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Management of stage III non-small cell lung cancer
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Management of stage III non-small cell lung cancer
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Literature review current through: Sep 2017. | This topic last updated: Sep 14, 2017.

INTRODUCTION — Development of a treatment plan for a patient with lung cancer depends upon the cell type (small cell versus non-small cell), an assessment of the patient's overall medical condition, and the tumor stage.

Stage III non-small cell lung cancer (NSCLC) includes a highly heterogeneous group of patients with differences in the extent and localization of disease. Many aspects of the treatment of stage III disease are controversial. Unfortunately, the data supporting treatment approaches in specific patient subsets are often subject to a number of limitations, for example that the trials involved heterogeneous patient populations; the definition of stage III disease has changed over time; and early studies were frequently inadequately powered to detect small differences in therapeutic outcome, were not randomized, or had limited duration of follow-up. Major improvements in therapy, including the use of more active chemotherapy agents and refinements in radiation and surgical techniques, also limit the interpretation of earlier clinical trials. Finally, improvements in pretreatment staging have led to reclassification of patients with relatively minimal metastatic disease as stage IV rather than stage III, leading to a prolonging in the apparent overall survival of both stage III and IV patients [1].

Taking these study limitations into consideration, the treatment approach for stage III disease presented here is consistent with guidelines from the American Society for Radiation Oncology (ASTRO) [2,3], which have been endorsed by American Society of Clinical Oncology (ASCO) [4].

The initial approach to staging of NSCLC and its implications for prognosis are discussed separately. (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".)

The management of malignant effusions (classified as stage IV disease in the seventh and eighth editions of the Tumor, Node, Metastasis [TNM] staging system) and the systemic treatment of advanced disease are discussed separately. (See "Management of malignant pleural effusions" and "Pericardial disease associated with malignancy" and "Overview of the treatment of advanced non-small cell lung cancer".)

STAGING

TNM staging system — The tumor (T), node (N), metastasis (M) system is used to stage NSCLC (table 1 and table 2) [5]. For the purposes of this topic, stage III disease refers to the eighth edition TNM staging system, which goes into effect January 1, 2018 but is scientifically valid at present. However, outside of the United States, the Union for International Cancer Control (UICC) has implemented the eighth edition changes as of January 1, 2017. (See "Tumor, Node, Metastasis (TNM) staging system for lung cancer", section on 'Eighth edition of the TNM system'.)

Historically, stage III lung cancer was defined as locoregionally advanced disease due to primary tumor extension into extrapulmonary structures (T3 or T4) or mediastinal lymph node involvement (N2 or N3) without evidence of distant metastases (M0). In the eighth edition of the TNM staging system, stage III lung cancers also include tumors greater than 5 cm in size with hilar, intrapulmonary, or peribronchial lymph node involvement (T3N1) or tumors greater than 7 cm (T4), regardless of lymph node involvement. In the previous (seventh) edition, T3N1 tumors were also considered stage III, but the lower size cutoff was 7 cm, not 5 cm, and tumors greater than 7 cm without lymph node involvement were considered stage IIB disease. While there were no differences in the N descriptors between the seventh and eighth editions of the TNM staging system, a new category stage IIIC was developed for those with T3/T4, N3 disease, while those with such tumors that have mediastinal involvement are now staged as IIIB rather than IIIA. (See "Tumor, Node, Metastasis (TNM) staging system for lung cancer", section on 'Eighth edition of the TNM system'.)

Mediastinal evaluation — An important component of the staging evaluation is an assessment of the mediastinal lymph nodes. Absence of tumor involvement of the mediastinal lymph nodes remains one of the most important factors in selecting patients for surgical intervention. Options for evaluation include mediastinoscopy and endoscopic bronchial ultrasound. Choice of procedure to obtain biopsy is discussed elsewhere. (See "Surgical evaluation of mediastinal lymphadenopathy", section on 'Selection of biopsy procedure'.)

Pathologic confirmation of tumor involvement of enlarged mediastinal lymph nodes (based upon computed tomography [CT] criteria) or metabolically active nodes (by positron emission tomography [PET] criteria) is recommended in patients who are otherwise potentially resectable.

If mediastinal lymph nodes are negative by pathologic evaluation, then resection of the primary tumor along with further mediastinal lymph node assessment at surgery is in order, similar to stage I and stage II disease. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Surgical candidates'.)

If mediastinal lymph nodes are pathologically involved by tumor, patients are often treated with definitive chemoradiation, although a select few may be offered bi- or trimodality therapy. (See 'N2 disease' below.)

For patients without suggestion of N2-3 lymph node involvement by both CT and PET criteria, the role of cytologic or pathologic evaluation of the mediastinal lymph nodes is more involved:

Invasive mediastinal staging is indicated for all patients with central tumors; those with potentially resectable T2, T3, and T4 tumors; and those with tumors with enlarged hilar lymph nodes by CT and/or clinical N1 involvement by PET, even if the mediastinum appears clean by both CT and PET criteria [6,7].

The role of preoperative pathologic evaluation of mediastinal lymph nodes for patients with a peripheral T1a primary lesion and no suggestion of N1 or N2-3 lymph node involvement by both CT and PET criteria is controversial:

Some centers proceed directly to primary resection without preoperative pathologic evaluation of mediastinal lymph nodes in view of the relatively low incidence of involved mediastinal nodes identified at mediastinoscopy in this selected population [8,9].

