Management of stage I and stage II non-small cell lung cancer

INTRODUCTION — The treatment for lung cancer depends upon tumor histology (small cell versus non-small cell), extent (stage), and patient-specific factors (eg, age, pulmonary function, comorbidity). The major subtypes of non-small cell lung cancer (NSCLC) include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, in decreasing order of frequency of occurrence. (See "Pathology of lung malignancies".)

Patients with NSCLC who have disease limited to one lung and not involving the mediastinum or more distant sites have localized stage I or stage II disease (table 1). Stage I plus stage II disease accounts for approximately 30 percent of patients with NSCLC [1]. In this setting, surgical resection is the primary approach to treatment if there are no contraindications. Stereotactic body radiation therapy is the treatment of choice for those who cannot be safely operated on or refuse surgery.

The approach to treatment of patients with stage I and stage II disease will be reviewed here. Overviews of other aspects of lung cancer are presented separately. (See "Clinical manifestations of lung cancer" and "Overview of the initial treatment and prognosis of lung cancer".)

STAGING — The tumor, node, metastasis (TNM) staging system is used for treatment planning and prognostic purposes in patients with NSCLC. The eighth edition of the TNM staging system (table 1) has now replaced the seventh edition. It is recognized that the studies cited in this topic may have used previous editions of the staging system, which is a limitation of existing data. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Tumor, node, metastasis (TNM) staging system for lung cancer".)

Clinical staging may underestimate the extent of tumor, and patients are restaged pathologically following surgery. The issue of when to and how to evaluate the mediastinum in patients with clinical stage I or II disease is discussed separately. (See "Management of stage III non-small cell lung cancer", section on 'Mediastinal evaluation'.)

When mediastinal lymph node involvement is detected, patients are reclassified as having stage III disease. (See 'Mediastinal lymph node dissection' below and "Management of stage III non-small cell lung cancer".)

GENERAL APPROACH TO TREATMENT — The general approach to treatment for patients with histologically confirmed NSCLC is summarized below.

●For peripheral stage IA and IB cancers that can be completely resected with lobectomy (or less), we suggest proceeding directly to surgery; those that are more central or require more than a lobectomy require multidisciplinary discussion regarding induction chemotherapy versus upfront surgery. For those with clinical stage II disease, we suggest induction chemoimmunotherapy followed by surgery rather than initial surgical resection. Event-free survival benefits have been observed with the addition of nivolumab to neoadjuvant platinum-based chemotherapy. However, there are no data to inform neoadjuvant treatment versus adjuvant treatment, and as such, proceeding directly to surgery may be an acceptable alternative.

Further discussion on selection of neoadjuvant systemic therapy, including incorporation of immune checkpoint inhibitors, is found elsewhere. (See "Systemic therapy in resectable non-small cell lung cancer" and "Systemic therapy in resectable non-small cell lung cancer", section on 'Patients receiving neoadjuvant treatment'.)

●For patients who proceed directly to surgery:

•Adjuvant chemotherapy is indicated for those with pathologic stage II disease. Adjuvant chemotherapy may also be indicated for patients with stage IB disease, especially those with high-risk features. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Stage IB disease'.)

Adjuvant chemotherapy is not indicated for patients with resected stage IA tumors. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Stage IA disease'.)

•Postoperative radiation therapy (RT) is indicated only for patients with positive surgical margins; it is not indicated for other patients with stage I or II disease.

•For those with pathologic stage III disease after resection, management is discussed elsewhere. (See "Management of stage III non-small cell lung cancer".)

●Definitive RT is an alternative for patients who are not candidates for surgery based upon comorbidities or who refuse surgery. Stereotactic body radiation therapy (SBRT) is preferred for those with lesions <5 cm. SBRT or full-dose conventional fractionation is indicated for those with larger lesions [2].

SURGICAL CANDIDATES — Surgery is the standard treatment for medically operable patients with clinical stage I and II NSCLC, in whom there is no evidence of mediastinal involvement prior to surgical resection. Although the role of surgery has not been validated through randomized trials, the favorable results reported in surgical series and the long-term survival data in these patients have led to surgery being the preferred treatment modality [3,4]. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Tumor, node, metastasis (TNM) staging system for lung cancer".)

As with malignancies at other sites [5], mortality associated with surgery is decreased and long-term survival is improved in hospitals performing a high volume of lung cancer resections [6].

Adjuvant systemic therapy is discussed elsewhere. (See 'Incorporation of Systemic therapy' below and "Systemic therapy in resectable non-small cell lung cancer".)

Preoperative evaluation — The preoperative evaluation and management of patients with potentially resectable lung cancer is discussed separately. (See "Preoperative physiologic pulmonary evaluation for lung resection" and "Strategies to reduce postoperative pulmonary complications in adults", section on 'Preoperative strategies'.)

