Systemic therapy in resectable non-small cell lung cancer

INTRODUCTION — Patients with stage I, II, or III (table 1) non-small cell lung cancer (NSCLC) are at substantial risk for recurrence and death even after complete surgical resection. Approximately 25 percent of patients with stage IB, 35 to 50 percent of stage II, and a greater percentage of those with pathologic stage III NSCLC eventually recur and die of their disease despite potentially curative surgery [1]. (See "Tumor, node, metastasis (TNM) staging system for lung cancer".)

The development of active platinum-based combinations and the completion of large clinical trials assessing the activity of adjuvant chemotherapy for resected NSCLC have led to the use of adjuvant chemotherapy to improve the outcome in patients with completely resected NSCLC.

The role of adjuvant systemic therapy for patients with completely resected NSCLC will be reviewed here. Other aspects of the initial treatment of patients with stages I, II, and III NSCLC are discussed separately. (See "Management of stage I and stage II non-small cell lung cancer" and "Management of stage III non-small cell lung cancer".)

DECIDING ON INITIAL SURGICAL RESECTION VERSUS NEOADJUVANT TREATMENT — The decision regarding initial surgical resection versus neoadjuvant treatment is discussed elsewhere. (See "Management of stage III non-small cell lung cancer", section on 'No clinical mediastinal involvement prior to surgery' and "Management of stage III non-small cell lung cancer", section on 'Clinical mediastinal (N2, N3) involvement' and "Management of stage I and stage II non-small cell lung cancer", section on 'General approach to treatment'.)

PATIENTS TREATED WITH INITIAL SURGICAL RESECTION

Candidate selection for adjuvant therapy — Generally, patients with a high risk of recurrence are most likely to derive benefit from chemotherapy, while those who have a low risk of relapse have a lower absolute benefit. Tumor, node, metastasis (TNM) staging is the most important prognostic factor determining the likelihood of relapse and therefore predicts those most likely to benefit from adjuvant therapy (table 1). Adjuvant chemotherapy is not indicated for patients with resected stage IA disease. Our approach according to stage is discussed below, and is consistent with expert guidelines [2]. Discussion of prognosis according to stage is found elsewhere. (See "Tumor, node, metastasis (TNM) staging system for lung cancer", section on 'Prognosis by stage'.)

Additionally, a number of molecular biomarkers to predict who may benefit from adjuvant chemotherapy are under study and are discussed below.

Although the stages are according to the eighth edition staging system, it is recognized that the studies cited may have used previous editions of the staging system, which is a limitation of existing data.

Stage I disease

Stage IA disease — Patients with stage IA disease should not receive adjuvant chemotherapy, given evidence suggesting worsened survival associated with adjuvant treatment.

In the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis, which included five studies with approximately 4600 patients with completely resected NSCLC, there was a trend toward worsened survival among patients with stage IA disease receiving adjuvant chemotherapy (hazard ratio [HR] of death 1.40, 95% CI 0.95-2.06) [3].

Although subsequent retrospective data have suggested improved outcomes with adjuvant chemotherapy for high-risk stage IA disease, data remain mixed, and we do not suggest adjuvant chemotherapy for any subsets of stage IA disease. In preliminary reporting of a Japanese retrospective review of patients with stage IA disease, among the 641 patients with high-risk factors (eg, an invasive component size of >2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion), adjuvant chemotherapy was associated with improvements in five-year rates of recurrence-free survival (81 versus 74 percent) and overall survival (OS; 93 versus 82 percent) [4]. Limitations in generalizability of this study are that it likely included many patients who were diagnosed based upon screening computed tomography (CT), and who were treated with a chemotherapy regimen not typically used outside of Japan (ftorafur plus uracil). By contrast, in a retrospective National Cancer Database study including over 10,000 patients, adjuvant chemotherapy did not impact OS among patients with pathologic T2N0 NSCLC with high-risk disease (defined by lymphovascular invasion, visceral pleural invasion, high-grade tumor, sublobar resection, tumor size) [5].

Stage IB disease — The role of adjuvant chemotherapy for patients with resected stage IB disease remains controversial. We offer adjuvant chemotherapy to medically appropriate patients with stage IB disease whose tumors display one or more high-risk features, including lymphovascular invasion, poor differentiation, or high standardized uptake value (SUV) on positron emission tomography (PET; variably defined as SUV 10 or more). However, there is no consensus among expert groups. For example, for patients with stage IB NSCLC, the American Society of Clinical Oncology (ASCO) Cancer Care Ontario guidelines do not endorse adjuvant chemotherapy for routine use because of the lack of definitive evidence establishing improved survival [6]. By contrast, the National Comprehensive Cancer Network (NCCN) guidelines consider either observation or adjuvant chemotherapy an appropriate option for patients with resected stage IB NSCLC, depending on risk factors for recurrence [7].