By contrast, other centers advocate offering preoperative pathologic evaluation of mediastinal lymph nodes because of the impact on management strategy when occult lymph node metastases are detected. As an example, in one study 6.5 percent of patients with T1 primary lesions had occult N2 disease despite a negative CT and PET of the mediastinum [6].

NO KNOWN MEDIASTINAL INVOLVEMENT — Surgical resection is a key component of the treatment of patients with stage III N0 or N1 NSCLC if a complete resection is technically feasible and the patient’s overall condition is satisfactory (table 1 and table 2).

Surgery is also used in patients with clinical stage I/II disease who ultimately are found to have pathologic stage III disease at resection (particularly if a thorough pre-resection mediastinal nodal evaluation had been negative).

Definitive radiation therapy (RT) may be an alternative for patients who technically are resectable but are not surgical candidates for other reasons. (See 'Poor performance status' below.)

Clinical settings

T3N1 disease — Tumors greater than 5 cm in size are now classified as T3 as in the eighth edition of the Tumor, Node, Metastasis (TNM) system (table 2). When tumors of this size are associated with N1 involvement, they are considered stage IIIA. The appropriate initial management of these patients involves surgical resection if technically feasible after negative invasive mediastinal staging, followed by adjuvant chemotherapy for those with completely resected disease. If a complete resection is not technically feasible, concurrent chemoradiotherapy is indicated. (See 'Adjuvant systemic therapy' below and 'Choice of chemotherapy' below and 'Administration of radiation' below.)

An exception to this approach is made for patients with a superior sulcus (Pancoast) tumor with hilar lymph node involvement or no lymph node involvement, which is generally treated with chemoradiotherapy followed by surgery. The management of Pancoast tumors is discussed separately. (See "Superior pulmonary sulcus (Pancoast) tumors".)

Multiple tumor nodules — In the eighth edition TNM staging system (as well as in the preceding staging system), discrete tumors in the same lobe as the primary are classified as T3, while nodules in another ipsilateral lobe are considered T4. Nodules in the contralateral lung are classified as M1a.

Patients with satellite nodules within the same lobe as the primary tumor are candidates for surgery as their initial treatment [10-12]. Patients with ipsilateral nodules in another lobe and negative mediastinal nodes may also be candidates for surgical resection, depending on the location and extent of disease [11,13,14]. Adjuvant chemotherapy is often recommended in this setting, but data are limited for this patient subset. (See 'Adjuvant systemic therapy' below.)

Although patients with solitary tumor nodules in each lung are considered stage IV, many of these patients actually have synchronous primaries and may have a favorable outcome if treated aggressively. A reasonable approach is full radiographic staging, combined with mediastinoscopy. If that evaluation is negative, a presumption of synchronous unrelated cancers and treatment as such is reasonable. (See "Multiple primary lung cancers".)

T4N0-1 disease — Historically, T4 lesions were considered unresectable by definition and were classified as stage IIIB. Even with improvement in surgical techniques, resectable T4N0-1 lesions are uncommon and most T4 lesions are best treated with definitive chemoradiation therapy, as for patients with mediastinal involvement. (See 'Choice of chemotherapy' below and 'Administration of radiation' below.)

A small subset of patients may be surgical candidates, but appropriate patient selection is of critical importance. Surgery for T4 disease is contraindicated in the presence of N2 involvement (stage IIIB) or if an incomplete resection is inevitable. The role for surgery in this patient group is not supported by firm evidence, but given the rarity of these tumors, it is unlikely that randomized data will ever be available. Considerations should include the operative morbidity and the experience at the given center. Preoperative induction chemotherapy or chemoradiotherapy may be of value [15,16]. (See 'Choice of chemotherapy' below and 'Administration of radiation' below.)

Clinical stage I/II, pathologic stage III — Surgical resection is the treatment of choice for patients who appear to have clinical stage I or II disease when pathologic involvement of mediastinal lymph nodes is not detected preoperatively. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Surgical candidates'.)

Despite careful preoperative evaluation, including endobronchial ultrasound (EBUS) and/or mediastinoscopy staging, mediastinal nodal involvement is identified in the final pathologic specimen in up to 20 percent of patients with larger central lesions. For patients with mediastinal lymph node involvement in a resection specimen, adjuvant chemotherapy can result in a significant survival benefit. Postoperative RT may also have a role for these patients and for those with positive surgical margins. (See 'Adjuvant systemic therapy' below.)

Adjuvant therapy

Adjuvant systemic therapy — Evidence from clinical trials indicates that adjuvant chemotherapy using contemporary platinum-based doublet regimens prolongs overall survival in patients with completely resected stage III disease. Adjuvant cisplatin-based chemotherapy is now considered the standard of care for patients with completely resected stage II and III NSCLC [17,18]. Data regarding the efficacy of adjuvant systemic therapy in stage III NSCLC are found elsewhere. (See "Adjuvant systemic therapy in resectable non-small cell lung cancer", section on 'Stage II and IIIA disease'.)