Some experts perform preoperative white light bronchoscopy, with or without autofluorescence bronchoscopy, to look for synchronous endobronchial lesions to help with preoperative planning. Details are discussed separately. (See "Flexible bronchoscopy in adults: Overview" and "Detection of early lung cancer: Autofluorescence bronchoscopy and investigational modalities", section on 'Planning therapy for early invasive cancer'.)

Lobectomy preferred in most cases — Lobectomy, the surgical resection of a single lobe, is generally accepted as the optimal procedure for most early-stage NSCLC, with exception made for those with small, peripheral tumors. (See 'Limited (sublobar) resection, in select groups' below.)

In patients with early-stage NSCLC undergoing lobectomy, video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS) are alternatives to open thoracotomy [7]. (See 'Video-assisted thoracoscopic surgery' below.)

Proximal tumors may not be readily resected by lobectomy, thereby requiring a more extensive procedure. In this situation, sleeve resection is preferred over pneumonectomy if possible, based upon equivalent oncologic results, better preservation of pulmonary function, and avoidance of the complications of pneumonectomy [8]. (See "Sequelae and complications of pneumonectomy".)

Historically, the data regarding the relative efficacy of limited resection compared with lobectomy are limited, with studies generally demonstrating an association between limited resection and worse local control and survival rates compared with lobectomy [9,10]. The best evidence, albeit still limited, came from the Lung Cancer Study Group trial 801. In this study, 276 patients with peripheral T1N0 (stage IA) NSCLC were randomly assigned during surgery to either lobectomy or a more limited procedure (ie, wedge resection, segmentectomy) after intraoperative assessment of hilar and lobar lymph nodes [9]. There was a threefold increase in the rate of local recurrence (5.4 versus 1.9 percent) and a trend toward lower survival rates with limited resection compared with lobectomy. It should be noted that the data from this study are approaching a quarter century, predating positron emission tomography scans for instance, and that this study grouped together the nonanatomic and anatomic sublobar resections. Additionally, the majority of the T1N0 lesions treated on this trial were larger than 2 cm in size.

However, there may be certain subsets of patients for whom limited resection yields similar results as lobectomy, for example, patients with small, peripheral tumors or older adult patients, particularly those with adenocarcinoma histology.

Limited (sublobar) resection, in select groups — A sublobar resection consists of the removal of one or more anatomic segments (segmentectomy) or, more commonly, of a nonanatomic wedge resection. Limited (sublobar) resection may be an option for patients with either small peripheral tumors or those who cannot tolerate a full lobectomy because of severely compromised pulmonary function, advanced age, or other extensive comorbidity. Advances in VATS and robotic surgery have facilitated the utilization of limited resections in selected high-risk patients. (See 'Video-assisted thoracoscopic surgery' below.)

Small peripheral tumors — Recent evidence suggests at least equivalent and possibly improved survival with sublobar resection versus lobectomy for patients with small-peripheral NSCLC. This approach should be limited to primary tumors ≤2 cm, located in the outer one-third of the lung parenchyma, with lobar nodes that are proven to be noninvolved on frozen section. A thorough nodal dissection with frozen section evaluation of all of the nodes harvested from the hilum up to the segmental tree should confirm the N0 status of the clinical stage I malignancy before committing to segmentectomy or wedge resection, and the presence of N1 involvement should mandate a lobectomy in individuals that have adequate cardiopulmonary reserves. Some small lesions are not amenable to sublobar resections due to their location; lobectomies are usually favored in such a scenario, although extended segmentectomies and bisegmentectomies have been reported.

In a randomized trial including 1106 patients with clinical stage IA (≤2 cm, consolidation to tumor ratio >0.5) peripheral NSCLC (outer one-third of the lung parenchyma), those assigned to segmentectomy experienced the following outcomes relative to the lobectomy group [11]:

●Improved five-year survival rates with segmentectomy relative to the lobectomy group (94.3 versus 91.1 percent; hazard ratio 0.66, 95% CI 0.47-0.93).

•The difference in survival appears to be related to death from causes other than the originally diagnosed lung cancer or postoperative complications, with 52 deaths in the lobectomy group and 27 deaths in the segmentectomy group attributable to other causes (largely other cancers). The study investigators attributed this difference to more extensive treatment for other lethal diseases in patients who received segmentectomy, as they had greater preservation of lung parenchyma.

●Similar five-year relapse-free survival rates (88.0 and 87.9 percent, respectively).

●More locoregional relapses (11 versus 5 percent). This result seemed incongruous with the overall survival benefit with segmentectomy, highlighting that survival differences were likely from other causes.

●Similar changes in forced expiratory volume in one second (FEV1) at one year.

●Similar grade ≥2 postoperative complications.

By contrast, in a separate randomized trial in 697 patients with peripheral NSCLC with a tumor of ≤2 cm and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, sublobar resection (wedge resection or segmentectomy) resulted in a similar overall survival (80 versus 79 percent) as lobar resection [12]. In this trial 59 percent of the sublobar resections were wedge resections. Locoregional recurrence rates were not statistically different in between the two groups: 13 percent for the sublobar group, 10 percent for the lobectomy. Five-year disease-free survival was similar (63.6 versus 64.1 percent). A nonclinically meaningful difference in FEV1 and forced vital capacity of 2 percentage points favoring the sublobar resection group was also observed.

