Early Distant Recurrence in Patients With Resected Stage I Lung Cancer: A Case Series of “Blast Metastasis”

Abstract

Operable stage I non–small-cell lung cancer portends a positive prognosis. However, the descriptive characteristics of patients who have developed early distant recurrence have remained poorly defined. Most of these patients with early distant recurrence were elderly smokers with adenocarcinoma. The 5-year survival from recurrence and surgery was 13.2%. Our 5-year survival was greater than the previously reported 5-year survival for stage IVb (0%).

Background:

The standard of care in the management of stage I non–small-cell lung cancer (NSCLC) has been anatomic lung resection with multistation lymph node sampling of ≥ 10 lymph nodes. The 5-year survival for NSCLC has ranged from 73% to 93% (for stage IB and stage IA, respectively) and will be more favorable for patients with fewer comorbidities and those with a higher state of premorbid functioning and who undergo surgical resection. Despite the positive prognosis for operable stage I NSCLC, a subset of patients will develop metastatic disease within as few as 12 months after resection. Using an institutional database, we have presented the data from 68 patients who had developed distant metastatic recurrence after resection of pathologic stage I NSCLC within 1 year after surgery.

Patients and Methods:

A retrospective study was conducted of a prospectively maintained intuitional database. The final cohort included patients with pathologic stage I NSCLC who had undergone anatomic resection but had subsequently presented with multiple sites of distant recurrence within 1 year. The study period extended from 2003 to 2020. Patients with broad local recurrence or recurrence at a single distant site were excluded. Kaplan-Meier analysis was used to estimate the 5-year survival.

Results:

A total of 2827 patients had undergone surgical resection for stage I NSCLC during the 17-year period and 68 met the criteria for inclusion. Most of the patients (n = 48) were smokers, and the dominant histologic type was adenocarcinoma (n = 37). After recurrence, 22 patients (33%) had undergone chemoradiotherapy and 19 (28%) had received chemotherapy alone. The mean and median overall survival were 23.7 and 14 months, respectively. The 5-year survival from recurrence and surgery were both 13.2%.

Conclusions:

Limited data are available on the risk factors for early metastasis after resected stage I NSCLC. The results from our cohort have demonstrated poor survival after recurrence. These data might be the basis for determining a phenotype for patients prone to early widespread metastasis despite seemingly curative surgical resection.

Introduction

Lung cancer is the leading cause of cancer-related death in the United States. It has a prevalence of 1.6 million of the total cases and accounts for 14% of all new malignancies in the United States.¹ The patterns of lung cancer incidence and mortality have a positive correlation with tobacco use. Of the lung cancer cases, 85% are non–small-cell lung cancer (NSCLC) and are diagnosed at an advanced stage.² For early-stage disease, surgery is the primary treatment, with a 5-year survival rates as high as 93%.³

The “Achilles heel” of surgical therapy for lung cancer is recurrence. The recurrence patterns can be classified as either local or distant. Distant recurrence can be further classified as single distant metastasis, pleural effusion, or multiple recurrence sites. Recurrence of any type has been closely linked to reduced overall survival.⁴

Despite improvements in preoperative staging and surgical techniques, some patients with stage I disease will develop recurrence after surgery. Some of these patients will develop recurrence at multiple distant sites within 1 year of resection. For the purposes of the present analysis, this phenomenon has been referred to as “blast metastasis.” The occurrence of this phenomenon suggests a complex interaction between host immunosurveillance, tumor immunoevasion, and other underlying tumor virulence factors and not necessarily surgical failure. Detecting the at-risk patient population could potentially guide the preoperative, intraoperative, and postoperative care for these patients.

We hypothesized that a specific clinical phenotype of patients might exist with an increased risk of developing “blast metastasis.”

Patients and Methods

We performed a retrospective study of 68 patients who had undergone surgical resection from 2003 to 2020 for pathologic stage I NSCLC and had developed recurrence within 1 year after resection. We queried our institutional prospectively maintained surgical database to identify patients meeting the inclusion criteria. The inclusion criteria were as follows: confirmed histologic diagnosis of lung cancer, clinical stage I (T1a-c, T2a, negative nodal disease) using the 8th edition of the American Joint Committee on Cancer TNM staging system,⁵ index surgical treatment (ie, segmentectomy or lobectomy with negative margins for stage I disease), and the development of distant metastasis within 12 months after surgery. Patients who had developed M1a disease or isolated locoregional metastasis or had received neoadjuvant chemotherapy or chemoradiotherapy were excluded. No restrictions on distant metastasis histologic type, adjuvant therapy after distant metastasis, or other factors were imposed. Distant metastasis was diagnosed using computed tomography/positron emission tomography (PET) scans.

