Treating lung cancer in patients with interstitial lung disease: what do we know?
Management of interstitial lung disease (ILD) remains a challenge for patients and healthcare providers. While pirfenidone and nintedanib, so termed anti-fibrotic agents, have been shown to slow decline in pulmonary function, decrease all-cause mortality and the rate of acute exacerbations (AE-ILD) in idiopathic pulmonary fibrosis (IPF) (1-4), morbidity and mortality remain high for IPF, the most deadly ILD (5,6). In addition to progressive decline in lung function and AE-ILD, patients with IPF are at risk for pulmonary hypertension, venous thromboembolism, and lung cancer (6-8). Patients with co-existent ILD and lung cancer have a worse survival than patients with lung cancer alone (9).
The treatment options for lung cancer in patients with ILD remain severely limited. Surgical resection may be contraindicated due to reduced lung function or comorbidities including pulmonary hypertension. Surgery, radiation, chemotherapy, and immunotherapy are associated with an increased risk of AE-ILD in patients with IPF and other types of ILD (10-13). In a cohort of 1,763 patients with ILD who underwent resection of lung cancer at 61 centers in Japan, AE-ILD occurred in 9.3% of patients with a mortality of 43.9% (13). In this study, lobectomy and segmentectomy were associated with increased acute exacerbation as compared to wedge resection (OR =3.8) (13). Given these limited treatment options, there is a pressing need to investigate alternative therapies beyond the traditional three pillars of cancer care. Interventional Oncology, the fourth pillar of cancer care, includes percutaneous ablation, also known as image-guided thermal ablation. Percutaneous ablation includes radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation, which are minimally invasive needle-directed therapies using either heat or cold to eradicate tumors (14). Percutaneous ablation has been shown to preserve lung function (15), a key advantage in patients with ILD who already have impaired lung function (6).
Most of the published data regarding treatment of thoracic neoplasms in patients with ILD relate to RFA. A systemic review found that rates of ILD-specific toxicity following RFA were similar to radiation therapy, but mortality associated with RFA was lower (16). In the general population, cryoablation has demonstrated the lowest rate of major complications compared to RFA and MWA (17), which suggests that it could be the safest thermal ablation modality for patients with ILD. However, data on percutaneous cryoablation in patients with ILD is limited to one institution (18-20).
A recently published retrospective single center cohort study by Kaseda et al. explores predictors of adverse events and mortality following the treatment of 609 tumors (median diameter 1.3 cm, range 0.2–10.2 cm) in 227 patients (24.7% with primary lung cancer) with 366 percutaneous cryoablation sessions from 2002 to 2016 (18). This study represents one of the largest cohorts to date on percutaneous lung cryoablation and includes 37 patients with interstitial lung disease, 15 of which had IPF. The Eastern Cooperative Oncology Group (ECOG) performance score was less than 2 for all patients. For all comers, mortality at 30- and 60-day was 0% and 0.5%, respectively, which compares favorably with surgical resection and radiation (21). The two fatalities at 60-days were attributed to AE-ILD, amounting to a 60-day mortality of 13.3% for the IPF subgroup and 5.4% for all ILD patients. The most common adverse event was a pneumothorax (18.0% of sessions) which required chest tube placement in 59.1%. Instances of pneumothorax without chest tube requirement are an expected outcome and no longer a complication as per the 2021 Society of Interventional Radiology guidelines (22). No general anesthesia was used for the ablation procedures.
A retrospective cohort study by Yamauchi from 2012 from the same institution includes 22 patients with 34 stage I primary lung cancers treated in 25 percutaneous cryoablation sessions between 2004 and 2010 (20). In this report, two fatalities were attributed to AE-ILD and the total number of patients with ILD was not specified. Lastly, a 2017 conference abstract by Ohtsuka from the same institution outlines a retrospective analysis of 11 patients with severe IPF and T1N0M0 non-small cell lung cancer who underwent percutaneous cryoablation between 2003 and 2016. Two fatalities at 90-day were attributed to AE-ILD, resulting in an 18.1% mortality for patients with IPF (19).
It is not uncommon for the same institution to publish multiple analyses on patients who underwent percutaneous thermal ablation of lung tumors since high-volume centers are still few and far between. In this setting, it is helpful to clearly define overlap between cohorts and reference prior work. The 2014 guideline on standardized reporting criteria of image-guided tumor ablation emphasizes the importance of providing a comprehensive description of the study population (23). Ideally, this would include information on overlap of the study cohort with other published studies. Without information regarding the overlap with other studies, it is unclear whether the two fatalities from AE-ILD reported in the three reports from the same institution refer to the same patients. As a result, reported mortality rates following percutaneous cryoablation in patients with IPF range from 13.3% to 18.1%, and this may have significant bearing on individual treatment decisions.
To improve the current knowledge in this area and better guide clinical decision-making, prospective studies are needed to further define risk factors for adverse events in patients with ILD, especially AE ILD. Factors such as ILD subtype, disease severity, or concurrent ILD treatments (i.e., use of antifibrotic therapy) may help inform the risk of complications with percutaneous ablation and other oncologic therapies. Biomarkers in peripheral blood may prove to be informative for predicting AE-ILD and other adverse events (24). Imaging biomarkers may identify patients with subclinical ILD (25). Also, functional evaluation is critical since functional impairment may or may not correlated with disease severity on imaging (25). To this end, a multidisciplinary approach involving specialized surgeons, pulmonologists, radiation oncologists, interventional oncologists, and radiologists is required. Interdisciplinary collaboration allows for the integration of clinical, radiologic, and pathologic information and stands to improve the management of patients with ILD. As therapeutic efficacy of ILD treatments improve over time, it is possible that lung cancer will become a significant driver of mortality in patients with ILD and further understanding of the risks of oncologic therapies in this population will be essential.
Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-316/coif). SBM is supported by NIH/NHLBI K23HL15033 and reports research funding from Pliant Therapeutics, Merck, and Boehringer Ingelheim, consulting fees from DevPro Biopharma, Gilead Sciences, and Roche, advisory board fees from APIE Therapeutics and Pliant Therapeutics, royalties from Wolters Kluwer, and speaking fees from Cowen. ML is supported by NIH/NHLBI 1R44CA250771-01. FJF reports salary support from the Wiliam M. Wood Foundation for related research, a leadership role in the Society of Interventional Oncology, and unrelated consulting for Pfizer. The other author has no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
- Richeldi L, Cottin V, du Bois RM, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med 2016;113:74-9. [Crossref] [PubMed]
- Nathan SD, Albera C, Bradford WZ, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med 2017;5:33-41. [Crossref] [PubMed]
- Petnak T, Lertjitbanjong P, Thongprayoon C, et al. Impact of Antifibrotic Therapy on Mortality and Acute Exacerbation in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Chest 2021;160:1751-63. [Crossref] [PubMed]
- Iwata T, Yoshida S, Fujiwara T, et al. Effect of Perioperative Pirfenidone Treatment in Lung Cancer Patients With Idiopathic Pulmonary Fibrosis. Ann Thorac Surg 2016;102:1905-10. [Crossref] [PubMed]
- Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med 2014;2:566-72. [Crossref] [PubMed]
- Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018;378:1811-23. [Crossref] [PubMed]
- Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med 2016;194:265-75. [Crossref] [PubMed]
- Margaritopoulos GA, Antoniou KM, Wells AU. Comorbidities in interstitial lung diseases. Eur Respir Rev 2017;26:160027. [Crossref] [PubMed]
- Alomaish H, Ung Y, Wang S, et al. Survival analysis in lung cancer patients with interstitial lung disease. PLoS One 2021;16:e0255375. [Crossref] [PubMed]
- Brown SW, Dobelle M, Padilla M, et al. Idiopathic Pulmonary Fibrosis and Lung Cancer. A Systematic Review and Meta-analysis. Ann Am Thorac Soc 2019;16:1041-51. [Crossref] [PubMed]
- Frank AJ, Dagogo-Jack I, Dobre IA, et al. Management of Lung Cancer in the Patient with Interstitial Lung Disease. Oncologist 2023;28:12-22. [Crossref] [PubMed]
- Fisher DA, Murphy MC, Montesi SB, et al. Diagnosis and Treatment of Lung Cancer in the Setting of Interstitial Lung Disease. Radiol Clin North Am 2022;60:993-1002. [Crossref] [PubMed]
- Sato T, Teramukai S, Kondo H, et al. Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg 2014;147:1604-1611.e3. [Crossref] [PubMed]
- Murphy MC, Wrobel MM, Fisher DA, et al. Update on Image-Guided Thermal Lung Ablation: Society Guidelines, Therapeutic Alternatives, and Postablation Imaging Findings. AJR Am J Roentgenol 2022;219:471-85. [Crossref] [PubMed]
- Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer 2015;121:3491-8. [Crossref] [PubMed]
- Chen H, Senan S, Nossent EJ, et al. Treatment-Related Toxicity in Patients With Early-Stage Non-Small Cell Lung Cancer and Coexisting Interstitial Lung Disease: A Systematic Review. Int J Radiat Oncol Biol Phys 2017;98:622-31. [Crossref] [PubMed]
- Jiang B, Mcclure MA, Chen T, et al. Efficacy and safety of thermal ablation of lung malignancies: A Network meta-analysis. Ann Thorac Med 2018;13:243-50. [Crossref] [PubMed]
- Kaseda K, Asakura K, Nishida R, et al. Feasibility and safety of percutaneous cryoablation under local anesthesia for the treatment of malignant lung tumors: a retrospective cohort study. J Thorac Dis 2022;14:4297-308. [Crossref] [PubMed]
- Ohtsuka T, Asakura K, Masai K, et al. OA12.03 Percutaneous Cryoablation for Lung Cancer Patients for Whom Surgery or Radiotherapy is Contraindicated Due to Idiopathic Pulmonary Fibrosis. J Thorac Oncol 2017;12:S290. [Crossref]
- Yamauchi Y, Izumi Y, Hashimoto K, et al. Percutaneous cryoablation for the treatment of medically inoperable stage I non-small cell lung cancer. PLoS One 2012;7:e33223. [Crossref] [PubMed]
- Stokes WA, Bronsert MR, Meguid RA, et al. Post-Treatment Mortality After Surgery and Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:642-51. [Crossref] [PubMed]
- Genshaft SJ, Suh RD, Abtin F, et al. Society of Interventional Radiology Quality Improvement Standards on Percutaneous Ablation of Non-Small Cell Lung Cancer and Metastatic Disease to the Lungs. J Vasc Interv Radiol 2021;32:1242.e1-1242.e10. [Crossref] [PubMed]
- Ahmed M, Solbiati L, Brace CL, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update. Radiology 2014;273:241-60. [Crossref] [PubMed]
- Konishi K, Gibson KF, Lindell KO, et al. Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;180:167-75. [Crossref] [PubMed]
- Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med 2012;185:1147-53. [Crossref] [PubMed]