Earlier observational studies have reported equivalent results to both historic and contemporary lobectomy cohorts with segmentectomy compared with lobectomy [13-17]. A 2014 meta-analysis suggests that this equivalence is only seen for lesions ≤2 cm in size [18]. Several prospective, nonrandomized studies have also reported favorable long-term survival following wedge resection (nonanatomic resection) or segmentectomy among patients with peripheral N0 lung cancers ≤2 cm in size [16,17,19,20], particularly those with adenocarcinoma with lepidic growth histology [21,22].

Older or frail adults — Data are mixed and limited in regards to whether limited resection may yield similar results as lobectomy in older adult patients, and we typically reserve limited resection for those who either cannot tolerate a lobectomy, or those with small, peripheral cancers, as discussed above. (See 'Small peripheral tumors' above.)

An analysis of the Surveillance, Epidemiology, and End Results (SEER) database of patients diagnosed with stage I or II NSCLC between 1992 and 1997 suggested similar survival outcomes with lobectomy and limited resection in patients over the age of 71 [23]. However, a subsequent SEER study of patients diagnosed with stage IA NSCLC between years 1998 and 2010 suggested worsened survival among patients older than 65 years treated with limited resection versus lobectomy (though equivalent survival outcomes were seen in the subset of these patients with adenocarcinoma histology) [24]. The discrepancy between the results of these retrospective analyses may reflect differences in patients enrolled as well as the time periods during which the studies took place.

Video-assisted thoracoscopic surgery — VATS is a minimally invasive approach to the treatment of early-stage NSCLC [25]. In high-volume centers with significant VATS experience, VATS lobectomy has been reported to decrease surgical morbidity, including perioperative pain, and seems to be particularly useful for those with significant medical comorbidities.

The decreased morbidity with VATS may enhance compliance with postoperative adjuvant chemotherapy. As an example, in a nonrandomized series of 100 consecutive patients who underwent lobectomy, patients managed with VATS had significantly fewer delayed (18 versus 58 percent with open thoracotomy) and reduced (26 versus 49 percent) chemotherapy doses [26]. (See "Systemic therapy in resectable non-small cell lung cancer".)

Although the efficacy of VATS compared with conventional surgical techniques has not been definitively established by randomized trials, retrospective data from the National Cancer Database, several large case series from high-volume centers, and a preliminary report of a multi-institutional study support the safety and efficacy of a VATS lobectomy for patients with stage I NSCLC without compromising cancer survival [3,27-31]. (See "Overview of minimally invasive thoracic surgery", section on 'Types of pulmonary resection'.)

More recently, robotic surgery has been used in the treatment of NSCLC. Early-reported experiences suggest an equivalence to VATS as a minimally invasive approach or with traditional open resection.

Another minimally invasive platform that has gained popularity in Europe and Asia is a uniportal VATS approach, with similar reported results.

Mediastinal lymph node dissection — For patients undergoing mediastinal lymph node evaluation at surgery, the optimal extent of lymph node resection is uncertain. A meta-analysis concluded that systematic mediastinal nodal dissection (levels 4, 7, and 10 for right-sided lesions and levels 5 or 6 and 7 for left-sided lesions (figure 1)) was associated with a small to moderate improvement in survival compared with lymph node sampling alone [32]. The improved results may reflect the improved accuracy of staging [33].

In 2006, the European Society of Thoracic Surgeons guidelines recommended systematic lymph node dissection in all cases to ensure complete resection. Lobe-specific nodal dissection was considered acceptable for peripheral T1 lesions if hilar and interlobar nodes were negative on frozen section evaluations [34]. Similar recommendations were proposed by the British Thoracic Society [35].

The North American phase III American College of Surgery Oncology Group Z0030 trial (NCT00003831) compared strategies of systematic lymph node dissection versus mediastinal lymph node sampling [36]. All patients initially underwent sampling of side-specific hilar and mediastinal lymph nodes. The 1111 patients whose sampled nodes were negative were then randomly assigned to a systematic nodal dissection or not. Systematic lymph node dissection did not improve survival of patients with early-stage NSCLC nor did it decrease the incidence of local or regional recurrence. Surprisingly, unsuspected N2 involvement was identified in only 3.8 percent of patients randomly assigned to systematic nodal dissection, possibly a reflection that the prerandomization lymph node sampling may have been quite thorough for many patients on this study.

Positive resection margins — Patients with microscopic involvement of the resection margin with tumor (R1) following seemingly complete resection have a significantly poorer prognosis than for those with negative microscopic margins (R0) [37-41]. Although postoperative radiation therapy (RT) is generally not indicated for patients with stage I or II NSCLC and negative surgical resection margins (R0), postoperative RT has been associated with improved survival for those with positive (R1) surgical resection in stage II and III patients in a large database study with improved overall survival [42]. (See 'Postoperative RT' below and "Management of stage III non-small cell lung cancer", section on 'Adjuvant postoperative RT'.)