In the LACE meta-analysis discussed above, among patients with stage IB disease, there was only a nonsignificant trend toward improved OS (HR of death 0.93, 95% CI 0.78-1.10) [3].

Studies have not clearly identified which patients with stage I disease might fall into a high-risk subset. Molecular markers may identify patients who are at higher risk of relapse who therefore may be more likely to benefit from adjuvant chemotherapy, though their use should be considered investigational.

Special considerations for those with somatic activating mutations in the epidermal growth factor receptor (EGFR) are discussed below. (See 'EGFR-mutated cancers' below.)

Stage II and III disease — For patients with completely resected stage II and III disease, we utilize adjuvant systemic chemotherapy with a cisplatin-based regimen, consistent with guidelines from ASCO and Cancer Care Ontario [6] and from the NCCN [7]. For patients with stage II to III resected NSCLC that has been treated with adjuvant platinum-based chemotherapy, we suggest an adjuvant checkpoint inhibitor. (See 'Adjuvant immunotherapy' below.)

While clinical trials from the 1970s and early 1980s did not show a consistent benefit with adjuvant chemotherapy [8], multiple subsequent large trials using adjuvant platinum-based combinations have demonstrated a benefit (table 2) [9-15]. Sufficient data are now available from these newer trials to conclude that adjuvant chemotherapy is useful for patients with completely resected, stage II and III NSCLC. While the adjuvant chemotherapy trials have not specifically analyzed patients with multiple tumors within the same lung (T3N0 or T4N0 disease), these patients are generally treated in the same manner as other patients with stage II and III disease and are managed with surgery and adjuvant chemotherapy. (See "Management of stage III non-small cell lung cancer", section on 'Multiple tumor nodules'.)

The improved survival with adjuvant chemotherapy using modern cisplatin-based regimens was demonstrated in the LACE meta-analysis that combined individual patient data from the five largest trials (table 2) [3,9-13]. In a pooled analysis of 4584 patients with completely resected NSCLC with a median follow-up of 5.2 years, adjuvant chemotherapy was associated with a decreased risk of death of 5.4 percent at five years compared with no chemotherapy (HR 0.89, 95% CI 0.82-0.96) [3]. The effect on survival varied by stage, but a benefit that reached statistical significance was seen only for patients with stage II (HR of death 0.83, 95% CI 0.73-0.95) and IIIA disease (HR of death 0.83, 95% CI 0.72-0.94). All five trials used cisplatin-based chemotherapy, although the IALT [9], European Big Lung [10], and the ALPI [11] trials each integrated cisplatin into multiple chemotherapy regimens (table 2). In addition, these three trials allowed the use of adjuvant thoracic radiation at the discretion of the treating clinician, as did the ANITA trial [12].

A subsequent Cochrane meta-analysis from the Non-Small Cell Lung Cancer Collaborative Group demonstrated a 4 percent OS benefit for adjuvant chemotherapy among 8447 patients in 26 trials treated surgically without radiation, although only nonsignificant trends were observed for patients with stage II and IIIA disease, which comprised a minority of the included patients (approximately one-third) [16].

Special considerations for those with somatic activating mutations in EGFR are discussed below. (See 'EGFR-mutated cancers' below.)

Stage IIIB/C — In the seventh edition TNM staging, all patients with stage IIIB had unresectable disease. The eighth edition groups rare patients with T3/T4N2 disease as stage IIIB; however, these patients are technically resectable. If the disease is completely resected, these patients are treated per the discussion above for stage II/III. However, the initial approach to most patients with stage IIIB/C disease typically does not include surgery, and therefore the issue of adjuvant chemotherapy is not relevant to these populations. Discussion of the management of patients with unresectable stage IIIB/C disease is found elsewhere. (See "Management of stage III non-small cell lung cancer", section on 'N3 disease'.)

Patients with stage IV disease are typically treated with systemic therapy, taking into account disease histology and genetics. Site-specific local management of metastases may also be indicated. In select instances of oligometastatic disease, definitive local treatment may be considered. The role of adjuvant systemic treatment after definitive treatment of oligometastatic disease is also discussed elsewhere. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Factors in choosing initial therapy'.)

