Evaluation and management of lung cancer in patients with interstitial lung disease

INTRODUCTION — Patients with fibrotic interstitial lung disease (ILD) are at increased risk for lung cancer, even after accounting for common risk factors, such as older age and a history of cigarette smoking [1,2]. This higher incidence is most likely due to the consequences of local inflammatory and fibrotic processes, as well as the impact of treating ILD with immunomodulatory medications that attenuate antineoplastic defense mechanisms.

Lung cancer is also more challenging to diagnose and manage in this population, contributing to inferior overall survival in patients with ILD who have concurrent lung cancer [2,3]. While many advances have improved the diagnosis and management of lung cancer in the general population, it is unclear whether or how this new evidence should be extrapolated to the subgroup of patients with fibrotic ILD, who are frequently excluded from major clinical trials.

This topic will review the evaluation of potential lung cancer in patients with fibrotic ILD and discuss specific management considerations that apply to these patients. The evaluation and management of lung cancer in general populations (ie, patients without ILD) are reviewed separately:

●Features of malignancy on chest imaging (see "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Diagnostic evaluation of the incidental pulmonary nodule")

●Bronchoscopy/endobronchial ultrasound (see "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer" and "Endobronchial ultrasound: Indications, contraindications, and complications")

●Transthoracic needle (see "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer")

●Surgical resection (see "Overview of the initial treatment and prognosis of lung cancer")

●Systemic therapy

•Non-small cell lung cancer (see "Systemic therapy in resectable non-small cell lung cancer" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer")

•Small cell lung cancer (see "Limited-stage small cell lung cancer: Initial management" and "Extensive-stage small cell lung cancer: Initial management")

EPIDEMIOLOGY — Patients with fibrotic ILD have an approximately fivefold increased risk of lung cancer, even after accounting for common risk factors, such as older age and a history of cigarette smoking [1,2], and have a disproportionately higher incidence of squamous cell carcinoma compared with non-ILD populations [4,5].

This increased risk of lung cancer is also present in patients (usually smokers) with milder interstitial lung abnormalities [3,6,7].

EVALUATION OF LUNG CANCER IN PATIENTS WITH ILD — ILD creates particular challenges for the identification of lung cancer because of the underlying radiographic abnormalities and potential risk of diagnostic procedures [2].

Approaches to lung cancer detection — The detection of lung cancer in patients with ILD typically starts in one of three settings:

●A lung nodule is noted as an incidental finding on chest imaging done for other reasons or is identified by histopathologic sampling performed for other purposes (eg, an incidental finding in the initial diagnostic evaluation of ILD).

●Lung cancer is detected in a patient with asymptomatic fibrotic ILD as part of a formal screening program (eg, based on age and smoking history), with chest imaging performed in the absence of any additional features.

●Targeted assessment for lung cancer is performed based on the presence of concerning symptoms or signs that suggest a high likelihood of malignancy.

Incidental detection of lung cancer in patients with ILD — The diagnosis of ILD is based on a comprehensive assessment that includes high resolution computed tomography (HRCT) and, often, bronchoalveolar lavage and/or histopathologic sampling. Chest CT is also frequently performed following this initial evaluation, primarily as an adjunct in patients with unclear progression and in patients with rapid deterioration of uncertain etiology, while bronchoalveolar lavage is frequently performed in patients with rapid respiratory worsening. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis" and "Prognosis and monitoring of idiopathic pulmonary fibrosis".)

Each follow-up CT should be specifically examined for the presence of new nodules, particularly given the greater difficulty of identifying nodules in the presence of potentially widespread parenchymal abnormalities.

Lesions suspicious for lung cancer that are discovered incidentally will require additional testing to confirm the diagnosis and identify the most appropriate treatment options for that individual. (See 'When to pursue sampling for lung cancer in patients with ILD' below.)

Lung cancer screening programs in patients with ILD — For patients with ILD and a history of cigarette smoking, the decision to participate in lung cancer screening requires consideration of the severity and trajectory of the ILD. Large clinical trials of predominantly older smokers have demonstrated substantial benefit from lung cancer screening programs in this relatively unselected population. (See "Screening for lung cancer".)