Chest wall involvement — For patients with stage IIB (T3N0M0) (table 1) disease due to chest wall invasion, en bloc resection may be indicated. In a series of 212 patients, resection was associated with a 40 percent five-year survival rate [43]. If lymph node involvement was detected at surgery (ie, stage IIIA), the five-year survival rate was only 12 percent.

Local recurrence after surgery — The incidence of local recurrence following surgery for stage I or stage II NSCLC varies from 6 to 55 percent in different studies.

The most extensive data come from a study of 975 consecutive patients with T1-T2, N0-N1, M0 primary tumors operated on at a single institution between 1995 and 2005 [44]. Local failures were defined as recurrence at the surgical margin, in the ipsilateral hilum, or in the mediastinum (ie, areas that would have been encompassed by postoperative [adjuvant] RT). The five-year incidence of local recurrence was 23 percent, with a median time to recurrence of 14 months. The five-year risk of any treatment failure was 42 percent, including local and/or distant relapses, as well as second primary lung cancers. The initial sites of treatment failure were local, combined local and distant, and distant only in 25, 29, and 46 percent of cases, respectively. On multivariate analysis, factors significantly associated with an increased risk of local recurrence included wedge resection or segmentectomy rather than lobectomy, squamous or large cell histology, and pathologic stage IB or II rather than IA (HRs 1.99, 1.98, and 2.02, respectively).

Patients with a local recurrence without distant metastases may be candidates for additional resection. When more surgery is not an option, patients may benefit from RT alone or chemoradiotherapy, and overall survival is similar to that with similarly staged patients managed initially with RT [45]. (See 'Nonsurgical candidates' below.)

Summary — Lobectomy is the procedure of choice for patients with stages I and II NSCLC and is preferred over pneumonectomy if the lesion can be completely resected. There are no randomized trials comparing open thoracotomy with VATS or RATS.

A more limited procedure is appropriate for those who are unable to tolerate conventional lobectomy [46]. Limited resections should be avoided for tumors >2 cm in size whenever possible. Segmentectomy may also be preferred over lobectomy in situations where additional resections may be envisioned, such as multiple ground glass opacities of which only one meets criteria for resection.

NONSURGICAL CANDIDATES — Radiation therapy (RT), using either stereotactic body radiation therapy (SBRT) or conventional fractionation, is the primary alternative to surgery for patients with clinical stage I or II NSCLC who have a significant comorbidity that precludes safe resection and for those who refuse surgery. Definitive RT is also used in selected patients without distant metastases who have a local recurrence following surgery [45].

Stereotactic body radiation therapy — SBRT delivers a very limited number of high-dose fractions (generally one to five) by using multiple convergent beams. SBRT employs image guidance, patient fixation, and high-precision targeting. This results in a rapid fall-off of dose at the edge of the target volume (tumor plus respiratory motion and a small margin). SBRT is the preferred RT technique for the definitive management of stage I lesions [47]. (See "Stereotactic body radiation therapy for lung tumors" and "Radiation therapy techniques in cancer treatment", section on 'External beam radiation therapy'.)

SBRT has a well-defined role in the management of patients who are not surgical candidates or who refuse surgery for peripheral stage I lesions [48]. The role of SBRT compared with surgery for patients who may be operative candidates has not been established in randomized trials.

Prospective phase II studies with SBRT in patients with small, peripheral, biopsy-proven NSCLC suggest that the local control rate is approximately 90 to 95 percent [49,50].

●Outcomes in retrospective series – The most extensive data come from a single institution experience that included 676 patients treated between 2003 and 2011 [49]. The median overall survival was 41 months (95% CI 35-47 months), the five-year local control rate was 89 percent, and the most likely pattern of failure was distant relapse (66 percent of the 124 total relapses observed).

In another series of 282 patients treated between 2008 and 2014, the two-year cumulative incidence of local recurrence was 4.9 percent and 26 percent for any recurrence [50].

●Outcomes compared with standard radiotherapy – In a phase II study including 102 patients randomly assigned to SBRT versus conventionally fractionated RT, there was no difference in progression-free or overall survival, despite the SBRT arm including more patients with T2 tumors [51]. The number of patients included in this study was likely too small to detect differences of the magnitude that could be present. However, patients receiving SBRT also experienced improved quality of life, with decreased pneumonitis (19 versus 34 percent) and esophagitis (8 versus 30 percent).

In a randomized trial in patients with inoperable peripherally located stage I NSCLC, compared with standard radiotherapy, SABR resulted in superior local control of the primary disease without an increase in major toxicity [52]. The findings of this trial suggest that SABR should be the treatment of choice for this patient group.

