Abstract

Abstract

The advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for the treatment of advanced non‐small cell lung cancer has resulted in an increasing number of long‐term survivors. Consequently, the emergence of second malignancy may have implications for their prognosis. This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥ 2 years developed second malignancy. It was suggested that by performing screening and examinations for the second malignancy, both malignancies could be controlled.

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INTRODUCTION

In 2019, lung cancer was reported to be the leading cause of cancer deaths in Japan and was associated with poor prognosis, especially in advanced stages (5‐year survival rate: 10–20%). ^{1 , 2} Before the discovery of driver oncogenes, corresponding molecular targeted agents, and immune checkpoint inhibitors (ICIs), cytotoxic chemotherapeutic agents were the mainstay treatment for advanced non‐small cell lung cancer (NSCLC). However, these agents offered limited effectiveness, with a median survival time (MST) of approximately 1year and often caused serious adverse events. ³

A turning point in NSCLC therapy came in 2002 with the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), which significantly improved NSCLC prognosis. ^{4 , 5} Osimertinib, the currently recommended first‐line therapy for advanced‐stage EGFR mutation–positive NSCLC, has demonstrated a significantly extended overall survival (OS) of 38.6months. ⁶ Subsequently, ICIs were introduced in the mid‐2010s, which were found to provide a long‐term survival comparable to that with conventional therapies. A study showed that the 5‐year survival rate was 31.9% in pembrolizumab‐treated advanced NSCLC cases that were EGFR mutation–negative, anaplastic lymphoma kinase (ALK) fusion gene–negative, and programmed death‐ligand 1 (PD‐L1) expression–positive (tumor proportion score≥50%). ⁷

Patients with lung cancer have a higher risk of developing secondary malignancies compared to the general population. In addition to smoking history, ⁸ secondary malignancies may develop in patients during the course of primary lung cancer treatment, owing to the carcinogenic effects of cytotoxic chemotherapy and radiotherapy. ⁹ Studies have reported a prevalence of 3.0%–3.14% for secondary malignancies in patients with NSCLC, with head and neck, urinary tract, prostate, and gastrointestinal tract malignancies being the most frequent. ¹⁰ During the time when cytotoxic chemotherapeutic agents were the treatment of choice, the limited survival time of patients often minimized the impact of secondary malignancies on the treatment course. Whereas with the advent of TKIs and ICIs, the number of long‐term survivors is increasing, which makes it more likely for other conditions, such as secondary malignancies, to contribute to patient prognosis. However, the full extent of this influence remains unclear.

Notably, most of the previous studies on secondary malignancies involved patients with surgically resectable lung cancer before the 2000s. ^{9 , 10 , 11} Thus, the characteristics and prognosis of patients with recurrent or advanced NSCLC who develop secondary malignancies while receiving TKIs and ICIs remain unknown. Therefore, this study investigated the characteristics of secondary malignancies and their impact on the course of lung cancer treatment in patients with recurrent or advanced NSCLC who were treated with TKIs and ICIs and achieved long‐term survival.

METHODS

RESULTS

Clinical characteristics of patients

Figure 1 illustrates the patient enrolment flowchart of the study. A total of 302 patients received first‐line chemotherapy between April 1, 2013, and March 31, 2020. Of these, 190 patients were excluded owing to death or were lost to follow‐up within 2years. Thus, only 112 patients who survived ≥2years were enrolled in this study. The median follow‐up period was 40.8months (range: 24.0–100.2months).

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FIGURE 1

Patient diagram. A total of 302 patients received first‐line chemotherapy between April 1, 2013, and March 31, 2020. Of these, 190 patients were excluded owing to death or lost to follow‐up within 2years. Ultimately, 112 patients who survived ≥2years were enrolled in the study.

Table 1 summarizes the patient and pathological characteristics. The median age at the time of first‐line chemotherapy was 68years (range: 40–85), and majority of the patients were males (60.7% vs. 39.3%). Adenocarcinoma was the most common histological type (n=101, 90.2%), followed by squamous cell carcinoma in (n=8, 7.2%) and NSCLC not otherwise specified (NSCLC‐NOS) (n=3, 2.6%). Among the 112 patients, 74 (66.1%) were smokers, and 38 (33.9%) were non‐smokers. ECOG PS scores at the start of first‐line chemotherapy were 0 for 56 patients (50.0%), 1 for 55 patients (49.1%), and 2 for one patient (0.9%). EGFR mutations and ALK rearrangements were identified in 44 (39.3%) and seven patients (6.3%), respectively. PD‐L1 expression was high (>50%) in 41 patients (36.7%), low (1–49%) in 21 patients (18.7%), negative in 21 patients (18.7%), and unmeasured in 29 patients (25.9%).

TABLE 1

Characteristics of patients who survived for at least 2years in this study.