For example, the National Lung Screening Trial enrolled 53,454 adults between the ages of 55 and 74 with at least a 30 pack-year smoking history and showed that annual low-dose CT over a period of three years reduced overall mortality by 6.7 percent [8]. Similar findings have been observed in other trials, including the NELSON randomized trial that used volume-based assessment of pulmonary nodules [9,10]. While these studies have typically excluded patients with known pulmonary fibrosis, the increased risk of lung cancer in patients with ILD suggests that screening CTs are also likely able to detect early-stage lung cancer in this population; however, the sensitivity and specificity for lung cancer of screening CTs in fibrotic ILD are unknown and are likely lower compared with non-ILD populations.

Of note, plain chest radiography is inferior to chest CT in screening for malignancy in general populations [8], and even less likely to be useful in the context of ILD that could potentially mask small nodules.

●Patient selection – The potential for screening programs to identify early-stage lung cancer in patients with ILD should be balanced against the lower likelihood of being able to effectively treat lung cancer in this setting. In the absence of direct evidence, these opposing considerations suggest it is appropriate to pursue lung cancer screening in patients with ILD who would be able to tolerate a curative intervention.

The benefit of lung cancer screening is less certain in patients unable to tolerate curative therapy, although advances in other therapeutic approaches may still justify early detection of lung cancer through screening programs. Lung cancer screening will similarly have limited benefit in patients who are unwilling or unable to tolerate further diagnostic tests, primarily including common histopathologic sampling techniques, such as bronchoscopy or a transthoracic needle biopsy. Decisions about lung cancer screening should be consistent with the individual patient’s goals of care. (See "Screening for lung cancer", section on 'Our approach to counseling for screening' and "Discussing goals of care".)

●Importance of acquiring continuous images – Multiple ILD-related factors justify acquiring continuous computed tomography (CT) images when screening for lung cancer in patients with ILD. Acquisition of continuous images (ie, with no gap between CT slices) is necessary given the increased prevalence of lung cancer in patients with ILD and the potential to miss small nodules, rather than the historical practice of acquiring gapped images for patients undergoing high resolution CT. The predominance of lung cancer in areas of fibrosis can also confound identification and characterization of nodules in these regions [4].

Symptom-driven evaluation for lung cancer in patients with ILD — Common symptoms of ILD overlap with those of lung cancer, most frequently including dyspnea, cough, and functional limitation. Additional symptoms and physical examination findings can infrequently occur as a direct consequence of ILD, including hemoptysis, weight loss, chest pain, clubbing, pleural effusion, and significant lymphadenopathy. The presence of these "red flag" features should prompt consideration of lung cancer and potentially further testing to evaluate possible causes, particularly if chest CT was not recently performed.

When to pursue sampling for lung cancer in patients with ILD — The decision to pursue histopathologic sampling in patients with ILD who have potential lung cancer is primarily based on the pretest likelihood of cancer, balanced against the potential for the patient to tolerate diagnostic procedures and effective therapy. In selected patients, it may be appropriate to forgo sampling of a suspected malignancy altogether if there is no likelihood of therapy being offered (eg, very severe ILD, advanced frailty) or if the patient would consider such therapy unacceptable.

Assessing pretest likelihood of lung cancer — The pretest likelihood of lung cancer in patients with ILD can be estimated based on a number of clinical and radiologic variables, in a similar fashion to patients without ILD.

●Clinical risk factors – Common clinical variables that suggest a higher likelihood of a nodule being malignant include older age, history of cigarette smoking, shorter duration of smoking cessation, and the presence of additional symptoms (eg, hemoptysis, weight loss) or physical examination findings (eg, clubbing, although clubbing can be seen in idiopathic pulmonary fibrosis [IPF]). (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Clinical features'.)

●Imaging features – Certain imaging features increase the likelihood of a nodule being malignant, such as pleural effusions and lymphadenopathy greater than 1.5 cm in short axis. These features are uncommonly related to ILD and should raise concern of malignancy or some other additional process. Patients with a milder extent of isolated lymphadenopathy (eg, without an associated nodule or suspected malignancy) are typically observed with serial chest imaging, with further diagnostics only pursued if there is substantial growth over time. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer".)