●Outcomes in patients with chronic obstructive pulmonary disease – SBRT may have a particular role in patients with severe chronic obstructive pulmonary disease. In a single-institution cohort study of 176 such patients, the actuarial three-year local control rate was 89 percent, and the one- and three-year overall survival rates were 79 and 47 percent, respectively [53]. In this patient population, SBRT avoided the risk of operative mortality.

●Outcomes in combination with immunotherapy (investigative approach) – Although the use of immunotherapy with SBRT in patients with early-stage lung cancer has shown promising results, further data are needed prior to incorporation into routine practice.

In an open-label, randomized phase II trial, 156 patients with stage IA to IIB NSCLC or isolated parenchymal recurrences (tumor size ≤7 cm) were randomly assigned to SBRT, with or without four cycles of nivolumab [54]. At a median of 33 months follow-up, the nivolumab-SBRT group had a better four-year event-free survival than the SBRT only group (77 versus 53 percent; hazard ratio [HR] 0.42, 95% CI 0.33-0.80). The rate of grade ≥3 events was 15 percent and 0 percent, respectively. Phase III trials are ongoing.

SBRT versus surgery — The results from nonrandomized phase I and II studies have led to comparisons of stereotactic body radiation therapy (SBRT) with surgery in patients who are surgical candidates [55-58].

Prior to 2010, three randomized trials were designed to compare the efficacy of SBRT with surgical resection for the operable patient population (American College of Surgeons Oncology Group Z4099, the ROSEL trial, and the Accuray trial). Unfortunately, all of these trials were closed prematurely due to poor accrual.

A combined analysis of two of these trials looked at outcomes in 58 patients: 31 treated with SBRT and 27 with surgery [56]. At a median follow-up of 40 months, the overall survival was better at three years in patients treated with SBRT compared with surgery (95 versus 79 percent; HR 0.14, 95% CI 0.02-1.19). However, there were no significant differences in rates of locoregional or distant recurrence or progression-free survival, and the improved overall survival may be attributable to a better safety profile with SBRT compared with surgery. However, this pooled analysis must be interpreted with caution given the very limited number of patients.

At least two other trials are now randomizing patients with operable stage I NSCLC to surgery or stereotactic ablative radiotherapy: the Joint Lung Cancer Trialist's Coalition STABLE-MATES trial (NCT02468024) and the Veterans Affairs Lung Cancer Surgery or Stereotactic Radiotherapy trial (NCT02984761). Mature randomized phase III data are required to provide a clearer picture of how SBRT may be incorporated into the treatment paradigm for resectable early-stage NSCLC.

In addition, retrospective analyses of large cohorts have provided data that may be useful in defining the risks and benefits but do not lead to a definitive conclusion:

●A retrospective analysis of 4065 patients with clinical stage I NSCLC compared outcomes with SBRT (n = 449) versus surgery (sublobar resection [n = 634] or lobectomy [n = 2986]) [57]. On multivariate analysis, cancer-specific mortality was significantly higher with SBRT compared with lobectomy (HR 1.4, 95% CI 1.09-1.94). However, the difference was not statistically significant when SBRT was compared with sublobar resection (HR 1.25, 95% CI 0.93-1.68). Short-term mortality was lower in patients managed with SBRT (90-day mortality for SBRT, sublobar resection, and lobectomy 1.4, 2.5, and 3.6 percent, respectively).

●The increase in short-term mortality was also observed in a National Cancer Database analysis of 8216 patients treated with SBRT versus 76,623 patients who underwent surgery [58]. All patients had cT1-T2a,N0,M0 disease. Overall mortality with SBRT was lower at both 30 and 90 days (0.7 versus 2.1 percent and 2.9 versus 3.6 percent, respectively). Furthermore, mortality for those managed with surgery increased progressively with stage, and differences were most pronounced for patients more than 70 years of age.

Conventionally fractionated radiation therapy — Historically, medically inoperable patients were usually managed with RT using doses of 45 to 66 Gy in fractions of 1.8 to 2 Gy over six weeks. A review of the literature that included approximately 2000 medically unresectable patients found that conventionally fractionated RT yielded a five-year cancer-specific survival rate between 13 and 39 percent [59].

For patients with primary tumors that are not amenable to resection or SBRT, definitive, standard-fractionation RT is an appropriate option.

There are no data to support the use of concurrent chemotherapy in conjunction with RT for patients with stage I and II NSCLC. Although chemoradiotherapy has a role in patients with stage III disease, caution should be exercised before presuming that benefits seen from addition of chemotherapy in a very fit population should be extrapolated into populations too compromised to receive the standard-of-care treatment for potentially curable stage I or II NSCLC.

Other ablative techniques — A number of other techniques are being studied to treat lung tumors in patients who are not surgical candidates, including both small primary NSCLCs and metastases.

●Both proton beam and carbon ion therapy have been used on patients with stage I NSCLC. The results suggest that these approaches yield results similar to SBRT. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)

●Other image-guided ablative techniques – A variety of other image-guided ablative techniques are being studied, including radiofrequency ablation, cryoablation, microwave ablation, laser ablation, and irreversible electroporation. There are inadequate long-term data with these techniques, and none of these have an established role in the routine management of stage I or stage II NSCLCs. (See "Image-guided ablation of lung tumors".)