Age at the time of first line chemotherapy [years, range]
Median	68 [40–85]
Sex (n, %)
Male	68 (60.7)
Female	44 (39.3)
Histology (n, %)
Adenocarcinoma	101 (90.2)
Squamous cell carcinoma	8 (7.2)
NSCLC‐NOS	3 (2.6)
Smoking history (n, %)
Current or previous	74 (66.1)
Never	38 (33.9)
Performance status (n, %)
0	56 (50.0)
1	55 (49.1)
2	1 (0.9)
Driver mutations/rearrangements (n, %)
EGFR	44 (39.3)
ALK	7 (6.3)
Negative/unknown	61 (54.4)
PD‐L1 tumor expression [22C3 assay] (n, %)
High (≥50%)	41 (36.7)
Low (1–49%)	21 (18.7)
Negative (<1%)	21 18.7)
Unmeasured	29 (25.9)
Second primary tumor (n, %)
Yes	10 (8.9)
No	102 (91.1)
Tumor location (n, %)
Pancreatic cancer	3 (30.0)
Bladder cancer	2 (20.0)
Esophageal cancer	2 (20.0)
Colorectal cancer	1 (10.0)
Rectal cancer	1 (10.0)
Prostate cancer	1 (10.0)
Myelodysplastic syndromes (MDS)	1 (10.0)
Gingival cancer	1 (10.0)

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Secondary malignancies in patients with NSCLC

During the follow‐up period, 10 patients (8.9%) developed secondary malignancies, including third primary malignancies (group 1), whereas the remaining 102 patients (91.1%) reported no such developments (group 2). The person‐years method was applied to the 112 long‐term survivors who were followed for ≥2years, resulting in 428 person‐years. Consequently, 10 cases of secondary malignancies were identified, calculated as 10/428= 0.02336, which corresponds to an incidence rate of 2.34% per person‐year. Table 2 summarizes the patient characteristics of each group. Notably, all group 1 patients had adenocarcinomas. Furthermore, group 1 demonstrated a higher proportion of smokers (90% vs. 63.7%) compared to group 2, although the difference was not statistically significant.

TABLE 2

Comparison of patient characteristics between group 1 (with secondary malignancies) and group 2 (without secondary malignancies).

	Group1 (N=10) (n, %)	Group2 (N=102) (n, %)	p value
Median age [year, range]	70 [51–82]	68 [40–85]	0.513
Sex			0.19
Male	8 (80.0)	60 (58.8)
Female	2 (20.0)	42 (41.2)
Histology			0.55
Adenocarcinoma	10 (100)	91 (89.2)
Squamous cell carcinoma	0 (0.0)	8 (7.8)
NSCLC‐NOS	0 (0.0)	3 (3.0)
Smoking history			0.094
Current or previous	9 (90.0)	65 (63.7)
Never	1 (10.0)	37 (36.3)
Driver mutations/rearrangements			0.165
EGFR	3 (30.0)	41 (40.2)
ALK	2 (20.0)	5 (4.9)
Negative/unknown	5 (50.0)	56 (54.9)
PD‐L1 [22C3 assay] expression			0.387
≥50%	3 (30.0)	38 (37.3)
<50% or unknown	7 (70.0)	64 (62.7)

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Table 3 and Figure 2 present the pathological characteristics and course of patients with secondary malignancies. The most commonly affected organs included the pancreas (three cases, 30%), bladder and esophagus (two cases each, 20%), and one case each affecting the prostate, rectum, colon, bone marrow (myelodysplastic syndrome [MDS]), and gingiva. Regarding diagnosis, six patients (50%) were diagnosed via imaging, whereas four patients (33.3%) were diagnosed based on physical examinations. The timing of onset for secondary malignancies did not show a clear trend, with six cases reported within 2years of lung cancer treatment initiation and six cases reported after 2years. Regarding interventions for secondary malignancies, seven patients (70%) underwent surgical treatment, while the remaining five received medical treatment or did not undergo any treatment. Furthermore, lung cancer treatment was interrupted following secondary malignancy diagnosis in four cases, resulting in death in three cases (two cases owing to secondary malignancies and one case owing to lung cancer).

TABLE 3

Pathological characteristics of patients with secondary malignancies (10 patients, 12 secondary malignancies).