●Risk prediction tools – There are multiple risk prediction tools that estimate the likelihood of a lung nodule being malignant, such as the Brock University cancer prediction equation (calculator 1) [11], although these were developed and validated primarily in patients without ILD. These calculators are based on the integration of common lung cancer risk factors, including patient age, sex, family history, smoking history, and manifestations of smoking-related disease, in addition to various nodule characteristics (eg, nodule size, density, location, presence of spiculation, and number). Despite being derived from non-ILD populations, these types of risk prediction tools may still be helpful in patients with ILD given the absence of population-specific calculators. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Assessing the risk of malignancy'.)

●Period of observation – For patients with a relatively small nodule, a period of observation with a repeat CT at three to six months can identify short-interval growth that would prompt a more aggressive approach toward histopathologic sampling, or stability in size that warrants continued observation.

●Role of FDG-PET – In some situations, clinical features and CT findings are sufficient to justify sampling of a nodule; however, additional testing is sometimes necessary to further inform the likelihood of malignancy and justify sampling. This is particularly true in patients with a relatively small nodule in whom there is a higher likelihood of a nondiagnostic procedure and in patients who have severe ILD or other reasons for a higher risk of complications from any sampling approach, such as pneumothorax, and the decreased ability of patients with ILD to tolerate such complications.

An 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan is often the next step in patients who require further assessment before sampling of a lung nodule, helping to confirm a nodule's metabolic activity or suggesting other potential areas of distant spread that may be more amenable to sampling. An important caveat of FDG-PET scans in patients with ILD is that ILD itself can often produce low-grade background metabolic activity, although this is typically minor and does not confuse interpretation of findings related to a solitary pulmonary nodule. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Positron emission tomography/computed tomography'.)

Importantly, the maximum standardized uptake of the background lung on FDG-PET is a potential risk factor for a post-operative acute exacerbation in patients with IPF and in the general population of patients with malignancy [12,13]; however, the impact of this risk factor on management decisions is unknown.

Assessing candidacy for diagnostic procedures and surgery — When evaluating a patient’s surgical risk in the context of known ILD, we review pulmonary function tests (spirometry and diffusing capacity for carbon monoxide) and potentially additional measures of oxygenation (eg, walking tests and cardiopulmonary exercise tests) performed within the past three to six months and consider both the severity and overall trajectory of the patient’s ILD. Patients with severely abnormal pulmonary function tests or who require oxygen supplementation are infrequently candidates for surgical resection, although there may be rare exceptions. (See "Preoperative physiologic pulmonary evaluation for lung resection" and "Evaluation of perioperative pulmonary risk".)

The evaluation of perioperative risk in general is described separately. (See "Evaluation of perioperative pulmonary risk" and "Evaluation of cardiac risk prior to noncardiac surgery".)

Diagnostic sampling for lung cancer in patients with ILD — The approach to sampling a nodule in patients with ILD closely follows the usual approach for patients without ILD, but with some additional considerations. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

●Selecting a site for sampling – In patients with ILD, the increased risk of complications from invasive procedures (eg, respiratory compromise or pneumothorax) increases the desire to sample extrapulmonary sources of tissue, when possible. Accessing potential sites of extrapulmonary metastatic disease enables avoidance of respiratory complications associated with lung biopsy and also confirmation of the advanced stage. An FDG-PET scan may help identify extrapulmonary sites of disease. (See 'Assessing pretest likelihood of lung cancer' above and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Sampling metastatic disease'.)

●Choice of procedure – The yield from bronchoscopy and, particularly, ultrasound-guided sampling techniques is likely similar to patients without ILD, but the potential for complications favors the procedure with the highest yield, rather than blind sampling methods (ie, bronchoscopy without ultrasound guidance). (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer".)

Transthoracic needle biopsies likely carry a similar greater risk of pneumothorax in patients with ILD, indicating the importance of carefully selecting patients, clearly communicating the increased risk of complication, and rapidly identifying any complications if they occur.

●Interpretation of cytopathology – Caution is needed when interpreting the results of cytopathology in patients with fibrotic ILD, as atypical cells in bronchoalveolar lavage can be misinterpreted as malignant [14]. The atypical cells appear to be related to the underlying inflammatory and/or fibrotic processes seen with ILD [15,16].

