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".)
PATIENT 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. The eighth edition TNM staging system is used for treatment planning and prognostic purposes in patients with NSCLC. The eighth edition has replaced earlier editions of the TNM staging system (table 1). Differences in TNM groupings between the seventh and eighth editions are shown in the table (table 2). 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. (See 'Investigational strategies' 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. (See 'Predictive biomarkers' below.)
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].
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 3) [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 3) [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 3). 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 3) [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 NSCLC that is either stage IB with high-risk features (eg, lymphovascular invasion, poor differentiation, etc) or stage II to III, we suggest 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. However, although adjuvant tyrosine kinase inhibitor (TKI) treatment improves disease-free survival (DFS) in patients with EGFR-mutated tumors, an improvement in survival has not been demonstrated at this point.
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). OS data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). These results led to a recommendation for study closure by the Data Safety Monitoring Committee. In the subset of patients with stage II to IIIA disease, two-year DFS rates were 90 and 44 percent, respectively (HR 0.17, 95% CI 0.11-0.26). However, 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. The effect on OS remains unknown. Results of this trial led to approval by the US Food and Drug Administration as adjuvant therapy for resected EGFR-mutant NSCLC [22].
Improvements in DFS (but not OS) have also been observed in trials of adjuvant first-generation EGFR TKIs, but of lesser magnitude [23-25].
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 [26]. 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 [27]. 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 preliminary results of a phase III study including 784 patients with stage II to IIIA nonsquamous NSCLC, median recurrence-free survival was 39 months among those assigned to pemetrexed/cisplatin and 37 months for those assigned to vinorelbine/cisplatin [28]. Three-year OS rates were 84 and 87 percent, respectively. Although these differences did not reach statistical significance, incidences of ≥grade 3 neutropenia were lower for the pemetrexed-containing arm (0.3 versus 12 percent), and completion rates were higher (88 versus 73 percent). 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 pemetrexed or vinorelbine, more patients were able to complete therapy without significant toxicity with pemetrexed compared with vinorelbine (96 versus 75 percent, respectively) [29].
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 [30]. 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) [31].
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 [32]. 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 [33].
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 IIIA NSCLC whose tumors have programmed cell death ligand 1 (PD-L1) expression on ≥1 percent of tumor cells, as determined by an FDA-approved test [34]. Adjuvant pembrolizumab has shown promising results, but does not have regulatory approval.
Relevant data are as follows:
●Atezolizumab – In the IMpower010 trial, among 882 patients with stage II to IIIA 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) [35]. 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. OS results were not mature with only approximately 20 percent of events collected, but HR for OS at this early timepoint among all patients with stage II to IIIA disease was 0.99 (0.73 to 1.33) and 0.77 (0.51 to 1.17) in the subset of PD-L1-positive tumors. Grade 3 or 4 events occurred in 22 percent receiving atezolizumab and 12 percent receiving best supportive care.
OS results are not mature. 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) [36]. 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. We await further data and regulatory approval prior to routine use of adjuvant pembrolizumab.
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' 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 [37]. 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 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 therapy and have programmed cell death ligand 1-positive tumors, adjuvant atezolizumab can be considered. (See 'Adjuvant immunotherapy' above.)
Neoadjuvant immunotherapy — 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 [38], 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 preliminary results of Checkmate 816, among over 350 patients with stage IB to IIIA 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) [39]. 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) [38].
Similarly, major pathologic responses have been observed in preliminary results of neoadjuvant trials with nivolumab and ipilimumab (in 33 percent [40]), as well as for atezolizumab (in 18 percent [41]). Perioperative durvalumab has also shown promising results in a single-arm study in patients with stage IIIA (N2) NSCLC [42].
INVESTIGATIONAL STRATEGIES
Predictive biomarkers — Molecular markers may provide additional information about the likelihood of relapse and benefit of adjuvant therapy, beyond that obtained from pathologic staging. Approaches and specific markers under study include gene expression profiling, abnormalities in the Kirsten rat sarcoma viral oncogene (KRAS) and p53 tumor suppressor gene, and DNA methylation markers. Additional studies will be required to determine whether these markers are useful in selecting patients for adjuvant platinum-based chemotherapy.