Special considerations

Patients requiring surgery and radiation — The indications for adjuvant chemotherapy among those who will be treated with surgery and radiation are the same as for those treated with surgery alone. Specifically, for patients with resected stage II or III disease, we recommend adjuvant chemotherapy rather than observation, regardless of whether radiation is indicated. Similarly, we only treat patients with stage I disease with adjuvant chemotherapy if their tumors have high-risk features, regardless of whether adjuvant radiation is indicated. Tumors historically referred to as stage IB >4 cm in the seventh edition staging are now considered stage IIA. Discussion of which patients should be treated with postoperative radiation, including those with positive margins as well as those with N2 disease, is found elsewhere. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Positive resection margins' and "Management of stage III non-small cell lung cancer", section on 'Adjuvant postoperative RT' and "Management of stage III non-small cell lung cancer", section on 'Adjuvant therapy'.)

Regarding timing of treatment, for those with N2 disease receiving RT, we administer chemotherapy prior to RT [17]. For patients with positive margins, chemotherapy may be given either concurrently, before, or after radiation.

A Cochrane meta-analysis from the Non-Small Cell Lung Cancer Collaborative Group included results based upon individual patient data from 2660 patients in 12 trials who were managed with surgery plus RT with or without adjuvant chemotherapy [16]. Approximately 95 percent of these patients had stage II or IIIA disease. There was an improvement in OS with adjuvant chemotherapy (HR of death 0.88, 95% CI 0.81-0.97), corresponding to a 4 percent increase in OS at five years (33 versus 29 percent). The meta-analysis did not detect a difference in outcome between patients who received chemotherapy before versus after RT.

Older adult patients — Although older adult patients have not been well represented in adjuvant trials, the available data suggest that older adults with resected NSCLC should not be excluded from receiving adjuvant chemotherapy based upon age alone. The decision to pursue adjuvant therapy should consider both the potential benefits of such treatment and the health of the individual patient. A fit older adult is likely to derive as much benefit from adjuvant chemotherapy as a younger individual, with similar tolerance of toxicities. For those with baseline comorbidities such as hearing loss that make cisplatin a suboptimal choice, carboplatin is a reasonable alternative (see 'Rationale for use of cisplatin over carboplatin' below). However, for frail older patients or those with significant comorbidities, the risks may outweigh benefits, and it is reasonable to omit adjuvant chemotherapy.

The role of adjuvant chemotherapy in appropriately selected older adult patients is supported by both the LACE meta-analysis and an unplanned subset analysis of the JBR.10 trial (which was one of the trials included in the meta-analysis) (table 2) [18,19]. It should be noted, however, that fewer than 10 percent of the patients in LACE were over 70 years of age and that two of the three positive studies excluded patients older than 75 years, illustrating that trials are limited in assessing this population. The LACE meta-analysis demonstrated that efficacy was not significantly different in older (≥70 years) compared with younger patients, even though older patients received lower doses and fewer cycles of chemotherapy [18]. In addition, no differences in severe toxicity were observed. Similarly, in JBR.10, patients >65 years received fewer cycles of chemotherapy (median, three versus four cycles in those ≤65 years) but experienced an OS benefit that was similar to that observed in younger patients [19].

Neither of these analyses can be generalized to assess the role of adjuvant chemotherapy in the broader population of older patients, since patients enrolled in the adjuvant chemotherapy trials represent a group that was likely more fit than those of similar age who were not enrolled. Therefore, decisions regarding adjuvant chemotherapy in the older adult patient must be individualized according to patient functional status. Special considerations for the use of chemotherapy in older adult patients are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

EGFR-mutated cancers — For patients with completely resected, epidermal growth factor receptor (EGFR)-mutated stage IB to IIIA NSCLC, we recommend adjuvant osimertinib, to be continued until progression or unacceptable toxicity for up to three years. Osimertinib is initiated after the completion of any indicated chemotherapy.

In a phase III double-blind trial of 682 patients with EGFR-mutant, stage IB to IIIA [20] NSCLC who had undergone a complete resection (with some patients receiving adjuvant chemotherapy), those assigned to adjuvant osimertinib (administered until recurrence for up to three years) versus placebo had improved two-year DFS rates relative to placebo (89 versus 52 percent; HR 0.20, 99% CI 0.14-0.30) [21]. At 24 months, 98 percent of the patients in the osimertinib group and 85 percent of those in the placebo group were alive without central nervous system (CNS) disease (overall HR for disease recurrence or death 0.18; 95% CI 0.10-0.33). These results led to a recommendation for study closure by the Data Safety Monitoring Committee. Benefits were maintained at longer follow up of 44 months (DFS HR 0.23) [22]. Osimertinib also improved OS (five-year OS rate of 88 versus 78 percent with placebo; HR 0.49, 95% CI 0.34-0.70) [23]. In general, the agent was well tolerated, with serious adverse events occurring in 16 percent receiving osimertinib and 13 percent receiving placebo. Patterns of recurrence demonstrated fewer CNS relapses in the osimertinib arm. Results of this trial led to approval by the US Food and Drug Administration as adjuvant therapy for resected EGFR-mutant NSCLC [24].