●Proceeding directly to wedge resection – Lung tissue sampling is not an absolute requirement prior to treatment. The risk of complications in patients with ILD indicates the potential utility of direct surgical resection of highly suspicious nodules, provided lung function is sufficient to support surgical resection. In particular, this approach is suggested for patients with a solitary pulmonary nodule >8 mm diameter with an intermediate or high likelihood of malignancy, but without evidence of lymph node involvement or metastatic disease. Proceeding directly to a diagnostic wedge resection is supported by American College of Chest Physicians guidelines, which suggest surgical diagnosis in patients with a high clinical probability of malignancy (>65 percent) in the general lung cancer population [17].

MANAGEMENT OF LUNG CANCER IN PATIENTS WITH ILD — The management of lung cancer in the setting of ILD follows the general principles followed in an unselected population, but should be tailored to the individualized risks of treatment associated with the patient's ILD diagnosis and severity and balanced against the expected prognosis attributable to the ILD itself. There are multiple mortality risk prediction tools available that can provide an estimated survival for patients with ILD [18,19], including some studies demonstrating the prognostic utility of these tools in patients with ILD and lung cancer [20,21]. (See "Overview of the initial treatment and prognosis of lung cancer" and "Prognosis and monitoring of idiopathic pulmonary fibrosis".)

General principles — Regardless of the treatment modality chosen, the risks of morbidity and mortality will be higher in patients with ILD compared with patients with lung cancer who do not have ILD. Of the treatment modalities available, radiation may be associated with the highest excess risk, in part because of the similarity of the mechanism of lung injury between ILD and irradiation. The general paradigm of lung cancer management in the setting of ILD, therefore, favors a surgical approach wherever safe and technically feasible, even in borderline medically operable patients who, in the absence of ILD, might be favored for a radiation-based approach. (See "Radiation-induced lung injury", section on 'Other factors' and "Preoperative physiologic pulmonary evaluation for lung resection".)

There are no ILD-specific randomized trials comparing treatments for lung cancer, and management decisions must, therefore, be based on lower levels of indirect evidence and tailored to the patient's preferences and risk factors. The informed consent process should include a frank discussion of the risks of treatment balanced against the risks of nontreatment.

Untreated lung cancer is associated with a substantial risk of morbidity and mortality. The prognosis of lung cancer is improving with advances in immunotherapy and targeted agents, but is still shorter than the projected life expectancies of most patients with ILD. Due to the high risk of death with untreated lung cancer, many patients and clinicians will accept the increased risks of toxicities in exchange for a chance at cure or delayed progression. Exceptions to this approach may include patients with very short ILD-related life expectancy or those with cancers that are documented to be very slow growing on serial imaging, such as small stage I adenocarcinomas arising from ground glass nodules.

The life-expectancy of patients with ILD and the subtype of IPF can be estimated by using predictive models such as the GAP risk assessment (table 1) and the ILD-GAP index [18,19]. (See "Prognosis and monitoring of idiopathic pulmonary fibrosis", section on 'Predicting disease progression'.)

Non-small cell lung cancer

Early-stage (stage I and II) cancer — The management of stage I and II non-small cell lung cancer (NSCLC) (table 2) recognizes the primacy of surgery in patients with sufficient physiologic reserve. Patients unfit for surgery are usually offered stereotactic ablative radiotherapy (SABR), conventional radiotherapy approaches, or image-guided ablation techniques, such as radiofrequency ablation (RFA) or microwave ablation. Recommendations for the general lung cancer population are discussed in detail separately. (See "Management of stage I and stage II non-small cell lung cancer" and "Stereotactic body radiation therapy for lung tumors" and "Image-guided ablation of lung tumors".)

●Surgical resection as preferred approach – In general, data support surgical resection as the primary treatment modality for early stage NSCLC, although cross-treatment comparisons are not available. A systematic review of treatment-related toxicity in patients with early-stage NSCLC and coexisting ILD identified 50 articles reporting on surgery, SABR, particle-beam therapy, or RFA [22]. In the surgical population, treatment-related mortality and ILD-specific toxicity were 2.2 and 12.0 percent, respectively. For the other modalities, the respective outcomes were 15.6 and 25.0 percent for SABR, 4.3 and 18.2 percent for particle therapy, and 8.7 and 25.0 percent for RFA.