Targeted therapy is not indicated outside of a clinical trial for patients with unresectable stage III NSCLC. For those with or without driver mutations, the use of adjuvant targeted therapy including cetuximab, erlotinib, and crizotinib is under evaluation in randomized clinical trials, but available results have not suggested a survival benefit [19,20]. Immunotherapy agents are also being evaluated on trial in these patients, for example nivolumab (NCT02595944).  

Adjuvant postoperative RT — Although survival is often limited by the development of distant metastatic disease, postoperative RT may prevent locoregional recurrence and improve survival in carefully selected patients. We use adjuvant radiation for patients with positive surgical margins, those with inadequate lymph node sampling in whom mediastinal node involvement was suspected, and those who are found at surgery to have involved N2 lymph nodes. Although some UpToDate experts typically use adjuvant postoperative RT for single or multiple involved N2 nodes, this is in the setting of limited data. Other UpToDate experts may omit postoperative RT for select cases of single-station N2 disease, in order to avoid excess toxicity (eg, if only one of many N2 nodes resected was positive).

When both adjuvant chemotherapy and RT are planned, RT should be given after completion of adjuvant chemotherapy since concurrent chemoradiotherapy might compromise the ability to deliver the recommended dose and cycles of chemotherapy. There are no data to support the use of adjuvant concurrent chemoradiotherapy.

Positive surgical margins – The strongest data supporting adjuvant RT for positive surgical margins come from a National Cancer Database study of 3395 patients who underwent a resection with positive surgical margins for stage II or III NSCLC between 2005 and 2011 [21]. Of these, 1207 received postoperative RT to a total dose from 50 to 74 Gy using contemporary RT techniques. Overall survival was longer for those given postoperative RT (median, 33.5 versus 23.7 months without RT; five-year survival rates, 32.4 versus 23.7 percent). On multivariable analysis, this difference was statistically significant (hazard ratio [HR] 0.80, 95% CI 0.70-0.92). On subset analysis, a similar improvement in overall survival was seen with postoperative RT regardless of whether patients had N0, N1, or N2 disease.

The role of radiation in treating patients with carcinoma in situ only at the surgical margin is uncertain. It is often recommended, given the improved prognosis than those with more extensive disease at the resection margins [22-25]. However, there is no evidence that RT improves the prognosis in these cases [22]. There are potential risks and benefits, and ultimately, the decision needs to be individualized, although in practice the presence of carcinoma in situ at the margins is rarely the sole decision-making factor regarding whether or not to use adjuvant RT.

Those found to have N2 involvement – Although data are somewhat conflicting, most studies suggest no detriment, and even possible benefit, with adjuvant RT for those with N2 disease who have undergone surgical resection. We therefore offer RT to those with a high likelihood of or confirmed N2 disease that has been managed surgically.

Results from the phase III ANITA trial, which evaluated adjuvant chemotherapy in patients with completely resected stage IB to IIIA NSCLC, suggest that the effect of postoperative RT is influenced by the extent of nodal involvement and the use of adjuvant chemotherapy [26,27]. For patients with N2 disease, survival was longer in patients who received postoperative RT than in those not given RT (median, 47 versus 24 months in those given adjuvant chemotherapy; 23 versus 13 months in those not given adjuvant chemotherapy) [26]. By contrast, for those with N1 disease, RT had a negative effect on survival in those given adjuvant chemotherapy (47 versus 94 months) but a positive effect in those not receiving chemotherapy (50 versus 26 months). Formal statistical comparisons were not performed because of the nonrandomized nature of this subset analysis.

While an earlier meta-analysis of nine randomized trials including 2128 patients suggested worsened outcomes with adjuvant RT (21 percent increase in relative risk of death, or a 7 percent absolute reduction in two-year survival), this detrimental effect appeared to be limited to patients with stage I or II disease on subgroup analysis [28]. There was no clear evidence of either an adverse or a beneficial effect for those with stage III disease. The results of this meta-analysis are subject to several important limitations [29]. For example, the RT techniques (eg, cobalt machines, single RT field) were outdated and greater than 30 percent of the patients included came from a single study in which larger-dose fractions (2.5 Gy) and higher total doses (up to 60 Gy) were permitted than is standard, likely increasing toxicity [30].

Radiation cardiotoxicity may have contributed to mortality in early studies using postoperative RT, with one study suggesting increased cardiac toxicity in the setting of dose-escalated RT (70 to 90 Gy) [31]. A decline in cardiac toxicity over time has been observed [32], which may have resulted from technical improvements in the planning and delivery of thoracic radiotherapy. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

Prospective randomized trials documenting the effectiveness of postoperative RT in these situations are needed. The ongoing EORTC/IFCT LUNG ART trial in Europe is evaluating the role of sequential postoperative RT in patients with completely resected N2 disease who have received pre- or postoperative chemotherapy (NCT00410683).

MEDIASTINAL (N2, N3) INVOLVEMENT — The optimal treatment of patients with stage III NSCLC with mediastinal involvement has not been clearly defined and many aspects of therapy remain controversial. A multidisciplinary approach that includes input from medical oncology, radiation oncology, and thoracic surgery is indicated prior to treatment. Key factors influencing the treatment planning include the extent of the primary tumor and nodal disease, the ability to achieve a complete surgical resection if indicated, and the patient’s overall condition and preferences.