Improvements in DFS (but not OS) have also been observed in trials of adjuvant first-generation EGFR TKIs, but of lesser magnitude [25-27].

Further study regarding the adjuvant use of targeted therapy among those with targetable genetic alterations is ongoing. The ALCHEMIST trial is actively enrolling patients with operable NSCLC and will perform genetic screening of their tumors (NCT02194738). Patients with tumors that have classic EGFR mutations were offered adjuvant erlotinib versus observation, and this study has completed accrual (NCT02511106). Patients with tumors that have anaplastic lymphoma kinase (ALK) gene rearrangement in their tumor are offered adjuvant crizotinib or observation (NCT02201992). Similarly, a study being conducted in Japan is evaluating the EGFR inhibitor icotinib versus placebo in the adjuvant treatment of patients with EGFR-mutant adenocarcinoma. Finally, a randomized phase III study for patients with ALK-positive tumors is comparing adjuvant alectinib with chemotherapy (NCT03456076).

Administration of adjuvant chemotherapy

Choice of chemotherapy regimen — For those receiving adjuvant therapy, we suggest the use of a cisplatin-based doublet, in agreement with guidelines from the National Comprehensive Cancer Network (NCCN) [7]. This is based on data from the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis discussed above, demonstrating decreased risk of death with cisplatin-based regimens [3]. The investigational incorporation of adjuvant immunotherapy is discussed below. (See 'Adjuvant immunotherapy' below.)

Cisplatin-based doublets — Data from the LACE meta-analysis were inadequate to establish the optimal cisplatin regimen. Our approach is to pair with cisplatin a third-generation cytotoxic agent such as pemetrexed for those with nonsquamous histology, or vinorelbine, gemcitabine, or docetaxel for those with squamous histology. A choice among these agents depends on the side effect profile and patient and provider preferences. Vinorelbine has been the most studied agent, but is associated with neuropathy as well as the greatest incidence of neutropenia and febrile neutropenia. Furthermore, it requires central intravenous access due to its vesicant properties. Docetaxel causes alopecia and has a higher incidence of febrile neutropenia than gemcitabine, and is also associated with pneumonitis and hypersensitivity reactions (for which steroid premedication is necessary). Gemcitabine is associated with thrombocytopenia. Pemetrexed is commonly chosen for those with nonsquamous histology given that it has the lowest incidence of febrile neutropenia and is not associated with alopecia or neuropathy.

The E1505 trial randomly assigned approximately 1500 patients with completely resected NSCLC to treatment with a cisplatin-based doublet with or without bevacizumab. Investigators were permitted to choose between vinorelbine, docetaxel, or gemcitabine for squamous histology, or any of these three agents or pemetrexed for those with nonsquamous histology. Each chemotherapy regimen led to similar overall survival (OS; either with or without bevacizumab) in a preliminary report, although this study was not powered to detect differences in survival between the doublets [28]. Vinorelbine was associated with a higher rate of neutropenia (57 percent) and febrile neutropenia (13 percent), and gemcitabine was associated with greater thrombocytopenia (18 percent), than other doublets. For nonsquamous histologies, pemetrexed was associated with less total grade 3 to 5 toxicity than other chemotherapy groups (64 percent versus 74 to 83 percent).

In the E1505 trial, there was no disease-free survival (DFS) or OS benefit from the addition of bevacizumab to a cisplatin-based chemotherapy doublet [29]. At a median follow-up of 50 months, OS was not increased (median, 86 months with bevacizumab versus not reached without bevacizumab; hazard ratio [HR] 0.99, 95% CI 0.82-1.19). Furthermore, the overall incidence of grade 3 to 5 toxicities was more frequent with bevacizumab (83 versus 67 percent).

For those with nonsquamous histology, pemetrexed is a favored partner with cisplatin due to better tolerability. In a phase III study including 783 patients with stage II to IIIA nonsquamous NSCLC, median recurrence-free survival with vinorelbine/cisplatin was 38 versus 43 months among those assigned to pemetrexed/cisplatin (HR 0.95, 95% CI 0.79-1.14) [30]. Three-year OS rates were 84 and 87 percent, and five-year OS rates were 76 and 75 percent, respectively (HR 1.0, 95% CI 0.81-1.34). Although these differences did not reach statistical significance, incidences of ≥grade 3 neutropenia were higher for the vinorelbine-containing arm compared with pemetrexed based therapy (12 versus 0.3 percent), and completion rates were lower (73 versus 88 percent) [31]. Similarly, in a previous phase II study in which patients with completely resected stage IB to T3N1 IIIA disease were randomly assigned to cisplatin and either vinorelbine or pemetrexed, fewer patients completed therapy without significant toxicity with vinorelbine compared with pemetrexed (75 versus 96 percent, respectively) [32].