In patients with ILD, surgery is associated with increased risk of morbidity and mortality compared with patients without ILD [23], along with a higher risk of recurrence [24]. Despite these risks, surgery can still achieve long-term survival and cure in many patients with ILD [22]. Sublobar resection may be associated with lower morbidity than lobectomy in ILD but is associated with worse recurrence-free survival [25]. In nonrandomized studies, perioperative pirfenidone treatment was associated with lower surgical adverse event rates, but data are insufficient to recommend perioperative pirfenidone in patients who are not already taking it for fibrotic ILD [26,27]. After surgery, pathologic examination may reveal indications for adjuvant chemotherapy. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Patients treated with initial surgical resection'.)

Preoperative physiologic evaluation is discussed in detail separately. (See "Preoperative physiologic pulmonary evaluation for lung resection" and "Strategies to reduce postoperative pulmonary complications in adults", section on 'Preoperative strategies'.)

●Stereotactic ablative radiotherapy (SABR) and radiofrequency ablation (RFA), as an alternative – SABR or RFA are offered to patients who are poor candidates for surgery. Selection between SABR and RFA should be primarily based on local expertise and patient preferences, as there is no clear evidence to suggest superiority of SABR or RFA as a second-choice modality. A systematic review showed that local control appeared to be better for SABR compared with RFA, although there was no difference in overall survival between these two modalities [28]. (See "Stereotactic body radiation therapy for lung tumors" and "Image-guided ablation of lung tumors".)

For patients who choose to undergo SABR, the ASPIRE-ILD clinical trial (NCT03485378) may provide guidance for treatment planning and delivery [29]. The trial stratifies patients by ILD severity using the ILD-GAP index [30]. For patients who do undergo SABR or conventional irradiation, particle beam therapy may provide enhanced sparing of lung tissue with decreased toxicity [31]. (See "Stereotactic body radiation therapy for lung tumors".)

Locally advanced (stage III) cancer — Management decisions in patients with stage III NSCLC and ILD are based on similar considerations as in stage I NSCLC, but the risks of treatment-related morbidity and mortality are higher due to larger lung volumes being resected or irradiated compared with earlier stage disease. Furthermore, optimal management of stage III NSCLC requires the incorporation of systemic therapy for maximum survival gains, which carries additional risk of toxicity for patients with ILD. This includes both the use of adjuvant chemotherapy in patients undergoing surgery, and concurrent chemoradiation, followed by immunotherapy for others. (See "Management of stage III non-small cell lung cancer".)

In general, a surgical approach is favored for patients with ILD, although risks of morbidity and mortality are higher than within a non-ILD population. In patients with N2 disease without ILD, we typically suggest definitive chemoradiation over a surgical approach, even though the surgery may be technically feasible. In contrast, for patients with ILD, the risks of concurrent chemoradiation are higher than in the general population, and we therefore recommend surgical resection in the setting of N2 disease, if safe and feasible.

In patients with pathologic stage II or III disease without ILD who undergo resection, chemotherapy with a platinum-based regimen provides a survival benefit compared with observation alone. In the non-ILD population, adjuvant chemotherapy with vinorelbine-cisplatin or pemetrexed-cisplatin is not associated with a decline in pulmonary function, although a nonsignificant decrease in diffusing capacity for carbon monoxide (DLCO) with vinorelbine-cisplatin has been reported [32]. Data in the adjuvant setting in the ILD/resected patient population are limited, and patients should, therefore, be carefully selected and monitored for potential drug toxicity. Chemotherapeutic agents with a higher risk of pulmonary toxicity, such as gemcitabine or docetaxel, should be avoided, if possible. (See "Systemic therapy in resectable non-small cell lung cancer".)

Concurrent chemoradiotherapy with adjuvant immunotherapy is the standard treatment in unresectable stage III NSCLC. Very limited data are available on the treatment of unresectable stage III NSCLC in patients with ILD. One study of 37 patients with ILD receiving first-line chemoradiotherapy (in the pre-immunotherapy era) reported a median survival of 34.6 months, with only one ILD-related death. On multivariable analysis, the underlying ILD pattern was associated with adverse event rates: ILD-related adverse events occurred in 82 percent of patients with a usual interstitial pneumonia (UIP) pattern on computed tomography (CT) and 31 percent of patients with a non-UIP pattern [33]. These data suggest that carefully selected patients may tolerate chemoradiotherapy in the setting of ILD.