Approach — When pathologic involvement of mediastinal lymph nodes is documented prior to surgical resection, a combined-modality approach is recommended if the patient is a candidate for treatment with curative intent. These patients are at high risk for both local and distant recurrence if managed with resection alone.

For most patients with clinically evident N2 disease, the approach is concurrent chemoradiotherapy, using platinum-based chemotherapy plus full-dose radiation therapy (RT). (See 'Chemoradiotherapy' below.)

However, in a highly selected subset of patients, induction chemotherapy or chemoradiotherapy followed by surgery may be appropriate options. (See 'Surgery in a select subset' below.)

For patients with N3 disease, concurrent chemoradiotherapy alone remains the standard of care. (See 'N3 disease' below.)

For patients who are not candidates for a combined-modality treatment approach, RT alone or sequential chemoradiotherapy might be considered. (See 'Poor performance status' below.)

N2 disease

Chemoradiotherapy — For most patients with clinically evident N2 disease, the approach is concurrent chemoradiotherapy, using platinum-based chemotherapy plus full-dose RT. Discussion of the appropriate chemotherapy regimen and radiation dose and schedule is found below. (See 'Choice of chemotherapy' below and 'Administration of radiation' below.)

Surgery in a select subset — Although chemoradiation is a standard option for patients with known mediastinal involvement, the role of surgery after induction chemotherapy or chemoradiation in certain settings is extensively debated. Among UpToDate experts, there is a variation in the threshold to offer surgery after induction therapy, given that, while local control may be improved, no randomized studies have demonstrated a survival benefit to this approach. In the setting of limited data, some experts treat essentially all stage III N2 disease with definitive chemoradiation.

Others, however, offer induction therapy followed by surgery to a select subset of patients, discussed in a multidisciplinary setting, incorporating input from medical, radiation, and surgical oncologists:

Although no prospective randomized data exist to define the subset who would benefit from surgery, factors that lead some experts to offer it include single-station N2 disease that was <3 cm prior to induction therapy, disease that can be resected via lobectomy rather than pneumonectomy, and disease that responded to induction therapy, as evidenced by clearance of mediastinal lymph nodes.

Contraindications to surgical resection include poor or borderline performance status, poor pulmonary function, active heart disease, progressive disease with induction therapy, extracapsular nodal extension, T4 disease, and multistation N2 disease.

Although need for pneumonectomy is not an absolute contraindication to surgery, such patients less frequently experience benefit from resection relative to those whose disease can be resected with a lobectomy, and the threshold to perform surgery in this setting is higher.

For those undergoing surgery, induction chemoradiation or chemotherapy alone may be administered, although this is an area of controversy. In a trial of 232 patients, preoperative sequential chemoradiotherapy did not improve survival relative to preoperative chemotherapy alone [33], results which were similar to that of an earlier meta-analysis of seven small prospective and retrospective studies [34]. However, clinical trials addressing this question have been limited by small sample size, lack of patients with bulky mediastinal disease, and the use of sequential rather than the concurrent chemoradiation strategy [33-37].

Although uncontrolled phase II studies suggested a survival benefit from surgery after induction therapy, randomized phase III trials have not confirmed a survival advantage for surgery following either neoadjuvant concurrent chemoradiotherapy or induction chemotherapy followed by RT [15,38-45]. In the Intergroup 0139 trial, including over 400 patients with stage IIIA NSCLC due to N2 disease receiving chemoradiotherapy, the use of surgery was not associated with an improvement in overall survival (five-year survival rate, 27 versus 20 percent; odds ratio [OR] 0.63, 95% CI 0.36-1.10) [41]. There was, however, a sevenfold increase in the control of the primary tumors and an improvement in five-year progression-free survival (PFS, 22 versus 11 percent).

An increase in early mortality associated with surgery, particularly in patients undergoing pneumonectomy (26 percent postoperative mortality), may have negated a potential benefit of resection in this subset and the overall group of patients receiving surgery [40,42]. An exploratory subgroup analysis suggested that trimodality treatment may be beneficial if a complete resection can be accomplished by lobectomy rather than pneumonectomy. However, this analysis is limited by its post-hoc design, with patients treated with pneumonectomy being more likely to have other adverse prognostic features.

The European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial also suggested that there was no overall survival difference after induction chemotherapy for those receiving surgery versus RT [43]. The two groups also experienced similar PFS. A criticism of this trial, however, is that the study only enrolled patients with unresectable disease, and after induction therapy, only 50 percent of those assigned to surgical resection achieved a complete resection. A third randomized trial, ESPATUE, suggested no survival benefit to surgery after induction therapy over definitive chemoradiation but was closed early due to slow accrual, and furthermore did not provide survival outcomes according to type of surgery [44].

In sum, these limited and mixed data suggest that survival may not be improved with surgery in an unselected population of patients with N2 disease. There may, however, be a benefit in regards to local control with surgery following induction therapy. Whether subgroups exist that may experience a survival benefit from surgery must be further elucidated.

N3 disease — Patients with N3 nodes are treated with definitive concurrent chemotherapy plus RT without surgery. Chemotherapy and RT have been combined in an effort to treat both locoregional and micrometastatic disease in patients with unresectable stage III NSCLC.