Details regarding administration of the various cisplatin chemotherapy regimens are presented separately. (See "Treatment protocols for non-small cell lung cancer" and "Treatment protocols for non-small cell lung cancer", section on 'Cisplatin plus pemetrexed' and "Treatment protocols for non-small cell lung cancer", section on 'Vinorelbine plus cisplatin'.)

Rationale for use of cisplatin over carboplatin — For most patients, cisplatin is the preferred option over carboplatin, given that a survival benefit has never been demonstrated for carboplatin in the adjuvant setting. However, carboplatin instead of cisplatin may be appropriate for patients with baseline hearing loss, significant existing neuropathy, or for those who may not be able to tolerate the emetogenic risk of cisplatin.

The only reported study of carboplatin, Cancer and Leukemia Group B (CALGB) 9633, which evaluated carboplatin with paclitaxel in patients with stage IB disease, was negative for a survival benefit [15]. This study was terminated early, per protocol, given initial results after a median follow-up of 34 months suggesting a survival benefit with adjuvant therapy. However, longer-term follow-up at 74 months did not confirm this benefit. It is unknown whether the limited number of participants due to the premature closure, the lack of inclusion of higher-stage tumors, or the use of carboplatin rather than cisplatin contributed to its overall negative results. Results of pertinent subset analyses are discussed above. (See 'Stage IB disease' above.)

Timing of chemotherapy — Although the optimal time of initiation of treatment is unknown for patients receiving adjuvant chemotherapy, treatment typically starts within eight weeks of surgery given that this was the timeframe used in the studies of adjuvant therapy. Based on the prospective LUNG-ART study, the routine prescription of postoperative radiation therapy (PORT) for all resected N2 disease is no longer recommended [33]. For situations where PORT is planned, it should be administered following completion of chemotherapy, typically within four to six weeks. While available data suggest that adjuvant radiation sequenced either before or after chemotherapy leads to similar outcomes [16], we administer radiation after the completion of adjuvant chemotherapy since either concurrent chemoradiotherapy or radiation followed by chemotherapy might compromise the ability to deliver the recommended dose and cycles of chemotherapy. Moreover, available evidence, albeit limited, suggests improved survival with sequential rather than concurrent chemotherapy and radiation. For example, in a National Cancer Database study of approximately 3500 patients with primary, non-metastatic NSCLC undergoing surgery followed by chemotherapy and radiation, those receiving sequential chemotherapy and radiation experienced improved survival compared with those receiving concurrent chemotherapy and radiation (55 versus 40 months, respectively, a difference that was statistically significant) [34].

For patients in whom either adjuvant immunotherapy or EGFR inhibition are indicated, these are initiated typically after completion of radiation.

Indications for PORT are found elsewhere. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Postoperative RT' and "Management of stage III non-small cell lung cancer", section on 'Adjuvant postoperative RT' and "Management of stage III non-small cell lung cancer", section on 'Adjuvant therapy'.)

Toxicities and quality of life — Data from the adjuvant chemotherapy trials included in the LACE meta-analysis suggest that toxicities associated with adjuvant chemotherapy are tolerable for most patients, and that quality of life (QOL) may actually be improved among those receiving treatment.

The most common severe adverse effects in the adjuvant chemotherapy studies were hematologic. For example, in the ANITA and JBR.10 studies, grade 3 or 4 neutropenia was observed in approximately 70 to 80 percent of patients [12,19]. Rates of febrile neutropenia were between 7 and 9 percent. Additionally, cisplatin is considered to be strongly emetogenic, and over one-quarter of patients experienced nausea and vomiting. Furthermore, approximately 15 percent of patients experienced fatigue. Toxicities that occurred in 10 percent of patients or less included constipation, peripheral neuropathy, fatigue, anorexia, hearing loss, and vomiting. Toxicities associated with specific cisplatin-based doublets are discussed above. (See 'Cisplatin-based doublets' above.)

The impact of adjuvant chemotherapy on QOL was assessed in a subset of 359 patients from JBR.10 who completed a baseline assessment [35]. Patients receiving adjuvant chemotherapy (cisplatin plus vinorelbine) had transient worsening in QOL due to fatigue, nausea, and vomiting. However, the QOL of patients treated with chemotherapy returned to baseline by nine months, except for symptoms of sensory neuropathy and hearing loss. Similarly, an analysis of all 482 patients looking at the quality-adjusted time without symptoms or toxicity found that adjuvant chemotherapy improved quality-adjusted survival despite the toxicity associated with chemotherapy [36].