Number	Age	Gender	PS	Treatment	Second malignancy	Histology of second malignancy	History of diagnosis	Time of onset (Months)
1	74	Male	0	Crizotinib a , b →alectinib	Rectal	Adenocarcinoma	Follow‐up CT	51.1m
					Pancreas	Adenocarcinoma	Follow‐up PET‐CT	71.5m
2	58	Male	1	Gefitinib→CDDP+PEM→osimertinib a →TS‐1→DTX→atezolizumab	Esophageal	Squamous cell carcinoma	Physical examination	65.5m
3	59	Female	1	Pembrolizumab a	Pancreas	Adenocarcinoma	Follow‐up PET‐CT	31.1m
4	82	Female	0	Pembrolizumab→PEM→TS‐1 a →pembrolizumab→VNR→TS‐1→GEM	Esophageal	Squamous cell carcinoma	Hematemesis	11.0m
5	55	Male	0	Alectinib→lorlatinib a →brigtinib	Prostate	Adenocarcinoma	Physical examination	38.6m
6	77	Male	0	Pembrolizumab→PEM→TS‐1 a →DTX→nab‐PTX→GEM→tepotinib	Bladder	Urothelial carcinoma	Follow‐up CT	26.9m
7	74	Male	0	CBDCA+PEM+atezolizumab a →DTX+RAM→TS‐1→GEM	Gingival	Verrucous carcinoma	Physical examination	16.2m
8	51	Male	0	Gefitinib a →osimertinib→CBDCA+PAC+BEV+atezolizumab→DTX+RAM	Colon	Adenocarcinoma	Physical examination	6.9m
9	70	Male	0	CBDCA+PEM+pembrolizuamb a	MDS	N/A	Thrombocytopenia	13.1m
10	70	Male	1	Osimertinib+antiangiogenesis a , b	Bladder	Urothelial carcinoma	Follow‐up CT	3.7m
					Pancreas	Adenocarcinoma	Follow‐up CT	24.9m

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Abbreviations: BEV, bevacizumab; CBDCA, carboplatin; CDDP, cisptatin; DTX, docetaxel; GEM, gemcitabine; nab‐PTX: nab‐paclitaxel; PEM, pemetrexed; PTX, paclitaxel; RAM, ramucirumab; TS‐1, tegafur gimeracil oteracil potassium; VNR, vinorelbine.

^a When secondary malignancy occurred.

^b When tertiary malignancy occurred.

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FIGURE 2

Treatment course of the patients with secondary malignancies.

Univariate analysis of risk factors for secondary malignancies

Table 4 summarizes the results of the univariate analysis with secondary malignancies as the outcome. Our findings revealed a non‐significant trend towards a higher incidence in smokers compared to non‐smokers. However, since all patients had adenocarcinomas, statistical analysis for histology was no longer performed.

TABLE 4

Univariate analysis for risk factors of secondary malignancies.

	Odds ratio	p value
	[95% confidence intervals]
Sex (male vs. female)	2.801 [0.566–13.85]	0.2069
Age (<75years vs. ≥75years)	0.744 [0.144–3.831]	0.7238
ECOG PS score (0 vs. ≥1)	1.560 [0.415–5.859]	0.5102
Smoking history	5.123 [0.624–42.04]	0.1282
(Current or previous vs. never)
Histology (non‐Sq vs. Sq)	NA	0.9987
EGFR mutation or ALK rearrangement	0.821 [0.224–3.012]	0.7667
(Negative/unknown vs. positive)
PD‐L1 TPS (22C3) (≥50% vs. <50%)	0.721 [0.176–2.958]	0.6506
First‐line treatment	1.428 [0.389–5.246]	0.591
(TKI vs. ICIs or ICIs+chemotherapy)

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DISCUSSION

The advent of TKIs and ICIs has significantly improved long‐term survival, even for patients with advanced‐stage NSCLC. ^{4 , 5 , 6 , 7} Therefore, the impact of diseases other than lung cancer, including secondary malignancies, cannot be ignored. To that end, trends in secondary malignancies and survival rates in patients with lung cancer have been investigated particularly studies on secondary malignancies after curative treatment for NSCLC. Despite this, to the best of our knowledge, this is the first study regarding secondary malignancies that developed during advanced‐stage NSCLC treatment. According to the cancer statistics, there were 1098000 new cancer cases in 2021 in Japan. With a population of 125502000, the estimated incidence rate was calculated to be 0.87% per person‐year. In contrast, in this study, the incidence rate of second malignancy was 2.34% per person‐year, indicating that the impact of secondary malignancies cannot be ignored.

