Editorial 

New Lungs for Lung Cancer—Perils and Promises

Ece Cali Daylan, Ramaswamy Govindan

JAMA Published Online: July 8, 2026

doi: 10.1001/jama.2026.11478

Despite the recent advances in systemic therapy, survival for patients with metastatic non–small cell lung cancer (NSCLC) without actionable genomic alterations in the tumor is limited.¹ A small subset of patients with NSCLC have lung-only metastatic disease and often die of progressive lung failure. In this issue of JAMA, a study by Bharat and colleagues² challenges an entrenched assumption that lung transplant has no role in the management of patients with advanced NSCLC with lung-only metastatic disease.

For decades, active malignancy has been largely viewed as a contraindication to lung transplant based on early experience showing high recurrence rates and poor survival.³ Lung transplant for lung cancer has not been rigorously studied in prospective trials. The first human lung transplant was performed in 1963 by James Hardy, MD.⁴Early studies of lung transplant in patients with bronchoalveolar carcinoma reported high recurrence rates, quickly dampening enthusiasm for this approach.^5,6 In addition, posttransplant immunosuppressive regimens have been associated with an increased risk of malignancies due to impaired immune surveillance. With the development of targeted agents and immune checkpoint blockade therapies, lung transplant for lung cancer largely fell out of favor.

The study by Bharat and colleagues² was a prospective, single-center, registry study including 404 patients. One-year survival from the time of eligibility evaluation completion was markedly higher in the group of 17 patients with medically refractory, lung-confined stage IV NSCLC who underwent lung transplant (survival of 100% [95% CI, 63.1%-100%] in cohort 1) than among 81 similarly evaluated patients who did not undergo transplant (survival of 40.8% [95% CI, 29.6%-53.1%] in cohort 2). Moreover, posttransplant survival among cancer recipients was noninferior to that of 306 lung transplant recipients without cancer (cohort 3); 1-year posttransplant survival was 100% (95% CI, 63.1%-100%) in cohort 1 vs 88.1% (95% CI, 83.7%-91.4%) in cohort 3. Clinically evident progression occurred in 4 of 17 transplant recipients in cohort 1 compared with 74 of 81 patients in cohort 2. One-year survival free of NSCLC recurrence or progression was 92.3% (95% CI, 56.6%-98.9%) among patients in cohort 1 compared with 5.6% (95% CI, 1.8%-12.6%) among patients in cohort 2.

Several aspects of this study are worth highlighting. First, a key feature of the study was careful patient selection. Patients selected for lung transplant were required to meet highly restrictive criteria beyond standard eligibility: lung-only disease, progression despite guideline-directed systemic therapy, and rigorous staging, including 18F-fluorodeoxyglucose positron emission tomography, brain magnetic resonance imaging, and systematic invasive mediastinal evaluation. Second, the study used a surgical technique to minimize dissemination (incorporating early pulmonary vein ligation and airway decontamination) and reduce intraoperative tumor spread. Third, several thoughtful methodological strategies were used to address inherent biases. Survival comparisons between patients who underwent transplant compared with patients who did not undergo transplant were anchored at the point of eligibility evaluation completion, aligning time zero across cohorts and mitigating guarantee-time bias. The study also used restricted mean survival time rather than hazard ratios to avoid unstable estimates in settings with few events. In addition, the use of comparator cohorts strengthens inference in the absence of randomization.

However, several caveats apply. First, the patient population enrolled in this study is a rare subset of NSCLC. Lung-limited stage IV NSCLC is a small subpopulation of metastatic NSCLC. Second, the baseline characteristics of cohort 1 differ markedly from those of the general population with metastatic NSCLC; the proportion of patients who never smoked was strikingly high (59%), and the median age at diagnosis was younger (61 years of age).² Third, unlike the typical cohort of patients with advanced NSCLC, the patients in cohort 1 in this study had fewer comorbidities (such as diabetes, chronic kidney disease, or emphysema). Fourth, despite being treatment refractory, the patients had a more indolent NSCLC disease course compared with the general population with advanced NSCLC, which was documented by the long median time of 49 months (IQR, 20-71; range, 5-80) from diagnosis to lung transplant.²

Fifth, even with the high-volume transplant center experience, nearly 25% of patients (4 of 17 in cohort 1) could not undergo dissemination-minimizing surgery due to anatomical restrictions, and 3 of these 4 patients developed lung cancer recurrence. Sixth, the median follow-up is very short at 343 days from eligibility evaluation completion for cohort 1, 221 days from eligibility evaluation completion for cohort 2, and 200 days from transplant for cohort 3; the shorter follow-up makes it harder to assess the long-term durability of disease control achieved with lung transplant.² In addition, the ethical implications are hard to ignore. Lung transplant operates within a zero-sum system. Each organ allocated to a recipient is unavailable to another recipient. Current allocation frameworks prioritize conditions with established and durable outcomes. The noninferiority framework used in this study aims to address these concerns by demonstrating that the outcomes in transplant recipients with cancer (cohort 1) were not substantially worse than those in the transplant recipients without cancer (cohort 3).

There is increasing evidence of a survival benefit by incorporating local consolidative treatment with radiation or surgery across all disease sites in patients with oligometastatic NSCLC.⁷ Retrospective studies of pulmonary resection for patients with oligometastatic disease demonstrate durable survival.⁸ Studies of cancer cell clonal evolution in patients with NSCLC, the timing and pattern of metastatic dissemination, and organ tropism demonstrate differences between primary and metastatic sites.⁹ Metastasectomy (eg, adrenalectomy or brain metastasis resection) may eliminate cancer subclones with higher invasive potential and could improve overall survival in oligometastatic disease. Bilateral lung transplant (with its obligatory immunosuppression) is far more complicated than simple metastasectomy.

Experience with liver transplant offers an instructive, though imperfect, analogy and some hope. The rationale is to treat the underlying chronic liver disease and cure hepatocellular carcinoma. In the 1960s, early human liver transplant attempts failed based on survival less than 1 month. Improving procurement procedures, refining immunosuppressive regimens, adopting advanced surgical techniques, and improving recipient selection substantially improved posttransplant survival.

The outlook for liver transplant for hepatocellular carcinoma changed substantially with the introduction of the Milan criteria in 1996 that emphasized optimal patient selection. Four-year survival of 75% was reported when patients with small unresectable hepatocellular carcinoma were selected for liver transplant.¹⁰ Since then, multiple studies have investigated expanded selection criteria and have incorporated down-staging treatments to extend transplant eligibility to a broader population with hepatocellular carcinoma. In fact, liver transplant recently showed improved overall survival compared with chemotherapy-only treatment (5-year overall survival: 56.6% vs 12.6%, respectively; hazard ratio, 0.37; P = .0003)¹¹ in patients with unresectable liver-only colorectal metastases. This trial used very strict selection criteria to enroll patients with favorable biology.¹¹

The study by Bharat and colleagues² has brought the issue of bilateral lung transplant to the forefront, albeit for a unique and rare subset of patients with advanced NSCLC. Before widespread adoption, it is critical to confirm these results in larger, multicenter, well-controlled, randomized studies including carefully selected patients with lung-confined metastatic, refractory NSCLC without evidence of mediastinal nodal or extra thoracic disease determined using state-of-the-art imaging and ultrasensitive cell-free DNA analyses.