Adjuvant immunotherapy — Atezolizumab is approved by the US Food and Drug administration (FDA) as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to III NSCLC (at least 5 cm or lymph node positive) whose tumors have programmed cell death ligand 1 (PD-L1) expression on ≥1 percent of tumor cells, as determined by an FDA-approved test [37]. Adjuvant pembrolizumab is FDA approved as adjuvant therapy following resection and platinum-based chemotherapy for patients with resected 8^th edition staging II to III NSCLC (at least 4 cm or lymph node positive), irrespective of PD-L1 expression [38].

Relevant data are as follows:

●Atezolizumab – In the Impower010 trial, among 882 patients with stage II to III NSCLC who had undergone surgery and up to four cycles of adjuvant cisplatin-based chemotherapy, those randomly assigned to 16 cycles of atezolizumab experienced improvements in DFS relative to best supportive care (at a median follow-up of 33 months, median DFS was 42 versus 35 months; HR 0.79, 95% CI 0.64-0.96) [39]. A greater magnitude of benefit was observed among the 476 patients with PD-L1 ≥1 percent (not evaluable versus 35 months; HR 0.66, 95% CI 0.50-0.88). Three-year DFS rates in the overall group were 56 versus 49 percent for atezolizumab versus best supportive care, and among those with PD-L1-positive disease, were 60 versus 48 percent, respectively. At a median of approximately 45 months follow-up, the rates of death with atezolizumab versus without atezolizumab were 26 versus 26 percent in the stage II to IIIA group (HR 0.95, 95% CI 0.74-1.24); 21 versus 28 percent in the stage II to IIIA PD-L1 tumor cell (TC) ≥1 percent group (HR 0.71, 95% CI 0.49-1.03); and 14 versus 28 percent in the stage II to IIIA PD-L1 TC ≥50 percent group (HR 0.43, 95% CI 0.24-0.78) [40]. There was a trend towards worsened survival with atezolizumab among those with stage II-IIIA PD-L1 TC <1% (HR 1.36, 95% CI 0.93-1.99), although this did not reach statistical significance. OS results remain immature. Grade 3 or 4 events occurred in 22 percent receiving atezolizumab and 12 percent receiving best supportive care.

Subset analysis did not show clear benefits to adjuvant atezolizumab in patients who were never-smokers, those with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-mutant tumors, and in those with tumor expression of PD-L1 in <50 percent of cells. These were not powered analyses, however while awaiting OS data, these characteristics should be taken into consideration in the risk-to-benefit discussion of adjuvant atezolizumab.

●Pembrolizumab – In the PEARLS/KEYNOTE-091 trial, among 1177 patients with completely resected stage IB (T ≥4 cm) to IIIA (per the AJCC seventh edition staging system) NSCLC, adjuvant pembrolizumab improved DFS relative to placebo in the overall group (54 versus 42 months; HR 0.76, 95% CI 0.63-0.91), with a nonsignificant trend towards improvement in those with tumor PD-L1 ≥50 percent (median not reached in either arm; HR 0.82) [41]. At a median follow-up of 36 months, OS results were immature (18-month rate of 91.7 versus 91.3 percent, respectively). Grade ≥3 adverse events occurred in 34 versus 26 percent with pembrolizumab and placebo, respectively.

Monitoring and post-treatment follow-up — Patients with lung cancer are at risk of relapse even after receipt of indicated adjuvant therapy, particularly within the first five years after treatment. As such, post-treatment follow-up with physical exam and imaging is indicated. The approach to and benefits of surveillance after therapy are discussed in detail elsewhere. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Post-therapy surveillance'.)

PATIENTS RECEIVING NEOADJUVANT TREATMENT

General principles — Neoadjuvant treatment may be an option in patients with potentially resectable disease, particularly those with single-station mediastinal nodal involvement, or superior sulcus tumors or chest wall invasion in the setting of N1 nodal involvement. (See "Management of stage III non-small cell lung cancer", section on 'Clinical mediastinal (N2, N3) involvement' and "Management of stage III non-small cell lung cancer", section on 'Preferred approach: Chemoradiotherapy, followed by durvalumab' and "Superior pulmonary sulcus (Pancoast) tumors", section on 'Induction chemoradiotherapy plus surgery'.)