Before the 2000s, a previous study including 860 patients with NSCLC reported that head and neck cancer (20.3%) was the most common secondary malignancy, followed by urothelial (10.4%) and prostate cancer (7.4%). ¹⁰ In contrast, our study reported pancreatic cancer (30%) as the most frequently reported secondary malignancy, followed by esophageal (20%) and bladder cancer (20%). This discrepancy may be attributed to not only the differences in TNM stage of the patients included in each study but also the shared lifestyle risk factors between primary and secondar malignancies. For instance, smoking has been established as a risk factor for lung, bladder, gingiva, and esophageal cancer. ^{8 , 12 , 13} Moreover, several cytotoxic chemotherapies have been associated with various secondary malignancies. ¹⁴ MDS and acute myelogenous leukemia (AML) were found to be the most common secondary malignancies linked with chemotherapy; some cases may even present with MDS before developing AML. ¹⁵ Conversely, the risk of secondary malignancies appears to be limited with molecular‐targeted drugs. Imatinib, a TKI used for chronic myeloid leukemia, has not been associated with any risk for secondary malignancy. ¹⁶ However, BRAF inhibitors used for melanoma have been associated with secondary skin cancers. ¹⁷ As previously mentioned, no reports have shown an association with second malignancies in patients with lung cancer receiving molecular targeted therapy. ICIs have been observed to inhibit hepatocellular carcinoma development in a mouse model of hepatic cirrhosis, suggesting a potential suppressive effect on secondary malignancies. ¹⁸ Moreover, pancreatic cancers, which are characterized by low PD‐L1 expression, minimal lymphocyte infiltration, and low expression of tumor‐specific neoantigen mutations, have been reported to be unresponsive to ICI therapy. ^{19 , 20} Thus, we hypothesize that ICIs may have an inhibitory effect on secondary malignancies, with the exception of immunologically “cold” cancers. Although the specific roles of therapeutic agents in the development of secondary malignancies remains uncertain, it is possible that the newer agents introduced after the year 2000 are intuitively involved in these mechanisms.

Univariate analysis revealed that smoking history may be associated with the development of secondary malignancies, underscoring the importance of monitoring patients with a history of smoking. Among the 12 patients with secondary malignancies, six patients (50%) were incidentally detected via imaging, making it the most common cause of diagnosis, whereas four patients (33%) were diagnosed based on physical check‐ups. Regarding their impact on treatment, four (67%) were cured by surgical treatment, one discontinued lung cancer treatment, and the remaining cases continued lung cancer treatment. The NCCN guidelines recommend imaging only the affected areas. ²¹ However, since secondary malignancies can also occur in the bladder, rectum, and colon, it may be beneficial to perform whole‐body CT scans in patients with higher risk for second malignancy. If such lesions have been detected and are highly suspicious for malignancy, biopsy and/or positron emission tomography CT (PET‐CT) should be considered for further evaluation. Additionally, regular medical checkups during the treatment period are recommended, as early diagnosis and treatment of secondary malignancies may avoid interruptions in chemotherapy and lead to long‐term survival after successful treatment.

Despite the insights offered in this study, certain limitations must be acknowledged. First, the study's single‐center, retrospective design may not accurately capture the actual epidemiology of secondary malignancies owing to the limited number of cases examined. In addition, it is difficult to establish causality since there was no control arm for direct comparison with groups not treated with TKI or ICI. Second, the lack of long‐term follow‐up data precludes any assessment of the impact of recurrent disease or third primary malignancies on prognosis. Third, it was difficult to include metachronous primary lung cancer in this study. Although it is well studied after surgical resection, in advanced stages, it is difficult to differentiate between metachronous primary lung cancer and recurrence of the disease. Some cases were diagnosed radiologically, others histologically, and there are likely cases that were treated without a definitive diagnosis. Moreover, when we reviewed the medical charts, there were few cases of suspected metachronous primary lung cancer in this population. Therefore, considering these limitations, further prospective, multi‐institutional studies with larger samples and long‐term follow‐ups are warranted to ensure validation and improve the reproducibility and generalizability of our findings.

This study found that 8.9% of patients with advanced NSCLC, who received TKIs, ICIs, or immune combination therapy and survived ≥2years, developed secondary malignancies. Univariate analysis suggests that smoking history was associated with secondary malignancies, and that all patients with NSCLC presented with adenocarcinomas. Our findings highlight the significance of early diagnosis and treatment, even during lung cancer treatment. In particular, regular monitoring must be done with imaging tests and physical examinations to identify suspicious lesions that warrant further investigation.

AUTHOR CONTRIBUTIONS

Conceptualization, YoM, TS; Data curation, YoM; Formal analysis, YoM; Investigation, YoM, TS, SK, SS; Methodology, YoM, TS; Resources, YoM, SK, HS, KK, IN, TM, YK, TA, RK, SS, TM, YM, KeT, NS, KT; Project administration, TS; Supervision, TS, KT; Writing ‐ Original Draft, YoM, TS; Writing ‐ Review & Editing, SK, HS, KK, IN, TM, YK, TA, RK, SS, TM, YM, KeT, NS, KT; Visualization, YoM, TS.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflicts of interest.

Notes

Masui Y, Shukuya T, Kataoka S, Shiozaki H, Kurokawa K, Nakamura I, et al. Second malignancy in advanced or recurrent non‐small cell lung cancer after the advent of molecular targeted drugs and immunotherapy. Thorac Cancer. 2024;15(32):2291–2297. 10.1111/1759-7714.15457 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

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