●Gene expression profiling – Gene expression profiles are being developed that may be useful in defining favorable and unfavorable prognostic subsets [43-46]. Results with these gene expression profiles have the potential to divide patients into different risk groups, and thus identify those who might benefit from adjuvant chemotherapy. However, at this time, gene profiles have not been incorporated in clinical practice for decisions regarding adjuvant chemotherapy, as there is no proof of predictive ability.
As an example of a gene profile, a 14-gene expression profile was developed in a cohort of 361 patients who had NSCLC resected at a single institution [46]. This profile used quantitative polymerase chain reaction (PCR) and was run on paraffin-embedded tumor tissue. This profile was then validated in two other cohorts, one with 433 patients who had undergone resection for stage I nonsquamous NSCLC and the other in 1006 patients who had undergone resection of stages I, II, or III nonsquamous NSCLC. In all three cohorts, approximately 80 to 90 percent of patients had adenocarcinoma. When the original criteria were applied to the validation cohorts, the five-year survival rates in the low-risk, intermediate-risk, and high-risk patients were 71, 58, and 49 percent, respectively. These differences could not be explained on the basis of other known prognostic factors.
●KRAS and p53 – Both p53 tumor suppressor gene and the KRAS oncogene have been implicated in the pathogenesis of NSCLC. Overexpression of p53 and mutation in KRAS may identify patients who are more and less likely, respectively, to derive benefit from adjuvant chemotherapy.
Abnormalities in these genes were studied in a subset of 253 patients from the JBR.10 adjuvant chemotherapy trial, which included patients with completely resected IB and II NSCLC [47].
•Overexpression of the p53 gene as assessed by immunohistochemistry was associated with a significantly poorer prognosis compared with those who were negative for p53 overexpression, but the benefit from adjuvant chemotherapy was greater among those with p53 overexpression. Patients with mutations in p53, which is associated with lack of expression, did not appear to benefit from adjuvant chemotherapy.
•Patients with mutations in KRAS in their tumor did not appear to benefit from adjuvant chemotherapy, while those with wildtype KRAS had improved outcomes with adjuvant chemotherapy. Similarly, in an analysis of biomarkers from 1532 patients in the Lung Adjuvant Cisplatin Evaluation (LACE)-bio study, patients with a mutation in KRAS codon 13 had significantly poorer outcomes when treated with adjuvant chemotherapy compared with those without a codon 13 mutation [48].
Despite these differences in outcomes with adjuvant chemotherapy, KRAS mutation status may not be prognostic of survival. In a pooled analysis of four trials including over 1500 patients, 300 of whom had KRAS mutations, there was no prognostic difference for overall survival (OS) for those with KRAS codon-12 or codon-13 mutations relative to those with wildtype KRAS [49].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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 5th to 6th 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 10th to 12th 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.)
●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 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 prefer cisplatin and pemetrexed, 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 IIIA NSCLC whose tumors have programmed cell death ligand 1 expression on ≥1 percent of tumor cells and who have not received neoadjuvant treatment, we suggest adjuvant atezolizumab (Grade 2B). (See 'Adjuvant immunotherapy' above.)
•For patients with completely resected, epidermal growth factor receptor (EGFR)-mutated NSCLC that is either stage IB with high-risk features (eg, lymphovascular invasion, poor differentiation, etc.), or stage II to IIIA, we suggest adjuvant osimertinib (Grade 2B), to be continued until progression or unacceptable toxicity for up to three years. However, the impact on overall survival is thus far unknown, and patients may reasonably opt for surveillance only. (See 'EGFR-mutated cancers' 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. 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.)
●Neoadjuvant immunotherapy – Neoadjuvant chemotherapy 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 addition of nivolumab to platinum-based doublet chemotherapy (Grade 2B). (See 'Neoadjuvant immunotherapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Nasser Hanna, MD, who contributed to an earlier version of this topic review.