INCORPORATION OF SYSTEMIC THERAPY — Both distant metastases and local recurrence can cause morbidity and/or death following potentially curative resection of NSCLC. Discussion of adjuvant systemic therapy, including patient selection, is found elsewhere. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Patients treated with initial surgical resection' and "Systemic therapy in resectable non-small cell lung cancer".)

The use of adjuvant osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant NSCLC is discussed elsewhere. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'EGFR-mutated cancers'.)

Incorporation of immunotherapy is also discussed elsewhere. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Adjuvant immunotherapy' and "Systemic therapy in resectable non-small cell lung cancer", section on 'Patients receiving neoadjuvant treatment'.)

POSTOPERATIVE RT — Postoperative radiation therapy (RT) may be recommended for patients with complete resection of N2 disease to improve local control, but should be delivered sequentially after adjuvant chemotherapy [60].

The evidence from multiple randomized trials indicates that postoperative RT can reduce the frequency of local recurrence. However, the impact of RT on overall survival is unclear [61-65]. Meta-analyses and a Surveillance, Epidemiology, and End Results database analysis suggested that postoperative RT may have a detrimental effect on survival [66-68].

The variable impact on survival is illustrated by the following trials:

●In a trial conducted by the Lung Cancer Study Group, 230 patients underwent complete resection of stage II or stage III squamous cell carcinoma with pathologic staging of the mediastinal lymph nodes and were then randomly assigned to RT or no further therapy [61]. Overall, approximately 82 percent of patients had T2 primary tumors, and 75 percent had N1 lymph node involvement. There was no difference in overall survival, but patients who had received postoperative RT had a lower frequency of recurrences in the ipsilateral lung or mediastinum compared with those treated with surgery alone (3 versus 41 percent).

●In a French trial, 728 patients with NSCLC (221 stage I, 180 stage II, and 327 stage III) were randomly assigned to RT or observation following surgery [64]. Five-year survival was significantly worse for those who received RT compared with those treated with surgery alone (30 versus 43 percent, respectively). This difference was due to a significant excess of deaths due to intercurrent disease in those receiving postoperative RT (five-year death rate 31 versus 8 percent). All patients treated with RT received a total dose of 60 Gy. The incidence of noncancer-related deaths was significantly higher in patients who received >2 Gy per fraction compared with those receiving standard daily fractions (26 versus 16 to 18 percent).

●In a subsequent trial that incorporated three-dimensional treatment planning, smaller RT fields, and a more conservative RT fractionation schedule (50.4 Gy in 28 fractions), 104 patients with pathologic stages IA and IB NSCLC were randomly assigned to adjuvant RT or no further treatment [65]. Only one patient treated with RT had a local recurrence (2 percent) compared with 12 in the control group (23 percent). Overall five-year survival was significantly improved with RT (67 versus 58 percent without RT).

These differences in outcome may be related to RT technique and/or patient selection. Postoperative RT clearly reduces the likelihood of locoregional recurrence. We do not recommend postoperative RT following resection of stage I or II NSCLC unless the surgical resection margins are positive. (See "Management of stage III non-small cell lung cancer", section on 'Adjuvant postoperative RT'.)

PROGNOSIS — The overall five-year survival in NSCLC is between 10 and 15 percent, primarily because approximately 70 percent of patients present with either locally advanced (stage III) or distant metastatic (stage IV) disease.

The most extensive data relating stage to prognosis come from a series of over 31,000 cases from the Surveillance, Epidemiology, and End Results (SEER) database used to validate the seventh edition tumor, node, metastasis staging system (table 2) [69]. In that series, survival progressively decreased with increasing clinical stage, with five-year survival rates for stages IA, IB, IIA, and IIB of 50, 43, 36, and 25 percent, respectively (figure 2) [69]. The five-year survival rates based upon pathologic staging are higher than those based upon clinical staging (73, 58, 46, and 36 percent for stages IA, IB, IIA, and IIB, respectively).

Among patients with stage I and II NSCLC, a number of factors in addition to stage may affect outcome. These include:

●Histology, including the presence of isolated tumor cells in regional lymph nodes

●Tumor grade

●Molecular markers

●Comorbidity

●Hospital case volume

Histology — Multiple studies have given conflicting results, and the preponderance of evidence suggests that histologic type of NSCLC is not a dominant predictor of prognosis when other variables are taken into consideration.

The presence of isolated tumor cells in lymph nodes that are detected by immunohistochemistry is not sufficient for reclassification as pathologically positive, and such lymph nodes are classified as pN0 [70]. However, patients whose lymph nodes contain such tumor cells appear to have a significantly poorer prognosis than those with negative lymph nodes by immunohistochemistry [71]. (See "Systemic therapy in resectable non-small cell lung cancer" and "Tumor, node, metastasis (TNM) staging system for lung cancer", section on 'Regional lymph node (N) classification'.)

