Practice-Changing Insights Into Secondary Cancers Among Lung Cancer Survivors

Practice-Changing Insights Into Secondary Cancers Among Lung Cancer Survivors

Clinically meaningful secondary cancer occurred in non-small cell lung cancer (NSCLC) survivors, both within and beyond the thorax and over a prolonged period, according to a new study by a multidisciplinary team of lung cancer experts at Memorial Sloan Kettering Cancer Center (MSK). The study was published in JAMA Network Open on December 9, 2025. (1)

Notably, the research also revealed that non-lung secondary cancers often occurred more than four years after local therapy for the primary cancer, were rarely detected via population screening, were mainly associated with hereditary cancer syndromes and pathogenic germline variants, and only borderline related to smoking history. (1)

“Our findings underscore the importance of risk-adapted, symptom-responsive survivorship care that includes evaluating heritable risk,” said MSK radiation oncologist Matthew McMillan, MD, lead author of the study. “Importantly, our findings do not support blanket expansion of routine cancer screening beyond the chest.”

Lung Cancer Survivorship

Treatment advances, broader access to care, earlier detection, and improved staging methods have led to longer survival times for patients with NSCLC in the United States over the past decade. (2) (3) (4) (5) (6) (7) (8)Accordingly, the population of NSCLC survivors keeps growing and is estimated to exceed 20 million by 2026. (9)

These survivors remain at risk for disease recurrence and secondary cancers, especially second primary lung cancers, (10) which often present as early-stage malignancies that may be curable with surgery. However, there are limited data on secondary cancer incidence. For early-stage survivors, recurrence rates range from 10% to 38%, and the risk of a second primary cancer is estimated at 1% to 2% annually. (11) (12)

While routine computed tomography (CT) scans detect most intrathoracic recurrences and second primary lung cancers, non-lung secondary cancers are often identified by chance or through patient-reported symptoms.

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MSK’s Survivorship Care for NSCLC Patients

“MSK transitions NSCLC patients who are disease-free to the Adult Survivorship Program about 24 months after completion of local therapy,” said Dr. McMillan. “Advanced practice professionals in thoracic surgery follow our survivors with coordination by multidisciplinary specialists.”

Routine surveillance at MSK includes a baseline chest CT scan about three months after local therapy, followed by repeat chest CT scans every three to four months in years 1 and 2, every six months in years 3 and 4, and annually thereafter. Positron emission tomography/CT, brain magnetic resonance imaging, or other imaging is conducted when warranted by symptoms or abnormal findings. Age-appropriate and guideline-concordant population screening for breast, colorectal, and prostate cancer is coordinated with primary care.

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Study Design

Dr. McMillan and colleagues assessed the incidence, timing, and outcomes of secondary cancers in a cohort of NSCLC survivors evaluated at MSK’s dedicated survivorship clinic between January and May 2019.

The analysis included data for 496 survivors of stages 1 to 3 NSCLC who had completed curative-intent local therapy (surgery and/or radiotherapy) at MSK and were disease-free for at least 12 months. (1)

The primary study outcomes were the incidence and timing of recurrence, non-lung secondary cancers, intrathoracic new cancers, extrathoracic new cancers, or death. The researchers also estimated overall survival (OS). (1)

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Study Results

Cohort Characteristics and Follow-up

Among 496 NSCLC survivors, 59% were female, and 41% were male, with an overall median age of 69 years (interquartile range [IQR] 63-74). The median IQR follow-up was 72 months (IQR 58-85) from the completion of local therapy, and 74% of patients were former smokers. (1)

Most patients, 75%, had adenocarcinoma, and 67% had stage 1, 14.5% had stage 2, and 17.5% had stage 3 disease. (1)

Cumulative Incidence of Secondary Cancers

The five-year cumulative incidences of first-event secondary cancers were as follows: (1)

  • 11.5% for recurrence
  • 5.6% for non-lung secondary cancer
  • 16.8% for intrathoracic new cancer
  • 10.4% for extrathoracic cancer

Characteristics and Detection of Secondary Cancers

At the end of the study period, 116 of 496 survivors (23%) had developed a secondary cancer, including 77 (15.5%) new second primary lung cancers at a median IQR of 56 months from local therapy and 39 (7.9%) non-lung secondary cancers at a median IQR of 52 months from local therapy. (1)

The most frequent non-lung secondary cancers were breast, prostate, pancreatic, and head and neck cancers. Of the 39 cases of non-lung secondary cancers, 27 or 69% were detected via patient-reported symptoms, and 12 or 31% were incidental findings. (1)

Importantly, no non-lung secondary cancers were first identified via population screening. Among 14 patients who developed non-lung secondary cancers with established screening recommendations, all were up to date with screening protocols at the time of diagnosis. (1)