While earlier studies examined sequential therapy (chemotherapy followed by RT) as a way to avoid overlapping toxicities, the superiority of concurrent chemoradiotherapy has been demonstrated by two large phase III trials [46-49]. In the Radiation Therapy Oncology Group (RTOG) trial 9410, 610 patients with unresected stage III disease were randomly assigned to two cycles of cisplatin plus vinblastine with concurrent or sequential RT (60 Gy in 30 fractions) [47]. Those receiving concurrent chemoradiotherapy experienced improvement in survival (median survival, 17.0 versus 14.6 months; hazard ratio [HR] for death 0.81, 95% CI 0.663-0.996). Acute grade 3 or higher nonhematologic toxicity was more frequent with the concurrent regimens, but late toxicity rates were similar. Similarly, in a Japanese study of 320 patients randomly assigned to cisplatin, mitomycin, and vindesine, with concurrent split-course thoracic RT (two courses of 28 Gy in 2-Gy daily fractions, separated by ten days) or to the same chemotherapy regimen followed by a single course of RT (56 Gy in 28 fractions), concurrent therapy was associated with improved response rate (84 versus 66 percent), median survival (17 versus 13 months), and two- and five-year survival rates (35 versus 27 percent and 16 versus 9 percent, respectively) [48,49].

Choice of chemotherapy — The optimal chemotherapy regimen for use with concurrent thoracic radiotherapy is not known. Some regimens may be associated with increased incidence of pulmonary toxicity, particularly those including gemcitabine [50].

The two chemotherapy regimens that have been most commonly used in the United States are the combination of cisplatin and etoposide and weekly carboplatin and paclitaxel:

Cisplatin plus etoposide Concurrent cisplatin (50 mg/m2 on days 1, 8, 29, and 36) plus etoposide (50 mg/m2 daily on days 1 to 5, and 29 to 33) with thoracic RT followed by two cycles of cisplatin plus etoposide was evaluated in a multicenter phase II trial of 50 patients with pathologically confirmed stage IIIB disease [51]. With an average follow-up of 52 months, the three- and five-year survival rates were 17 and 15 percent, respectively. Treatment was complicated by grade 4 neutropenia in 32 percent and grade 3 or 4 esophagitis in 20 percent of patients. In a subsequent phase II trial, better results were seen with the same concurrent chemoradiation regimen followed by docetaxel consolidation, but the use of consolidation chemotherapy in this setting has been called into question by subsequent data [52,53]. (See 'Approaches not routinely used' below.)

Weekly carboplatin paclitaxel – In a randomized phase II trial, carboplatin (area under the curve [AUC] = 2) and paclitaxel (45 mg/m2) given weekly with radiotherapy (63 Gy) followed by two cycles of consolidation therapy (carboplatin AUC = 6, paclitaxel 200 mg/m2) resulted in a median survival of 16.3 months [54]. Carboplatin and paclitaxel was the regimen used in RTOG 0617, discussed below. (See 'Dose and method of delivery' below.)

These two regimens were compared in a randomized trial of 191 patients with stage III NSCLC receiving concurrent thoracic radiation (60 to 66 Gy). At a median follow-up of 73 months, those receiving cisplatin plus etoposide had an improved three-year survival rate (41 versus 26 percent; absolute difference 15 percent, 95% CI, 2 to 28 percent) and trend towards improved overall survival (23.3 versus 20.7 months; HR 0.76, 95% CI 0.55-1.05) [55]. The frequency of ≥grade 3 esophagitis was greater with cisplatin plus etoposide (20 versus 6 percent) but ≥grade 2 radiation pneumonitis was less frequent (19 versus 33 percent). Given that the two regimens demonstrated comparable overall survival; that cisplatin and etoposide was associated with greater esophagitis; that those receiving carboplatin and paclitaxel did not receive the two consolidative cycles typically administered with this regimen; and that this was a small study, we continue to use either regimen pending further data.

While some UpToDate contributors prefer the standard regimens above, the combination of pemetrexed and cisplatin has emerged as another option for stage III patients with non-squamous cell histology. In a phase III trial of approximately 600 patients, pemetrexed-cisplatin with RT and pemetrexed consolidation was associated with similar survival as standard therapy, in this case cisplatin-etoposide with RT and a nonpemetrexed consolidation treatment (median overall survival [OS], 27 versus 25 months; HR 0.98, 95% CI 0.79-1.20), and a lower incidence of drug-related grade 3 to 4 adverse events (64 versus 77 percent) [56]. Although the trial was closed early due to a lack of observed survival benefit, this combination is an acceptable alternative to the regimens above.

Administration of radiation — The standard dose fractionation regimen of RT with chemotherapy for stage III NSCLC remains 60 Gy in 30 daily fractions. Intensity-modulated radiation therapy (IMRT) is preferable to 3D RT because of the decreased risk in pneumonitis. Although data are still evolving, proton radiation is also an acceptable option.

Dose and method of delivery — The dose and method of delivery of radiation was extensively studied in the RTOG 0617 phase III trial [57], in which 544 patients with unresectable stage III A/B NSCLC were randomly assigned in a two-by-two design to one of two systemic therapy regimens (carboplatin plus paclitaxel with or without cetuximab) and to either standard-dose (60 Gy/30 daily fractions) or high-dose RT (74 Gy/37 daily fractions). All patients received two cycles of consolidation chemotherapy with full doses of carboplatin and paclitaxel. RT was given either with 3D conformal techniques or by IMRT.