Tumor grade — A retrospective review from the Mayo Clinic of clinical outcomes among 5018 patients included a multivariate analysis that revealed that tumor grade was third behind stage and treatment administered in its predictive value for outcome, with a stepwise decrease in survival from well differentiated to moderately differentiated to poorly differentiated to undifferentiated. This same association of poorer outcomes with less well-differentiated tumors was also statistically significant in the 1765 patients who were treated with surgery alone [72].

Comorbidity — The importance of comorbidity was illustrated in a report of 451 patients undergoing resection for stage I NSCLC at a single institution over a five-year period [73]. The three-year survival rates were significantly worse with increasing severity of comorbidity (86, 75, 69, and 70 percent for no, mild, moderate, and severe levels of comorbidity, respectively).

Hospital case volume — Patients operated on for NSCLC at hospitals that perform large numbers of procedures have significantly lower perioperative mortality rates than those treated at lower-volume institutions. In one report based upon Medicare claims data, the adjusted odds ratio for mortality in patients treated at hospitals with the highest volume (more than 46 procedures yearly) was 0.70 compared with the lowest volume hospitals (fewer than nine procedures yearly) for lobectomy and 0.62 for patients treated with pneumonectomy [6].

Hospital volume also affects five-year survival. In an analysis of over 2000 patients from the SEER database, five-year survival was better among individuals undergoing resection at high-volume centers (44 versus 33 percent at low-volume centers) [74].

POST-THERAPY SURVEILLANCE — The rationale for surveillance following the initial treatment of NSCLC is for early detection of recurrent disease or a second primary lung cancer.

Approach — A history, physical examination, and chest computed tomography (CT) are suggested every six months during the first two years after treatment and annually thereafter, although there are no data from randomized trials supporting the value of CT [3]. However, it should also be noted that many of these patients have a smoking history and would potentially benefit from screening CTs even if they had not been treated for lung cancer, based on age and number of pack-years.

When planning post-treatment surveillance, care should be taken to limit the number of CT scans if possible, particularly in younger individuals, given concerns about second malignancies induced by radiation exposure. The specific follow-up schedule for CT imaging for an individual patient may be more or less frequent, depending upon risk factors for recurrence (eg, stage, histologic features, positron emission tomography characteristics, etc). (See "Radiation-related risks of imaging".)

Annual low-dose CT may be continued beyond five years for patients who have no evidence of disease since these individuals are at risk for a second primary lung cancer as well as for recurrence.

There are no data comparing full-dose, diagnostic, contrast-enhanced CT with low-dose, noncontrast CT. Given the desire to minimize radiation exposure and the potential for continued screening for many years, some clinicians use low-dose CT even in the initial period after NSCLC treatment.

Smoking cessation is indicated, and patients should receive counseling, advice, and pharmacotherapy if needed. These recommendations are consistent with guidelines from the National Comprehensive Cancer Network. (See "Overview of smoking cessation management in adults".)

Efficacy of surveillance — There are few randomized trials comparing different surveillance strategies in patients with NSCLC. Available evidence does not establish a clear-cut benefit for aggressive surveillance following treatment with curative intent, although more second primary lung cancers may be diagnosed, potentially at a curable stage [75,76].

Available data are illustrated by the following studies:

●In an open label, randomized trial in patients with stage I to IIIA NSCLC (according to the sixth edition of the TNM classification) who had undergone surgery, those randomly assigned to CT based follow-up (clinic visits, chest x-rays, thoracoabdominal CT scans, and fiberoptic bronchoscopy for non-adenocarcinoma histology) experienced a median overall survival of 8.5 years, versus 10.3 years among those with minimal follow-up (visits and chest x-rays), a difference that was not statistically significant (HR 0.95, 95% CI 0.83-1.10) [76]. Differences in disease-free survival were also not statistically significant (median not reached versus 4.9 years). Recurrence was detected in 33 percent in the CT base follow-up and 28 percent in the minimal follow-up group. Second primary lung cancer was diagnosed in 4.5 percent in the CT-based follow-up group and 3.0 percent in the minimal follow-up group.

●A retrospective review analyzed outcomes in 130 patients, 67 of whom were followed with a strict follow-up policy (examination, chest radiograph, biannual CT) and the remainder evaluated only if symptoms developed [77]. Mortality was the same in both groups.

●A prospective observational study included 192 patients who had a chest radiograph every three months and bronchoscopy plus CT scans every six months [78]. Of the 136 patients with recurrent NSCLC, 85 were diagnosed by a scheduled procedure, 36 of whom were asymptomatic. More than twice as many thoracic recurrences documented by a scheduled test were eligible for potentially curative resection (22 of 85 versus 6 of 51 [26 versus 12 percent]).

Management of isolated thoracic recurrence — Approximately one-third of patients who relapse initially have an isolated recurrence in the ipsilateral thorax [79]. Although most of these patients will eventually develop widely disseminated disease, definitive therapy is indicated if there is no evidence of other metastases after careful evaluation [3].