The clinical characteristics and demographic data were obtained by a retrospective review of the patients’ medical records. The University of Pittsburgh institutional review board approved the study. Overall survival was calculated from the date of surgery to the date of death or the last follow-up visit. Disease-free survival was calculated from the date of surgery to the date of first distant recurrence. Data are presented as numbers, percentages, or the mean ± standard deviation, as appropriate.

Kaplan-Meier analysis was used to estimate the 5-year survival. All statistical analyses were performed using Stata (StataCorp, College Station, TX).

Results

During the study period, 2827 patients had undergone surgical resection of stage I NSCLC and 68 (2.4%) met our criteria. The cohort’s median age was 65.7 years, and 56% were women. Of the 68 patients, 32 (61%) were former smokers. The average forced expiratory volume in 1 second and diffusing capacity of carbon monoxide was 1.8 L and 70.3%, respectively. Of the 68 patients, 31 (45.6%) had had a Charlson comorbidity index range of 3 to 4 (Table 1).

Table 1.

Demographic Data (n = 68)

Variable	n (%) or Mean ± SD
Age, y	65.7 ± 9.2
Sex
Male	30 (44.1)
Female	38 (55.9)
BMI, kg/m2	28 ± 5.6
CCI
1–2	13 (21.3)
3–4	31 (50.8)
5–6	12 (19.7)
>6	5 (8.2)
Smoking history
Never smoker	4 (7.7)
Former smoker	32 (61.5)
Current smoker	16 (30.7)
FEV1, L	1.8 ± 0.7
DLCO, %	70.3 ± 22.3

Abbreviations: BMI = body mass index; DLCO = diffusing capacity of carbon monoxide; FEV₁ forced = expiratory volume in 1 second; SD = standard deviation.

Of the 68 patients, 26 (38%) had had a diagnosis of stage T2 disease, but the mean tumor size was 2.5 cm, with a right upper lobe predominance (n = 19; 27%). The mean standardized uptake value on PET scan was 8.8 g/mL. Invasive mediastinal staging (endo-bronchial ultrasonography or mediastinoscopy) was performed in 18 patients (26%; 3, endobronchial ultrasonography; 15, mediastinoscopy). Lobectomy was the most common surgical resection performed in this group (66%), followed by segmentectomy (34%). Adenocarcinoma was the most common pathologic finding in the surgical specimen, with evidence of mild to moderate tumor-infiltrating lymphocytes (TILs) in 43% of the specimens. Most (51.5%) of the malignancies had evidence of angiolymphatic invasion and EGFR (epidermal growth factor receptor) amplification. The common sites for distant metastatic involvement after surgical resection were bone, liver, brain, and the adrenal glands (Table 2).

Table 2.

Tumor Characteristics

Variable	Mean ± SD or n (%)
Tumor size, cm	2.5 ± 0.9
Surgical margin, mm	23.8 ± 19.5
SUV on PET	8.8 ± 7.4
Tumor stage (n = 66)
T1a	1 (1.5)
T1b	19 (28.8)
T1c	20 (30.3)
T2a	26 (39.4)
Tumor location (n = 42)
Right upper lobe	19 (45.2)
Right lower lobe	7 (16.7)
Left upper lobe	8 (19)
Left lower lobe	8 (19)
Histologic type (n = 58)
Adenocarcinoma	37 (63.8)
Adenocarcinoma, mixed	2 (3.4)
Squamous cell	12 (20.7)
Squamous cell, mixed	7 (12.1)
Surgical approach (n = 68)
Lobectomy	44 (64.7)
Segmentectomy	23 (33.8)
Sleeve lobectomy	1 (1.5)
TILs (n = 32)
Mild	15 (46.9)
Moderate	14 (43.8)
Severe	3 (9.4)
Angiolymphatic invasion (n = 55)
Yes	35 (63.6)
No	20 (36.3)
Tumor markers (n = 64)
EGFR amplification	35 (54.7)
PD-1/PD-L1	13 (20.3)
KRAS	12 (18.8)
Lymph nodes harvested, n	13 ± 10
Mediastinoscopy (n = 65)
Before surgery	9 (13.8)
At surgery	6 (9.2)
EBUS before surgery (n = 65)	3 (4.6)
Distant sites (n = 64)
Bone	19 (30)
Liver	19 (30)
Brain	18 (28)
Adrenal gland	8 (12.5)

Abbreviations: EBUS = endobronchial ultrasonography; EGFR = epidermal growth factor receptor; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; PET = positron emission tomography; SD = standard deviation; SUV = standardized uptake value; TILs = tumor-infiltrating lymphocytes.