High-dose (74 Gy) RT was associated with a shorter survival and an increased risk of death compared with conventional-dose (60 Gy) RT (median, 20 versus 29 months; HR 1.38, 95% CI 1.09-1.76). Multivariate analysis suggested that the poorer survival may have been related to higher doses of radiation to the heart.

A secondary analysis of 482 patients comparing 3D conformal techniques and IMRT found similar two-year OS, distant metastasis-free survival, and local failure rates between the two methods of delivery [58]. IMRT was associated with lower heart doses and less ≥grade 3 pneumonitis (7.9 versus 3.5 percent; multivariate odds ratio [OR] 0.41, 95% CI 0.17-0.99).

The addition of cetuximab to carboplatin plus paclitaxel did not significantly improve OS (median, 25 versus 24 months; HR 1.07, 95% CI 0.84-1.35) and was associated with a significant increase in grade 3 or greater toxicity (86 versus 70 percent).

Although standard doses of radiation are appropriate with chemoradiotherapy, data suggest that higher-dose RT may be beneficial if chemotherapy cannot be given. In a meta-analysis of 21 trials including 3800 patients, the majority of whom had stage III disease, higher than conventional-dose RT led to poorer survival in trials where chemotherapy was used (median survival ratio for higher versus lower radiation doses, 0.83; 95% CI 0.71-0.97) but improved survival when chemotherapy was not used (median survival ratio for higher versus lower radiation doses, 1.13; 95% CI 1.04-1.22) [34]. However, in practice, patients for whom chemotherapy cannot be administered often have significant morbidity, raising the question of whether higher-dose radiation may be actually be a feasible option in such patients.

Proton beam therapy as an alternative to standard radiation — Retrospective data suggest radiation with protons may be associated with superior survival compared with standard radiation, though given the lack of prospective, randomized data, either are appropriate options.

In a retrospective study including almost 140,000 patients with stage II or III NSCLC treated with thoracic RT, 193 of whom received proton RT, those receiving nonproton therapy experienced worsened survival (HR 1.35, 95% CI 1.10-1.64) [59]. However, in this study, receipt of proton RT was associated with higher income levels, raising the possibility of confounding variables. Prospective, randomized validation of these data is necessary.

Early-phase data have also suggested efficacy of proton RT. In an open-label, single-arm phase II study, 64 patients with unresectable stage III NSCLC received concurrent chemotherapy (carboplatin-paclitaxel) and passively scattered proton RT (74-Gy relative biological effectiveness) [60]. In this group, median OS was 26.5 months, five-year OS was 29 percent, and five-year PFS was 22 percent. Rates of grade 2 and 3 acute esophagitis were 28 and 8 percent, respectively. Acute grade 2 pneumonitis occurred in 1 (2 percent) patient. Late toxic effects were uncommon, and there were no acute or late grade 5 toxic effects.

These data suggest that proton RT may be an effective and tolerable alternative to standard RT in unresectable stage III NSCLC.

Fractionation schedule — The standard fractionation schedule remains 60 Gy in 30 daily fractions.

Multiple trials have explored the use of altered dose fractionation schedules in order to improve the therapeutic index of RT for NSCLC. These approaches include hyperfractionation (two or three fractions per day with a lower dose per fraction over the standard treatment duration), accelerated fractionation (using a standard fraction size and total radiation dose, given over a shorter overall time), or a combination of hyperfractionation and acceleration.

The most extensive information comes from a meta-analysis incorporating data from 2000 patients, 1637 of whom had stage III disease, who were randomly assigned to an altered regimen or conventional fractionation (five daily fractions per week of 1.8 to 2 Gy, with a minimum dose of 60 Gy) [61]. The analysis was limited to trials in which chemotherapy was identical in both treatment arms. Modified fractionation resulted in a relatively modest improvement in overall five-year survival (10.8 versus 8.3 percent; HR 0.88, 95% CI 0.80-0.97) that was not dependent on stage. However, the modified fractionation schedules resulted in a significantly higher incidence of severe esophageal toxicity (19 versus 9 percent, OR 2.44).

More studies are required to address which RT regimen is best administered with concurrent chemotherapy. Modified RT schedules remain less commonly utilized than a conventional once-daily radiation plan, due in part to the logistical challenges for patients and treating centers, as well as the increased toxicity.

Approaches not routinely used

Induction therapy – Induction chemotherapy prior to concurrent chemoradiotherapy may be useful if a tumor cannot be encompassed in a safe RT treatment portal without an unacceptably high risk of radiation pneumonitis. In such cases, chemoradiotherapy or definitive RT alone can be administered subsequently if an adequate response to the induction chemotherapy is obtained. However, induction chemotherapy prior to concurrent chemoradiotherapy should not routinely be pursued, given increased toxicity without a survival advantage in a phase III trial conducted by the Cancer and Leukemia Group B (CALGB) [62].

Consolidation therapy – The administration of additional chemotherapy following the completion of a full course of cisplatin-based chemotherapy and radiation has not demonstrated a survival advantage [53,63]. However, two cycles of consolidative chemotherapy following radiation are usually given with the weekly carboplatin/paclitaxel regimen, as the weekly dose is not considered adequate systemic treatment.

