Approximately 6% of patients with stage I to III lung cancer develop a second primary lung cancer within 5 years of their initial diagnosis, according to research presented at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer.¹

Analysis of data from the National Lung Screening Trial showed a rate of second primary lung cancer of approximately 1% to 2% per patient year over a follow-up period of approximately 3 to 5 years. The median time to diagnosis of metachronous primary lung cancers was 2.7 years. 

“More than one-quarter (27%) of second primary cancers were diagnosed over 4 years after the date of first primary lung cancer diagnosis, which illustrates the importance of lifelong follow-up,” said study author Alexandra L. Potter, a researcher at Massachusetts General Hospital and President of the American Lung Cancer Screening Initiative.

Alexandra L. Potter

As Ms. Potter explained, with the onset of lung cancer screening in the United States, the number of patients diagnosed with early-stage lung cancer is increasing. Many patients whose screen detected lung cancers achieve excellent long-term survival, said Ms. Potter, raising the importance of examining the risk of developing second primary lung cancer in this population. 

According to Ms. Potter, the risk of second primary lung cancer among lung cancer survivors has been shown to be four- to sixfold greater compared to the risk of lung cancer in the general population after adjusting for age, sex, race, and calendar year.

Study Methods

For this study, Ms. Potter and colleagues examined the incidence, timing, and survival of second primary lung cancers using data from the National Lung Screening Trial, a large-scale randomized trial that compared the effectiveness of low-dose computed tomography (CT) vs chest x-ray in reducing lung cancer mortality.

The National Lung Screening Trial enrolled 53,454 high-risk individuals aged 55 to 74 years who currently smoked or had quit smoking within the past 15 years. For the present study, the researchers included patients diagnosed with clinical stage I to III initial primary lung cancer. Second primary cancers were categorized as either synchronous or metachronous. Synchronous primary lung cancers were defined as second primary lung cancers that were diagnosed within 6 months of the first primary lung cancer, while metachronous primary lung cancers were defined as second primary lung cancers that were diagnosed more than 6 months after the diagnosis date of the first primary lung cancer.

Results

Of the 1,971 patients diagnosed with lung cancer in the National Lung Screening Trial, 1,405 patients were diagnosed with clinical stage I to III initial primary lung cancer. The incidence of second primary lung cancer was 5.8%, of which 55% were synchronous and 45% were metachronous second primary lung cancers.

The median follow-up time of patients diagnosed with synchronous primaries was 29.8 months, while the median follow-up time of those diagnosed with metachronous primaries was 65.9 months. Most patients who developed synchronous or metachronous lung cancer in the study cohort underwent surgery for their initial primary lung cancer.

“Among patients with stage I disease, the incidence of metachronous primary lung cancer increased with increasing time from the date of first primary lung cancer diagnosis,” said Ms. Potter. 

Similar trends were observed among patients diagnosed with stage II to III second primary lung cancer. However, no second primaries were diagnosed more than 5 years after the date of first primary lung cancer diagnosis among patients with stage II and III first primary lung cancer, said Ms. Potter.

For patients diagnosed with synchronous and metachronous primary lung cancers, 5-year overall survival from the date of initial primary lung cancer diagnosis was 55.2% and 90.0%, respectively. Ten-year overall survival from the date of initial primary lung cancer diagnosis was 39.5% and 30.8% for synchronous and primary lung cancers, respectively.

Overall survival from the date of second primary lung cancer diagnosis was similar for patients diagnosed with synchronous and metachronous second primary lung cancers. For patients diagnosed with metachronous second primary lung cancers, 5-year overall survival was 51.8%, and 10-year overall survival was 22.2%. 

Expert Commentary

Abstract discussant Anand Devaraj, MD, PhD, Professor in Thoracic Radiology at Royal Brompton and Harefield hospitals, and Professor of Thoracic Radiology at the National Heart and Lung Institute, Imperial College London, highlighted the increased risk of second primary tumors among current smokers.

“Greater than 70% of the causes of death in this group was from lung cancer, illustrating the importance of combining smoking cessation with screening not just at baseline when participants are first invited but also [later] for participants who have an ongoing smoking history,” said Dr. Devaraj.

Dr. Devaraj also discussed data regarding pathology. While most synchronous tumors occurred when the primary lung cancer was adenocarcinoma, a significant proportion (approximately one-quarter) also occurred when the primary tumor was squamous cell carcinoma, he explained. Furthermore, said Dr. Devaraj, between 38% and 46% of synchronous or metachronous tumors had the same histology as the primary tumor. 

“I mentioned these two points because we often face the dilemma in clinical practice of differentiating synchronous or metachronous tumors from metastatic disease or recurrence,” he explained. “When faced with multifocal synchronous, subsolid lesions on a computed tomography scan, for example, many of us can feel confident that we’re dealing with synchronous primary tumors. But in the setting of bilateral solid nodules, especially in stage II or III disease when the primary is squamous cell carcinoma, it becomes much more challenging.”

According to Dr. Devaraj, the gold standard for confirming a synchronous or a metachronous tumor is showing differential pathology between the primary and the secondary lung tumor. 

“However, as was shown in this study, a significant portion of synchronous tumors [between 38% and 46% in this study] can manifest as the same pathology as the primary tumor,” he continued. “In this setting, subcategorization with molecular analysis can be of use.” 

DISCLOSURE: Dr. Potter had no relevant financial disclosures. Dr. Devaraj disclosed financial relationships with Boehringer Ingelheim, Brainomix, Roche, Galecto Biotech, and Galapagos.

REFERENCE

1. Potter AL, Pan M, Mathey-Andrews C, et al: Incidence, timing, and survival of second primary lung cancer in patients in the National Lung Screening Trial. 2022 World Conference on Lung Cancer. Abstract OA05.03. Presented August 7, 2022.