Clinicopathologic Features and Management

The 77 cases of second primary lung cancers were predominantly adenocarcinomas (77%), followed by squamous cell carcinoma (14%), with small-cell histology uncommon (5%). The median (IQR) time from completion of local therapy to second primary lung cancer was 56 months (IQR 38-77). (1)

The non-lung secondary cancers spanned a large spectrum with stage at diagnosis as follows: in situ (7.7%), stage 1 (44%), stage 2 (7.7%), stage 3 (20.5%), and stage 4 (20.5%). Most non-lung secondary cancers had been treated with surgery (62%), followed by systemic therapy (21%). Three of 39 survivors who developed non-lung secondary cancers received no cancer-directed treatment (8%). (1)

Multivariable Associations with Non-Lung Secondary Cancer

Notably, having a hereditary syndrome or a pathogenic germline variant was associated with a significantly higher risk for non-lung secondary cancer (Fine–Gray subdistribution hazard ratio [SHR] = 10.76, p < 0.001). (1)

Smoking history (per 10 pack years) was not independently associated with non-lung secondary cancer risk in the adjusted Fine–Gray model (SHR 1.00; 95% CI, 0.97–1.03; P = .85). In the prespecified cause-specific Cox sensitivity analysis, the association for pack-years was borderline inverse (HR 0.88; 95% CI, 0.77–1.00; P = .05). (1)

Overall Survival

OS from completion of local therapy was not reached for the total cohort. The OS point estimates at years 2, 3, and 5 were 99.8%, 97.7%, and 93.2%, respectively. Among patients with non-lung secondary cancers, the 2-year OS from secondary cancer diagnosis was 73.3%. (1)

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Study Implications

“Two findings from our study were the most actionable. First, about 1 in 5 patients with non-lung secondary cancers presented with metastatic disease and experienced a poor OS of about 20 months, highlighting the consequence of extrathoracic late events,” said Dr. McMillan.

“Second, most non-lung secondary cancers were prompted by patients’ symptoms, and nearly one-third were incidental, with no events identified by population screening. At the same time, almost 13% of survivors developed extrathoracic cancer or metastases without concurrent thoracic findings, indicating that thoracic surveillance alone is insufficient for identifying clinically meaningful events,” he said.

“Overall, we need risk-aligned care strategies for NSCLC survivors, including increasing patient education about red-flag symptoms, low-threshold diagnostic evaluation of extrathoracic complaints, and evaluation of hereditary risk for secondary cancers,” Dr. McMillan said. “Simply expanding population screening beyond the existing guidelines will not address the issues our study has identified.”

The study was supported by funding the National Institutes of Health/National Cancer Institute cancer center support grant P30 CA008748. Dr. McMillan reported receiving fees from Janssen Research & Development, LLC, for professional services and activities outside the present study. Refer to the paper for disclosures for other investigators.

Learn more about MSK lung cancer clinical trials.

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  1. McMillan MT, Yariv O, Raoof S, et al. Risk and Outcomes of Secondary Cancer Among Lung Cancer Survivors After Definitive Treatment. JAMA Netw Open. 2025;8(12):e2547831.
  2. Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med. 2020;383(7):640-649.
  3. Muthusamy B, Patil PD, Pennell NA. Perioperative Systemic Therapy for Resectable Non-Small Cell Lung Cancer. J Natl Compr Canc Netw. 2022;20(8):953-961.
  4. Jones GS, Baldwin DR. Recent advances in the management of lung cancer. Clin Med (Lond). 2018;18(Suppl 2):s41-s46.
  5. Liu Y, Colditz GA, Kozower BD, et al. Association of Medicaid Expansion Under the Patient Protection and Affordable Care Act With Non-Small Cell Lung Cancer Survival. JAMA Oncol. 2020;6(8):1289-1290.
  6. Potter AL, Rosenstein AL, Kiang MV, et al. Association of computed tomography screening with lung cancer stage shift and survival in the United States: quasi-experimental study. BMJ. 2022;376:e069008.
  7. Kratzer TB, Bandi P, Freedman ND, et al. Lung cancer statistics, 2023. Cancer. 2024;130(8):1330-1348.
  8. Rami-Porta R, Call S, Dooms C, et al. Lung cancer staging: a concise update. Eur Respir J. 2018;51(5):1800190.
  9. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271-289.
  10. Surapaneni R, Singh P, Rajagopalan K, Hageboutros A. Stage I lung cancer survivorship: risk of second malignancies and need for individualized care plan. J Thorac Oncol. 2012;7(8):1252-1256.
  11. Pepek JM, Chino JP, Marks LB, et al. How well does the new lung cancer staging system predict for local/regional recurrence after surgery?: A comparison of the TNM 6 and 7 systems. J Thorac Oncol. 2011;6(4):757-761.
  12. Hamaji M, Allen MS, Cassivi SD, et al. Surgical treatment of metachronous second primary lung cancer after complete resection of non-small cell lung cancer. J Thorac Cardiovasc Surg. 2013;145(3):683-691.