The mean disease-free survival was 5.8 months (range, 1–11 months). After the diagnosis of distant recurrence, 22 patients (33%) had undergone chemoradiotherapy and 19 patients (28%) had undergone chemotherapy alone. Two patients had undergone a second surgical resection. The mean and median overall survival (interval from surgery to the last day of follow-up or death) were 23.7 months (range, 3–124 months) and 14 months for the overall cohort, respectively. The 5-year survival for the entire cohort from the initial operation was 13.2% (Figure 1, Table 3).

Figure 1.

Kaplan-Meier Curve Showing the 5-Year Survival for Patients With Resectable Stage I Non–small-cell Lung Cancer Complicated by Distant Recurrence Within 1 Year of Surgery

Table 3.

Adjunct Therapy After Distant Recurrence and Survival Outcomes

Variable	n (%) or Mean ± SD
Postrecurrence therapy (n = 58)
Chemoradiotherapy	22 (37.9)
Chemotherapy	19 (32.8)
Radiotherapy	9 (16.3)
Disease-free survival, mo	5.8 ± 2.6
5-Year survival, mo	18.7 ± 29.4

Abbreviation: SD = standard deviation.

Discussion

We retrospectively described the demographic data, tumor characteristics, and survival outcomes for 68 patients who had undergone surgical resection for pathologic stage I NSCLC, and developed multiple distant sites of recurrence within 1 year of surgical treatment. To date, limited data describe the characteristics of patients who present with this form of aggressive disease within a short period after lung resection. In our study, most of the patients had been former smokers, with a predominant histologic type of adenocarcinoma, and undergone a lobectomy.

Analysis of our data revealed several interesting findings. First, these patients showed a tendency to have larger tumors with a high standardized uptake value on computed tomography/PET, which are also risk factors for nodal spread. The 5-year overall survival of 13.2% was better than the reported 5-year overall survival of stage IVb NSCLC, which has been typically closer to 0%.⁶ However, further context of these findings is still to be determined. Two patients had undergone repeat resection after the index surgery for stage I NSCLC in our cohort. Additionally, the preponderance of characteristics for these patients was similar to those of all patients who develop lung cancer because they were elderly smokers with adenocarcinoma.

Ginsberg and Rubinstein,⁷ and others, have highlighted the risk factors for locoregional occurrence, including sublobar resection, a high smoking index, a lymph node harvest of < 15, and histologic type other than adenocarcinoma. However, the reported data have remained scarce regarding the predictors of distant metastasis for patients with resectable stage I NSCLC.^4,7,8 The distant recurrence rates have varied from 14% to 31% in resectable stage I NSCLC.^9,10 Hung et al^4,10 had suggested that stage T2a adenocarcinoma resulted in a lower probability of freedom from distant metastasis in patients with resectable stage I NSCLC. They showed that distant metastases had occurred within 2 years of surgical resection in ~84% of patients.^4,10 However, most of the patients (62%) had died within 1 year of the development of distant metastases.¹⁰ Sawyer et al¹¹ reported that non–squamous histologic features and tumor size > 5 cm predicted for a poor distant metastasis-free rate in patients with resected stage I NSCLC.

We also found various degrees of TILs in our cohort, confirming the favorable prognostication of TILs in resectable NSCLC.^12,13 A comparison between the present cohort and patients without recurrence could provide further insight regarding the prognostic value of TILs in early-stage disease in the setting of early distant recurrence.

The present study had several limitations. Patient selection bias and reporting bias were inherent shortcomings of our analysis. We did not compare our group of patients with a similar group without signs of distant recurrence to detect observed changes that might correspond with the existing data (despite the limited data available on the risks of distant recurrence). Also, the study period was broad, which could have introduced a bias because the staging systems and best practices could have changed. Ultimately, a robust comparison with patients without recurrence would allow us to further elucidate the clinical phenotype of “blast metastasis.” Despite these limitations, our study has characterized the multiple clinical factors for patients who had presented with distant recurrence within 1 year after surgical resection.

Clinical Practice Points.

• Advanced age, smoking history, biopsy-proven adenocarcinoma, and right upper lobe predilection at surgical resection were demographically dominant in the present series of patients with resectable stage I NSCLC who had developed early distant recurrence.

• TIL data were available for 50% of the patients; however, the TIL presence was severe in < 10%.

• Patient- and tumor-related risk factors might influence the development of early widespread recurrence after surgery for stage I NSCLC.

• Further study is warranted to better characterize and, ultimately, predict the at-risk population.