Consolidation durvalumab in patients without ILD improves survival versus observation alone after chemoradiotherapy, without a major increase in pneumonitis risk [34]. However, durvalumab use in the real-world setting has been associated with significantly higher rates of pulmonary toxicity. The use of consolidation durvalumab in patients with ILD post-chemoradiation must be carefully considered in the context of the patient's pattern of ILD, severity of pulmonary function abnormalities, and the risk of other concurrent therapies (eg, radiation pneumonitis). Discussion on a case-by-case basis by a multidisciplinary team, including respirology experts in ILD management, is recommended. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

Advanced-stage (stage IV) cancer — Systemic therapy is the mainstay of treatment for incurable, advanced-stage NSCLC. Factors influencing the choice of systemic therapy include the presence of a driver mutation (such as epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ROS oncogene 1 [ROS1]), the level of programmed cell death ligand 1 (PD-L1) tumor expression, histology, and patient comorbidities and symptoms. In patients with ILD, additional consideration must be given to the risks of pulmonary toxicity or ILD exacerbation from the systemic agents. Pulmonary toxicity has been reported with the use of most novel agents in NSCLC therapy, notably gemcitabine, taxanes, topoisomerase-1 inhibitors, and immune checkpoint inhibitors. (See "Overview of the initial treatment of advanced non-small cell lung cancer".)

●Patients with targetable driver mutations – EGFR inhibitors may be associated with a low risk of pulmonary toxicity. Pneumonitis has occurred in association with small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib, with an overall incidence of 0.3 percent, but higher rates were seen in Japan at 1 percent [35]. This risk may be significantly higher if TKIs are used sequentially with programmed cell death protein 1 (PD-1) checkpoint inhibitors, as has been observed in the case of osimertinib [36,37]. Concomitant steroid administration with TKIs may limit pulmonary toxicity. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Immune-related toxicities with EGFR TKI after immunotherapy'.)

Lung toxicity with ALK inhibitors is also estimated at approximately 1 percent and is more common with brigatinib relative to other TKIs, occurring as an early event within 48 hours [38]. Thus, agents with lower risk of pulmonary toxicity like alectinib are preferred over brigatinib as initial therapy for those with ILD and ALK-positive advanced NSCLC. Although the incidence of targetable alterations is uncommon in the ILD lung cancer population, the benefit of kinase inhibitor therapy is deemed to outweigh the risk for those with targetable aberrations in EGFR, ALK, and ROS1.

●Patients lacking driver mutations

•Immunotherapy – PD-1 and PD-L1 checkpoint inhibitor therapies are now a standard part of first-line therapy in patients without targetable aberrations, either as monotherapy in selected patients with high PD-L1 tumor expression or in combination with chemotherapy. These agents are associated with a significant risk of pneumonitis in the non-ILD patient population, and the risk of pulmonary toxicity is estimated to be higher in those with pre-existing pulmonary abnormalities, including those with idiopathic pulmonary fibrosis (IPF) and other forms of ILD [39,40]. Thus, careful selection of patients is required, ideally based on a multidisciplinary team discussion that includes ILD expertise and considers the potential response to therapy balanced against the risk of toxicity that is primarily related to the type and severity of underlying pulmonary disorder. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

A systematic review and meta-analysis analyzed 179 patients with mild ILD treated with PD-1/PD-L1 inhibitors for NSCLC in 10 observational studies [40]. The risk for any grade pneumonitis was higher in patients with ILD compared with patients without ILD (27 versus 10 percent), as were the risks of grade ≥3 pneumonitis (15 versus 4 percent). Despite these increased risks, the pooled overall response rate to single agent PD-1/PD-L1 inhibitors was 34 percent, which is comparable to response rates in those without ILD in randomized trials. Imaging consistent with UIP did not increase the likelihood of pneumonitis compared with other radiographic ILD patterns.

•Chemotherapy – Chemotherapy-induced lung toxicity is more common in those with pre-existing ILD, with an approximately fivefold increase in risk, and may be higher in those with a radiographic pattern of UIP [41,42]. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

Vinorelbine, paclitaxel, and nab-paclitaxel appear associated with the least toxicity in the ILD lung cancer population [42]. Agents such as gemcitabine and docetaxel should be avoided in patients with ILD, provided other options are available.

