLC. For cohort 2, survival was calculated at 2 and 5 years; 2-year survival was for comparison with the cohort 1 survival.

Age at diagnosis, sex, race, marital status and histology were extracted from SEER. Racial categories included white, black and other. Histology was based on the International Agency for Cancer Research codes and divided into squamous cell carcinoma, adenocarcinoma or others [19]. A modified version of the National Cancer Institute (NCI) Charlson comorbidity index incorporating both ICD-9 and ICD-10 codes was calculated from Medicare claims in the year prior to diagnosis [20, 21].

Statistical analysis

Cohort 1: Kaplan–Meier curves and the log-rank test were used to assess differences in 2-year OS according to receipt of immunotherapy. A sensitivity analysis was conducted on those who received immunotherapy versus those on chemotherapy. Multivariable Cox-proportional hazards regression models evaluated the independent association of immunotherapy with OS, adjusting for age, sex, race, marital status, comorbidities, and histology.

Cohort 2: Kaplan–Meier curves and the log-rank test were used to assess differences in 2- and 5-year OS in stage I–II versus stage III patients. Multivariable Cox-proportional hazards regression models evaluated the independent association of stage with OS, adjusting for age, sex, race, marital status, comorbidities, and histology.

Within each cohort, differences in years of median survival between groups were calculated and used to simulate potential additional person years of survival per 100 000 diagnoses if those in the higher-risk group moved to the lower-risk group. The percentage of patients switching from the higher to lower risk group was allowed to vary from 10 to 100.

RESULTS

Patient characteristics

Of 3744 patients with stage IV NSCLC, 377 were treated with immunotherapy. A total of 1122 patients were treated with chemotherapy without the addition of immunotherapy (Table 1). Those with immunotherapy were significantly younger, more likely to be married, with squamous cell carcinoma, and with a significantly lower comorbidity score, compared to the rest of stage IV patients. A total of 15 817 patients were diagnosed with stage I–III NSCLC. Patients with stage I–II NSCLC were younger, more likely female, white, married, with adenocarcinoma, and with slightly higher comorbidity score than stage III patients (Table 1).

Patient survival

Stage IV patients on immunotherapy survived an average of 14.8 months, while the remaining stage IV patients’ survival was 4.1 months. Those treated with chemotherapy survived an average of 9.2 months (Fig. 1a and b). Two-year survival was significantly greater with immunotherapy, compared to both the remaining stage IV patients and to those treated with chemotherapy. After adjustment, there remained a significant improvement in OS with immunotherapy [HR_adj: 0.49, 95% confidence interval (CI): 0.43–0.56] versus the remaining stage IV patients (HR_adj: 0.71, 95% CI: 0.62–0.82) versus chemotherapy (Table 2).

Stage I–II patients had an average survival of 44.2 versus 10.2 months in stage III (P < 0.001). Survival was significantly better both at 2 and 5 years in stage I–II than stage III patients (Fig. 1c). After adjustment, those with stage I/II disease had significantly higher OS than those with stage III (HR_adj: 0.36, 95% CI: 0.35–0.37) (Table 2).

Stage shift simulation

Of 3397 patients diagnosed with stage IV NSCLC who did not receive immunotherapy, their median survival was 10.7 months (0.89 years) less than those who received immunotherapy. If 25% of them were treated with immunotherapy, there would be a gain of 22 292 person-years of survival per 100 000 diagnoses. Among the 1122 patients treated with chemotherapy, the median survival was 5.6 months (0.47 years) shorter than those treated with immunotherapy. A shift of 25% to immunotherapy would result in 11 667 additional person-years of survival per 100 000 diagnoses (Table 3).

Among 7144 patients diagnosed at stage III from 2010 to 2012, the median survival was 34.0 months (2.83 years) less than those diagnosed at stage I/II. If 25% of these patients were diagnosed as stage I–II, there would be a gain of 70 833 person-years of survival per 100 000 diagnoses (Table 3).