Historic studies of neoadjuvant cytotoxic chemotherapy were underpowered as these closed when the more rapidly accruing adjuvant studies discussed above demonstrated survival advantage. In meta-analyses, the overall survival (OS) advantage of neoadjuvant and adjuvant therapies appear comparable [42]. The National Comprehensive Cancer Network guidelines consider neoadjuvant chemotherapy an option for patients of a stage to merit adjuvant therapy. The individual recommendation for neoadjuvant therapy varies drastically by clinician and region. The patients most likely to be referred for neoadjuvant therapy are those with node-positive disease or comorbidities that are being optimized prior to surgical resection.

For patients receiving neoadjuvant therapy, the selection of neoadjuvant chemotherapy regimen follows the same principles as in the adjuvant setting. Those who received systemic chemotherapy in the neoadjuvant setting generally are not treated with adjuvant chemotherapy. For patients who received neoadjuvant chemotherapy only (no immunotherapy) and have programmed cell death ligand 1-positive tumors, adjuvant atezolizumab can be considered. (See 'Adjuvant immunotherapy' above.)

Neoadjuvant/perioperative immunotherapy — Neoadjuvant and perioperative use of immune checkpoint inhibitors has shown improvements in event-free survival, overall survival, and pathologic response rates.

●Neoadjuvant strategies – Nivolumab is approved by the US Food and Drug Administration for use in combination with platinum-based chemotherapy for the neoadjuvant treatment of patients with resectable NSCLCs that are ≥4 cm or node positive [43], and we suggest its use for most such patients, but do not offer it for those whose tumors harbor an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genetic mutation.

In the neoadjuvant setting, in Checkmate 816, among over 350 patients with stage IB >4 cm to III resectable NSCLC and no known EGFR/ALK genetic mutation, the addition of nivolumab to neoadjuvant platinum-doublet chemotherapy improved pathologic complete response rates (24.0 versus 2.2 percent; odds ratio 13.9, 99% CI 3.5-55.8), without decreasing the percentage who underwent definitive surgery (83 versus 75 percent) or increasing grade ≥3 adverse events (34 versus 37 percent) [44]. Median event-free survivals with and without nivolumab were 32 versus 21 months (hazard ratio [HR] 0.63, 97% CI 0.43-0.91). A prespecified interim analysis for OS resulted in an HR of 0.57 (99.7% CI 0.30-1.07); although this did not cross the threshold for statistical significance, the majority of patients were still living at the time of this analysis (74 percent) [43].

Similarly, major pathologic responses have been observed in neoadjuvant trials with nivolumab and ipilimumab (32 percent, 80% CI 19-43 [45,46]); nivolumab, ipilimumab, and chemotherapy (50 percent, 80% CI 35-61 [46]); as well as for atezolizumab (in 18 percent, 95% CI 11-28 [47]).

●Perioperative strategies – Perioperative strategies incorporating immunotherapy have also demonstrated benefits and pembrolizumab is approved in this setting [38]:

•Perioperative pembrolizumab has improved event-free and overall survival, in a randomized, placebo-controlled trial [48]. Among 397 patients with resectable stage II to IIIB NSCLC, the incorporation of neoadjuvant pembrolizumab with cisplatin-based chemotherapy, followed by adjuvant pembrolizumab for up to 13 cycles, improved event-free survival relative to chemotherapy alone (62 versus 41 percent at 24 months, respectively; HR 0.58, 95% CI 0.46-0.72). A pathological complete response occurred in 18 percent in the pembrolizumab group and 4 percent in the placebo group. Overall survival was also superior (median, not reached versus 52 months; HR 0.72, 95% CI 0.56-0.93) [49]. Grade ≥3 adverse effects occurred in 45 and 37 percent, respectively.

•Separately, among 802 patients with treatment-naïve, stage II to IIIB NSCLC, the addition of perioperative durvalumab to neoadjuvant platinum-based chemotherapy improved median event-free survival relative to placebo plus platinum-based chemotherapy (not reached versus 26 months; HR 0.68, 95% CI 0.53-0.88) [50]. At 24 months, event-free survival was 63 percent in the durvalumab group and 52 percent in the placebo group. Grade ≥3 adverse events of any cause were similar in the two groups (42 percent with durvalumab and 43 percent with placebo).

•Nivolumab has been studied in a comparable trial, Checkmate 77T, which enrolled patients with resectable stage II to III NSCLC without known EGFR/ALK alterations [51]. Patients were randomized to four cycles of neoadjuvant platinum-doublet chemotherapy with nivolumab or placebo. Post-operatively nivolumab or placebo was continued for one year. The study showed an improvement in event-free survival, HR 0.58 (95% CI 0.42-0.81, p = 0.00025). Perioperative nivolumab is not yet approved by the US Food and Drug administration.

We await further data and/or regulatory approval prior to routine clinical use of perioperative durvalumab or nivolumab.