●Palliative measures in all patients – Patients with stage IV cancer also remain candidates for palliative radiation for disease sites that are causing symptoms. Care should be taken in delivery of radiation to intrathoracic targets, with the use of minimally sufficient doses and conformal techniques wherever possible. (See 'Palliative care' below.)

●Investigative options – In addition to its activity in IPF and other progressive fibrosing ILDs [43,44], nintedanib has limited activity in NSCLC. It improves survival in patients with advanced, pretreated lung adenocarcinoma when combined with docetaxel, an approved regimen in Europe [45]. The addition of nintedanib also improves overall survival when added to carboplatin and nab-paclitaxel in patients with nonsquamous advanced NSCLC, although nintedanib has not been approved for this indication [46].The safety and efficacy of other antifibrotic agents, such as pirfenidone, in combination with lung cancer therapy in the ILD population remains unknown. There are also minimal data on interactions between antifibrotic agents and immune checkpoint inhibitors, particularly whether these agents can provide any protection against ICI pneumonitis.

Small cell lung cancer

Approach — One of the first steps in selecting treatment options for small cell lung cancer (SCLC) is to ascertain whether the patient has limited-stage (LS) or extensive-stage (ES) disease. LS-SCLC is defined as disease that is limited to the ipsilateral hemithorax and regional lymph nodes and can be encompassed in a safe radiotherapy field. Thorough staging, including positron emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) of the brain, is indicated for all patients. (See "Limited-stage small cell lung cancer: Initial management", section on 'Staging'.)

The general management paradigm for limited-stage SCLC in non-ILD patients includes surgical resection followed by chemotherapy for stage I disease and chemoradiotherapy for patients with higher stage disease (including those with nodal involvement). For those with extensive-stage disease who do not have ILD, chemotherapy plus checkpoint inhibitors are typically recommended. However, the treatment approach for SCLC in patients with ILD must account for severity of ILD, avoiding or mitigating interventions that might exacerbate ILD, such as checkpoint inhibitors. (See "Limited-stage small cell lung cancer: Initial management" and "Extensive-stage small cell lung cancer: Initial management".).

Limited stage, resectable disease — For patients with ILD, limited stage SCLC, and adequate pulmonary function, we suggest primary surgical resection followed by chemotherapy. In the non-ILD setting, a large United States National Cancer Database study of 28,621 potentially resectable SCLC patients included 393 patients with clinical stage II or III disease who received primary surgical treatment [47]. Five-year overall survival was 25 and 18 percent for stages II and III, respectively.

Surgical resection may be a consideration in patients with ILD who have stage II or III SCLC, given the risks associated with radiotherapy. Although SCLC is usually characterized by bulky hilar and mediastinal nodes that are unresectable, a surgical approach to therapy may avoid some of the morbidity of radiation therapy in the minority of patients with more minimal and potentially resectable nodal burden.

Unresectable disease — Patients with nonresectable SCLC and ILD have been successfully treated with etoposide and either cisplatin or carboplatin. In patients with SCLC and ILD, response rates with systemic therapy in limited and extensive stages are high, ranging from 63 to 88 percent, respectively [48-50]. Median progression-free survival estimates range from 4.5 to 5.5 months, and overall survival ranges from 7 to 10 months, although these numbers include patients with both limited and extensive stage. The frequency of acute worsening of ILD varied across studies from 2 to 15 percent. (See "Extensive-stage small cell lung cancer: Initial management" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)

The addition of immune checkpoint inhibitors (ICI), monoclonal antibodies against PD-L1, to initial chemotherapy has been shown to improve survival modestly in ES-SCLC. However, approximately 5 percent of patients treated with ICI develop pneumonitis, sometimes severe, raising the concern that patients with underlying ILD might be at particular risk. Thus, we do not favor routine use of ICIs in patients with SCLC and ILD, and instead individualize the decision regarding immunotherapy in extensive SCLC according to assessment of potential risks and benefits. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for addition of immune checkpoint inhibitors to chemotherapy'.)