DISCUSSION

In this analysis, we show that any intervention at a population level inducing a shift to lower NSCLC stages would obtain a larger improvement in survival than the introduction of novel therapies, such as immunotherapy, in late-stage NSCLC. While prior studies have individually explored the association of CT screening andtargeted and immune-based therapies [2–5] with a decrease in NSCLC mortality, the relative contribution of early detection versus immunotherapies in improving lung cancer survival has never been examined and directly compared. We believe that understanding this is critical to determine whether resources should be allocated to early detection through screening or towards advanced, novel immunotherapy development. With limited precedent, we sought to examine to what extent the decrease in NSCLC population mortality can be attributed to early detection, and the consequent stage shift, or to better immunotherapy intervention.

Consistent with prior literature, we demonstrated that on a population level, survival significantly increases among patients with stage IV NSCLC treated with immunotherapy, from 4.1 months in patients receiving only chemotherapy to 14.8 months with immunotherapy. The significant improvement in 2-year OS among stage IV patients receiving immunotherapy persisted after adjusting for several confounders, corroborating at a population level several landmark studies [11–16, 22, 23]. In phase 3 clinical trials of patients with advanced NSCLC who were previously treated or had disease progression during platinum-based chemotherapy, patients treated with PD-1/PD-L1 inhibitors had an overall median survival of 12.2–13.8 months [12–14], significantly more than what was observed in those treated with docetaxel whose median OS was only 9.4–10.4 months [12–14]. Survival benefit was seen regardless of the PD-L1 expression level but was enhanced in patients with higher PD-L1 expression levels [12, 15, 22].

When looking at stage I-III NSCLC, the median OS was 44.2 months for patients with stage I and II disease, which was significantly greater compared to the median survival of 10.2 months for those diagnosed at stage III, and that persisted after adjusting for demographics, tumour characteristics, and comorbidities. On a population level, our findings further reinforce the substantially greater survival that patients have when they are diagnosed at an early stage, which has a 5-year survival of 53–92% while stage III disease drops to 26–36% [10]. Several landmark studies have reported increased detection of early-stage disease with low-dose CT screening [6–9]. In fact, in the National Lung Screening Trial, of 649 positive screening tests, 70.2% was stage I and II with late-stage accounting for only 29.8% [6].

Given the survival benefit of both early detection and immunotherapies, we sought to determine the relative contribution of early detection versus immunotherapies in improving LC survival. We observed that if a patient with stage IV NSCLC was treated with immunotherapy, they would gain an average of 10.7 months. This translated into a gain of 22 292 person-years of survival per 100 000 diagnoses if 25% of patients received immunotherapies. This survival gain was substantially less compared to what was projected for early detection. Patients being diagnosed at stage I or II gain a median survival of 34.0 months, which equated to a gain of 70 833 person-years of survival per 100 000 diagnoses if only 25% of the cohort shifted stage. These findings suggest that early detection could translate into a stage shift at diagnosis that could substantially modify life expectancy. Even with the best immunotherapy treatment available, stage IV NSCLC is associated with high mortality rates, and the gain in survival with immunotherapy is modest, certainly less than what is obtained by an early cancer diagnosis, when NSCLC is at a curable stage.

Although we are not in a position to conduct cost-effectiveness analyses, our findings provide significant insight into how resources should be allocated for the treatment of NSCLC. Along with immunotherapies providing a modest gain in survival, they are associated with significant cost, which might not be cost-effective or affordable for a large section of the population [24]. Based on a cost-effectiveness analysis of pembrolizumab as first-line treatment in locally advanced or metastatic NSCLC, the cost would be $136 228.82 per quality-adjusted life year for patients with PD-L1 expression ≥50% [24]. The cost increases as the PD-L1 expressions decrease [24]. In contrast, the costs of early detection by low-dose CT are modest, around $300 per scan. Low-dose CT screening based on a routine basis according to guidelines costs $81 000 per quality-adjusted life year, which is significantly lower compared to immunotherapies [25]. However, we recognize the growing use of neoadjuvant immunotherapies in resectable early-stage NSCLC, as they improve pathological response rates and in turn prolong patient survival [26]. With increasing early detection through low-dose CT screening, it is quite likely the use of induction immunotherapy will continue to expand, leading to early detection further increasing the expenses for immunotherapies.