●For patients with an isolated thoracic recurrence after surgical resection, further resection should be considered if the recurrence is in a stage I or II pattern and the patient can tolerate further surgery.

●For those with a stage I or II pattern of recurrence who are not candidates for further resection, radiation therapy is a reasonable salvage treatment option [80,81].

●For patients with a recurrence in a stage III pattern of disease, definitive chemoradiotherapy should be considered. (See "Management of stage III non-small cell lung 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 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

●Definition of early stage – Only a minority of patients with non-small cell lung cancer (NSCLC) have pathologic stage I and II disease when diagnosed (table 1). In contrast to locally advanced (stage III) and disseminated (stage IV) disease, early-stage disease is frequently curable with aggressive therapy. (See "Tumor, node, metastasis (TNM) staging system for lung cancer".)

●Mediastinal staging – Clinical staging may underestimate the extent of tumor, and patients are restaged pathologically following surgery. The issue of when to and how to evaluate the mediastinum in patients with clinical stage I or II disease is discussed separately. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Management of stage III non-small cell lung cancer".)

●Surgical candidates

•For clinical stage IA and IB cancers that can be completely resected with lobectomy (or less), we suggest proceeding directly to surgery rather than radiation or induction systemic therapy (Grade 2C); those that are more central or require more than a lobectomy require multidisciplinary discussion evaluating options including induction systemic therapy followed by surgery, as well as SBRT. While surgery is considered standard treatment for operative candidates, particularly given its role both in staging and as therapy, there is growing evidence supporting SBRT as an alternative in selected stage I patients. (See 'Surgical candidates' above and 'Stereotactic body radiation therapy' above.)

•For those with clinical stage II disease, we suggest induction chemoimmunotherapy followed by surgery rather than initial surgical resection or radiation (Grade 2C). Event-free survival benefits have been observed with the addition of nivolumab to neoadjuvant platinum-based chemotherapy. However, there are no data to inform neoadjuvant treatment versus adjuvant treatment, and as such, proceeding directly to surgery may be an acceptable alternative.

•For patients with clinical stage IA, peripheral NSCLC located in the outer one-third of the lung parenchyma with consolidation to tumor ratio >0.5, we suggest segmentectomy rather than lobectomy (Grade 2C). This assumes the procedure is technically feasible and that the lobar nodes are proven noninvolved on frozen section. For other patients undergoing surgery, we suggest lobectomy rather than a more limited procedure (ie, wedge resection or segmentectomy) if the patient has an adequate pulmonary reserve (Grade 2C). More limited procedures may be preferred over lobectomy in situations where additional resections may be envisioned (eg, multiple ground glass opacities of which only one meets criteria for resection). Pneumonectomy or sleeve resection is required for proximal tumors that cannot be resected by lobectomy. (See 'Lobectomy preferred in most cases' above and 'Limited (sublobar) resection, in select groups' above.)

•Video-assisted thoracoscopy (VATS) is associated with decreased operative morbidity and a faster recovery. VATS may be a suitable option for selected patients, although its equivalence to open resection has been demonstrated only in single institution retrospective series and small prospective trials. (See 'Video-assisted thoracoscopic surgery' above.)

•Patients with tumor involving the mediastinal lymph nodes in the final surgical specimen are classified as pathologic stage III and treated accordingly. (See "Management of stage III non-small cell lung cancer".)

●Nonsurgical candidates

•For patients with local failure but no nodal involvement and impaired pulmonary function or medical comorbidity that precludes surgical resection and for those who refuse surgery, we recommend treatment with SBRT rather than conventionally fractionated, definitive RT, if appropriate technical expertise is available (Grade 1B). Other ablative techniques (eg, radiofrequency ablation, cryoablation) are experimental but may be an alternative where expertise is available. (See "Stereotactic body radiation therapy for lung tumors", section on 'Primary NSCLC' and "Image-guided ablation of lung tumors".)

•For patients with nodal spread who are not surgical candidates, we recommend definitive, standard-fractionation RT (Grade 1B). (See 'Nonsurgical candidates' above.)

●Adjuvant therapy

•Adjuvant systemic treatment for resected NSCLC is discussed elsewhere. (See "Systemic therapy in resectable non-small cell lung cancer".)

•We recommend not giving adjuvant RT following complete resection of stage I and II NSCLC with negative resection margins (Grade 1B). (See 'Postoperative RT' above.)

•We recommend postoperative RT for patients with positive surgical resection margins (Grade 1B). (See 'Postoperative RT' above and "Management of stage III non-small cell lung cancer", section on 'Adjuvant postoperative RT'.)

●Surveillance — After the initial treatment, we suggest a history, physical examination, and periodic chest computed tomography (CT) imaging (Grade 2C). The frequency of chest CT imaging may vary depending upon the risk of recurrence. (See 'Post-therapy surveillance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Howard (Jack) West, MD, who contributed to earlier versions of this topic review.