Palliative care — When formulating a treatment plan for patients with ILD and lung cancer, the potential risks and benefits of curative versus palliative therapy should be discussed with the patient in the context of their values and preferences and taking into account the prognosis of their underlying ILD. An approach to conversations about serious illness is provided in the table (table 3). A stepwise approach to a goals-of-care discussion can also be helpful and is described separately. (See "Discussing goals of care", section on 'REMAP: A stepwise approach'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease" and "Society guideline links: Diagnosis and management of lung cancer" and "Society guideline links: Screening for lung cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Interstitial lung disease (The Basics)" and "Patient education: Idiopathic pulmonary fibrosis (The Basics)" and "Patient education: Lung cancer (The Basics)" and "Patient education: Lung cancer screening (The Basics)" and "Patient education: Non-small cell lung cancer (The Basics)" and "Patient education: Small cell lung cancer (The Basics)")

●Beyond the Basics topics (See "Patient education: Lung cancer risks, symptoms, and diagnosis (Beyond the Basics)" and "Patient education: Small cell lung cancer treatment (Beyond the Basics)" and "Patient education: Non-small cell lung cancer treatment; stage IV cancer (Beyond the Basics)" and "Patient education: Non-small cell lung cancer treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Lung cancer prevention and screening (Beyond the Basics)".)

SUMMARY AND RECOMMENDATIONS

●Introduction – Patients with interstitial lung disease (ILD) have an increased risk of lung cancer and toxicities from treatment of lung cancer. (See 'Introduction' above and 'Epidemiology' above.)

●Diagnosis of lung cancer in patients with ILD – The approach to the diagnosis of lung cancer in patients with ILD is generally similar to patients without ILD, with the main exception that the consequences of potential pulmonary complications from invasive procedures are greater in patients with ILD. The decision to pursue histopathologic sampling must balance the pretest likelihood of cancer against the potential for the patient to tolerate diagnostic procedures and effective therapy. (See 'Approaches to lung cancer detection' above and "Screening for lung cancer" and "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer".)

We use a risk prediction tool, such as the Brock University cancer prediction equation (calculator 1), to help estimate the likelihood that a given lung nodule is malignant and guide which diagnostic methods to employ in an individual patient. (See 'When to pursue sampling for lung cancer in patients with ILD' above.)

●Management – Management decisions in patients with ILD and lung cancer require careful consideration of potential toxicities weighed against the potential benefits. The risks of treatment should also be evaluated in light of the potential harms from untreated lung cancer. (See 'Management of lung cancer in patients with ILD' above.)

•NSCLC – For patients with ILD and adequate pulmonary function who have stage I or II non-small cell lung cancer (NSCLC), we suggest surgical resection as the initial treatment, rather than radiation therapy (RT) (Grade 2C), provided there are no other serious comorbidities. The extent of surgical resection must balance the risks of toxicity against the oncologic benefits of a wider resection, but in the setting of ILD, where lung function is expected to deteriorate over time, preservation of lung parenchyma with sublobar resection may be warranted.

For patients who are not candidates for surgery, there is no clear evidence to suggest superiority of stereotactic ablative radiotherapy or radiofrequency ablation as a second-choice modality. (See 'Non-small cell lung cancer' above.)

•SCLC – For patients with ILD and T1 or T2, node negative small cell lung cancer (SCLC) (table 2), we suggest surgery rather than other modalities, as initial treatment (Grade 2C). Surgery may also be considered in higher stage SCLC to avoid the risks associated with radiation therapy. (See 'Small cell lung cancer' above.)

•Locally advanced disease (SCLC or NSCLC) – In locally advanced unresectable cancers (NSCLC or SCLC), concurrent chemoradiotherapy may be delivered, although the risks of toxicities are higher than in a non-ILD population. (See 'Non-small cell lung cancer' above and 'Small cell lung cancer' above.)

•General considerations regarding systemic therapy — The risks and benefits of systemic therapy with chemotherapy, targeted therapy, and immune checkpoint inhibitors should be assessed for each individual patient, considering the goals of therapy (curative versus palliative), the ILD diagnosis and severity, and the anticipated prognosis from ILD. Higher risk therapies, such as checkpoint inhibitors, should be discussed on a case-by-case basis with a multidisciplinary team, including those with ILD expertise. (See 'General principles' above and 'Palliative care' above and "Overview of the initial treatment and prognosis of lung cancer" and "Prognosis and monitoring of idiopathic pulmonary fibrosis".)