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: Diagnosis and management of 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: Non-small cell lung cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Non-small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction – Patients with non-small cell lung cancer (NSCLC) are at substantial risk for recurrence and death even after complete surgical resection. The development of active platinum-based combinations and the completion of large clinical trials assessing the activity of adjuvant chemotherapy for resected NSCLC have led to the use of adjuvant chemotherapy to improve the outcome in patients with completely resected NSCLC. (See 'Introduction' above.)

●Deciding on neoadjuvant treatment versus initial surgical resection – The decision regarding initial surgical resection versus neoadjuvant treatment is discussed elsewhere. (See "Management of stage III non-small cell lung cancer", section on 'No clinical mediastinal involvement prior to surgery' and "Management of stage III non-small cell lung cancer", section on 'Clinical mediastinal (N2, N3) involvement' and "Management of stage I and stage II non-small cell lung cancer", section on 'General approach to treatment'.)

●For patients treated with initial surgical resection

•Stage IA disease – We do not use adjuvant chemotherapy for patients with resected stage IA disease given evidence for worsened outcomes with adjuvant therapy. (See 'Stage IA disease' above.)

•Stage II and III NSCLC – We recommend adjuvant chemotherapy rather than observation for patients with stage II and III NSCLC following potentially curative surgery (Grade 1A). We also offer it to patients with high-risk stage IB disease, specifically those with tumors with high-risk features including lymphovascular invasion, high nuclear grade, or high avidity on positron emission tomography (PET). Given the lack of clear survival benefit in these patients, a reasonable alternative is to forego adjuvant chemotherapy in these patients. (See 'Stage II and III disease' above and 'Stage IB disease' above.)

The indications for adjuvant chemotherapy among those who will be treated with surgery and radiation are the same as for those treated with surgery alone. (See 'Patients requiring surgery and radiation' above.)

•Choice of adjuvant systemic therapy – For patients receiving adjuvant chemotherapy, we suggest treatment with a cisplatin-based doublet (Grade 2B). Bevacizumab is not indicated in the adjuvant setting. (See 'Choice of chemotherapy regimen' above.)

-The optimal chemotherapy regimen has not been determined in randomized trials. For patients with squamous histology, cisplatin with vinorelbine, docetaxel, or gemcitabine is an appropriate option, with a choice among them determined by the side effect profile and patient and provider preferences. (See 'Cisplatin-based doublets' above.)

-For patients with nonsquamous histology, we suggest cisplatin and pemetrexed (Grade 2C), although cisplatin with either vinorelbine, gemcitabine, or docetaxel is also a reasonable option. (See 'Choice of chemotherapy regimen' above.)

-The use of carboplatin-based regimens (eg, carboplatin plus paclitaxel) should be limited to patients with significant comorbidity and those who cannot tolerate a cisplatin-based regimen. (See 'Choice of chemotherapy regimen' above.)

-For patients with stage II to III resected NSCLC that has been treated with adjuvant platinum-based chemotherapy, we suggest an adjuvant checkpoint inhibitor (Grade 2B). Adjuvant atezolizumab is approved by the US Food and Drug Administration (FDA) in tumors that are ≥5 cm or lymph node positive and have programmed cell death ligand 1 (PD-L1) expression on ≥1 percent of tumor cells, while adjuvant pembrolizumab is FDA approved for tumors ≥4 cm or lymph node positive, irrespective of PD-L1 expression. (See 'Adjuvant immunotherapy' above.)

-For patients with completely resected, epidermal growth factor receptor (EGFR)-mutated IB to IIIA NSCLC we recommend adjuvant osimertinib (Grade 1B), to be continued until progression or unacceptable toxicity for up to three years. (See 'EGFR-mutated cancers' above.)

•Timing of adjuvant chemotherapy – Although the optimal time of initiation of treatment is unknown for patients receiving adjuvant chemotherapy, treatment typically starts within eight weeks of surgery. For situations where postoperative radiation therapy is planned, it should be administered following completion of chemotherapy, typically within four to six weeks after completing adjuvant chemotherapy. (See 'Timing of chemotherapy' above.)

●For those receiving neoadjuvant treatment – Neoadjuvant therapy may be an option in patients with potentially resectable disease, particularly those with node-positive disease. For patients receiving neoadjuvant treatment whose tumors are either ≥4 cm and/or node positive, and that lack a driver mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK), we suggest the incorporation of either nivolumab or pembrolizumab with platinum-based doublet chemotherapy (Grade 2B). If pembrolizumab is chosen, it is continued in the adjuvant setting. (See 'Neoadjuvant/perioperative immunotherapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Nasser Hanna, MD, who contributed to an earlier version of this topic review.