In one trial of 243 patients with stage III NSCLC treated with RT and concurrent cisplatin plus etoposide, the 166 patients without progression were randomly assigned to three cycles of docetaxel consolidation or to observation [53,63]. The median OS was 25 months, and there was no difference between those managed with docetaxel consolidation and those assigned to observation. Similarly, in a trial of 437 patients conducted in Korea and China, there was no improvement in either PFS or OS with three additional cycles of docetaxel and cisplatin administered as consolidation chemotherapy [64].

Prophylactic cranial irradiation (PCI) – PCI is not recommended for patients with stage III NSCLC outside the setting of a clinical trial given lack of survival benefit [65-69]. In the largest trial (RTOG 0214), 356 patients with stage III NSCLC were randomly assigned to PCI (30 Gy in 15 fractions) or observation following initial therapy with surgery and/or thoracic RT with or without chemotherapy [67,68]. The incidence of brain metastases was significantly decreased with PCI compared with observation (one-year rate, 7.7 versus 18.0 percent). However, there was no difference in OS (five-year rate, 26 versus 25 percent for PCI and observation, respectively) [70].

SPECIAL CONSIDERATIONS

Older adult patients — Treatments for stage III NSCLC should not be withheld on the basis of age alone, although decisions should take comorbidity and performance status into consideration. (See "Systemic chemotherapy for cancer in elderly persons" and "Comprehensive geriatric assessment for patients with cancer" and "Comprehensive geriatric assessment".)

Combined-modality therapy can be beneficial in selected older adult patients, although it is associated with an increase in toxicity. This was illustrated by a Japanese trial, in which 200 patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy with radiation therapy (RT) plus concurrent carboplatin (30 mg/m2, five days per week for four weeks) or RT alone [71]. RT consisted of 60 Gy in 30 fractions over six weeks for both groups. At a median follow-up of 19 months, the combined-modality approach significantly prolonged overall survival (OS; median, 22 versus 17 months; hazard ratio [HR] 0.68, 95% CI 0.47-0.98). The addition of carboplatin to RT was associated with grade 3 or 4 leukopenia, neutropenia, and thrombocytopenia in 64, 57, and 29 percent of cases, respectively.

Secondary analyses of older adult patients enrolled in larger trials also support the use of concurrent chemoradiotherapy in carefully selected, fit patients [72,73]. These analyses of multicenter trials have focused on older adult patients with particularly good performance status. However, the findings may not be applicable to patients with an impaired performance status [74]. Furthermore, older adult patients treated with chemotherapy and/or RT may be at increased risk of cardiac disorders, even if they were free of such problems prior to the diagnosis of NSCLC [75].

Poor performance status — No standard approach exists for poor-risk patients who are not candidates for standard combined-modality therapy. Thoracic radiotherapy, preferably with sensitizing chemotherapy (eg, single-agent), or sequential chemoradiotherapy are reasonable approaches in the absence of more definitive data. For patients who are asymptomatic, we do not defer treatment. (See "Systemic therapy for advanced non-small cell lung cancer in elderly patients and patients with a poor performance status".)

The benefits of RT include palliation of tumor-related symptoms, local control of tumor growth, and possibly a survival advantage. The use of RT alone for patients with stage III NSCLC consistently results in a median survival of about 10 months and five-year survival rates of around 5 percent [76-79]. Factors that have been associated with an improved prognosis following definitive RT include small primary tumor and limited total tumor volumes [79]. An early randomized trial suggested that RT (40 to 50 Gy) provided a modest, but significant, survival advantage at one year compared with patients not receiving RT (18 versus 14 percent) [80]. Shorter courses of RT (eg, 30 Gy in 10 fractions or 17 Gy in 2 fractions) are useful for the palliation of thoracic symptoms (eg, dysphagia, hemoptysis, or dyspnea due to airway obstruction) in patients who are not candidates for more aggressive therapy [81].

One trial examined the effect of delayed treatment among asymptomatic patients. Among 230 patients with minimally symptomatic, unresectable NSCLC, randomly assigned to immediate RT or initial supportive care followed by RT at the onset of symptoms, survival between the two groups was similar (8.3 versus 7.9 months, respectively), and the rate of symptom control was similar. However, the treatment intent in this trial was palliation rather than cure and these survival times are grossly inferior to other trial results using immediate chemoradiotherapy. Given these limitations, we recommend immediate rather than deferred treatment whenever possible.

Interstitial lung disease — Patients with baseline interstitial lung disease are at risk of worsened toxicities associated with radiation therapy. Baseline lung disease should be taken into consideration in determining an optimal treatment plan. Toxicities associated with radiation for those with interstitial lung disease are discussed in more detail elsewhere. (See "Radiation-induced lung injury".)

Immunotherapy — Despite multimodality treatment, the prognosis for unresectable stage III NSCLC remains poor, with five-year OS rates of approximately 15 percent [64,82]. Therefore interest exists in developing newer treatment paradigms, for example incorporation of immunotherapy. Results of this strategy are promising, though we await OS data or approval by the US Food and Drug Administration for this indication prior to routine clinical use in stage III NSCLC. Given the promising results seen in regards to progression-free survival (PFS), however, other experts may reasonably choose to offer this therapy off-label. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition".)