At the same time, low-dose CT for eligible patients can serve as a preventative health measure for many other smoking-related health conditions [27, 28]. In fact, among 52 726 at-risk patients who underwent screening, nearly a quarter had CT evidence of emphysema with 77% of these patients having no prior COPD diagnosis [27]. Moreover, low-dose CT also offers an opportunity to assess cardiovascular health [28]. Out of 3110 patients who underwent low-dose CT for recommended lung cancer screening, 25.9% were found to have moderate or severe coronary artery calcification with nearly 74% of whom underwent changes in their medication regimen [28]. Despite the health benefits and cost-effectiveness, the uptake of LC screening with low-dose CT remains limited and stable with 4.5% and 5.9% of adults aged 55–80 years in 2010 and 2015, respectively, who met guidelines, received a CT scan within the prior year [29]. Thus, greater patient adherence to low-dose CT screening is needed to further actualize the primary and secondary benefits of early detection.

Our study has several strengths. We analysed a large US population-based dataset to quantify how much of the observed decline in NSCLC population mortality could be attributed to early detection, and the consequent stage shift, or to better immunotherapies against PD-1/PD-L1. We based our analysis on the SEER program, which captures and classifies all newly diagnosed cancers across several US areas. Moreover, while prior clinical trials have independently assessed survival among patients undergoing either low-dose CT LC screening or immunotherapy for late-stage disease, this is the first study that compared both and evaluated the relative contribution of early detection versus immunotherapy on NSCLC survival in a real-world situation. The results based on population-level data are more generalizable and more representative of the entire US population rather than focusing on subpopulations, which can be the case with single-centre studies or randomized clinical trials.

Limitations

The findings from this retrospective study should be interpreted within its limitations. We used a database that only contained pre-selected demographic and clinical variables. We did not have available data for smoking, family history of respiratory cancer, occupational exposure, and driver mutations, such as epidermal growth factor receptor, which would provide increased insight. Moreover, we lack detailed information on the diagnostic method, thus limiting us from measuring the rate of CT scan uptake among the study population. The immunotherapy group was limited to 2015, when several of the newest drugs were not yet available in clinical practice. For example, in 2020, the FDA-approved combination therapy of nivolumab with ipilimumab, which has a greater survival benefit than monotherapy. Furthermore, we did not have patient-level details on immunotherapy treatment, including the duration of treatment, why some patients were not offered immunotherapy, and why treatment was terminated in certain patients.

CONCLUSION

In this cohort study, during the observed years, earlier stage at diagnosis contributed to almost 3 years of life expectancy. Comparatively, gains from immunotherapy were ½ year, even after assuming the best-case scenario of all stage IV patients responding well to immunotherapy. Given the relative affordability of early detection screenings, every effort should be made to increase screening availability, and resources should be directed towards risk reduction and early diagnosis. While we recommend immunotherapy for NSCLC patients who benefit from it, we suggest that the larger picture should focus on lung cancer risk reduction, smoking cessation, and early detection.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

ACKNOWLEDGEMENTS

The views expressed in this study do not reflect those of Milliman Inc, which employs Mr. Bruce Pyenson and provides actuarial consulting services to many organizations in health care.

Funding

No funds, grants, or other support were received.

Conflict of interest: Mr. Bruce Pyenson reported serving as a commissioner on the Medicare payment Advisory Commission outside the submitted work. No other disclosures were reported.

DATA AVAILABILITY

This study used the linked SEER-Medicare database. Requests for access to the SEER-Medicare dataset can be made through the National Cancer Institute at https://healthcaredelivery.cancer.gov/seermedicare/obtain/requests.html. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumour registries in the creation of the SEER-Medicare database.

Author contributions

Parth Patel: Conceptualization; Data curation; Formal analysis; Writing—original draft; Writing—review & editing. Raja Flores: Conceptualization; Data curation; Formal analysis; Resources; Supervision; Writing—original draft; Writing—review & editing. Naomi Alpert: Conceptualization; Data curation; Formal analysis; Writing—original draft; Writing—review & editing. Bruce Pyenson: Conceptualization; Formal analysis; Resources; Supervision; Writing—original draft; Writing—review & editing. Emanuela Taioli: Conceptualization; Data curation; Formal analysis; Resources; Supervision; Writing—original draft; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks the anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CT

  Computed tomography

 
• LC

  Lung cancer

 
• NSCLC

  Non-small-cell lung cancer

 
• OS

  Overall survival

 
• PD-1/PD-L1

  Programmed cell death protein 1–programmed death ligand 1

 
• SEER

  Surveillance, Epidemiology, and End Results