In a phase III trial, over 700 patients with unresectable stage III NSCLC without progression after at least two cycles of platinum-based chemoradiotherapy were randomly assigned to the programmed death ligand 1 (PD-L1) antibody durvalumab or placebo in a 2:1 ratio [83]. Relative to placebo, durvalumab increased the median PFS (16.8 versus 5.6 months; HR for disease progression or death 0.52, 95% CI 0.42-0.65), response rate (28 versus 16 percent; relative risk [RR] 1.78, 95% CI 1.27-2.51), and median time to death or distant metastasis (23.2 versus 14.6 months; HR 0.52, 95% CI 0.39-0.69). The benefit in PFS with durvalumab was observed irrespective of PD-L1 expression before chemoradiotherapy and was evident in both smokers and nonsmokers. OS results are immature. Grade 3 or 4 adverse events occurred in 30 percent of the patients who received durvalumab and 26 percent of those who received placebo, with the most common severe adverse event being pneumonia. These results demonstrate efficacy and tolerability of durvalumab for treatment of unresectable stage III NSCLC in patients who experience an objective response or stable disease following completion of chemoradiotherapy.

POSTTHERAPY SURVEILLANCE — Few if any data are available to support evidence-based guidelines for posttreatment surveillance of patients with NSCLC. Nevertheless, recommendations from the American Society of Clinical Oncology are available and are discussed in detail elsewhere. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Post-therapy surveillance'.)

For patients who have an isolated thoracic recurrence, radiation therapy (RT) may also have a role, either alone or in combination with chemotherapy. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Management of isolated thoracic recurrence'.)

For those with recurrence at a distant site, management follows similar lines as for others with metastatic disease. (See "Overview of the treatment of advanced non-small cell 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

Stage III non-small cell lung cancer (NSCLC) includes a highly heterogeneous group of patients with differences in the extent and localization of disease. Many aspects of the treatment of stage III disease are controversial. A multidisciplinary approach is considered essential for management of stage III disease. (See 'Introduction' above.)

Historically, stage III lung cancer was defined as locoregionally advanced disease due to primary tumor extension into extrapulmonary structures (T3 or T4) or mediastinal lymph node involvement (N2 or N3) without evidence of distant metastases (M0). In the eighth edition of the Tumor, Node, Metastasis (TNM) staging system, stage III lung cancers also include tumors greater than 5 cm in size with hilar, intrapulmonary, or peribronchial lymph node involvement (T3N1) or tumors larger than 7 cm (T4), regardless of lymph node involvement (table 1 and table 2). (See 'TNM staging system' above and "Tumor, Node, Metastasis (TNM) staging system for lung cancer".)

For patients with T3N1 cancers or multiple tumor nodules with negative mediastinal lymph nodes, surgery is indicated if complete resection is technically feasible, with adjuvant chemotherapy following resection. If complete resection is not technically feasible, concurrent chemoradiotherapy is indicated. (See 'T3N1 disease' above and "Adjuvant systemic therapy in resectable non-small cell lung cancer", section on 'Stage II and IIIA disease'.)

Although survival is often limited by the development of distant metastatic disease, postoperative radiation therapy (RT) may prevent locoregional recurrence and improve survival in carefully selected patients. We use adjuvant radiation for patients with positive surgical margins, those with inadequate lymph node sampling in whom mediastinal node involvement was suspected, and those who are found at surgery to have N2 disease. Some, but not all, UpToDate experts may omit postoperative RT for select cases of single-station N2 disease, in order to avoid excess toxicity (eg, if only one of many N2 nodes was positive). (See 'Adjuvant postoperative RT' above.)

For most patients, having clinically evident N2 disease, the approach is to treat with concurrent chemoradiotherapy, using platinum-based chemotherapy plus full-dose RT. However, some UpToDate experts offer induction therapy followed by surgery to select patients. (See 'Chemoradiotherapy' above and 'Surgery in a select subset' above.)

Although no prospective randomized data exist to define the subset who would benefit from surgery, factors that lead some UpToDate experts to offer it include single-station N2 disease that was <3 cm prior to induction therapy, disease that can be resected via lobectomy rather than pneumonectomy, and disease that responded to induction therapy.

Contraindications to surgical resection include poor or borderline performance status, progressive disease with induction therapy, extracapsular nodal extension, T4 disease, and multistation N2 disease.

For patients with N3 disease, concurrent chemoradiotherapy alone is the standard of care. (See 'N3 disease' above.)

For those receiving definitive chemoradiation, widely used regimens include cisplatin plus etoposide, in conjunction with once daily RT to a total of 60 Gy. An alternative "radiosensitizing chemotherapy" approach uses weekly carboplatin plus paclitaxel with approximately 60 Gy of radiation, followed by two cycles of consolidation with this same chemotherapy combination at standard systemic doses. The combination of pemetrexed and platinum agents has emerged as another acceptable alternative for stage III patients with nonsquamous cell histology. (See 'Choice of chemotherapy' above and 'Administration of radiation' above.)

For poor-risk patients who are not fit enough to withstand the rigors of standard combined-modality therapy, we offer thoracic radiotherapy, preferably with sensitizing chemotherapy (eg, single-agent), or sequential chemoradiotherapy, though data in this setting are limited. (See 'Poor performance status' above.)

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