Management of Stage III Non-Small Cell Lung Cancer - UpToDate

04/10/2018 Management of stage III non-small cell lung cancer - UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Management of stage III nonsmall cell lung cancer
Authors: Steven E Schild, MD, Suresh S Ramalingam, MD, Eric Vallières, MD, FRCSC
Section Editors: Rogerio C Lilenbaum, MD, FACP, Joseph S Friedberg, MD
Deputy Editor: Sadhna R Vora, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2018. | This topic last updated: Sep 28, 2018.
INTRODUCTION — Development of a treatment plan for a patient with lung cancer depends upon the cell
type (small cell versus nonsmall cell), an assessment of the patient's overall medical condition, and the tumor
stage.
Stage III nonsmall 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 followup.
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 initial treatment of advanced nonsmall 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 went into effect January 1, 2018. (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
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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 nonsmall 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 N23 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 N23 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 preresection 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 [1012]. 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".)
T4N01 disease — Historically, T4 lesions were considered unresectable by definition and were classified
as stage IIIB. Even with improvement in surgical techniques, resectable T4N01 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 nonsmall 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 platinumbased doublet regimens prolongs overall survival in patients with completely resected
stage III disease. Adjuvant cisplatinbased 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 "Systemic therapy in resectable nonsmall 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 singlestation N2 disease, in order to avoid excess toxicity (eg, if only
one of many N2 nodes resected was positive). When both adjuvant chemotherapy and radiation are planned,
radiation is administered sequentially after chemotherapy. (See 'Timing with chemotherapy' below.)
● 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; fiveyear
survival rates, 32.4 versus 23.7 percent). On multivariable analysis, this difference was statistically
significant (hazard ratio [HR] 0.80, 95% CI 0.700.92). 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 [2225]. 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 decisionmaking
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 metaanalysis 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 twoyear 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 metaanalysis 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 largerdose 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 doseescalated 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).
Timing with chemotherapy — 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.
Sequential chemoradiotherapy is supported by observational data from the National Cancer Database in
patients receiving both chemotherapy and postoperative RT [33,34]. For example, in 757 patients with an R0
resection of the primary tumor found to have N2 disease, the median overall survival was longer for patients
who received chemotherapy before their RT rather than concurrently (median, 59 versus 40 months; p
<0.001) [33]. In 277 patients with R1/R2 disease at surgery, there was no benefit from concurrent
chemoradiotherapy (median overall survival, 42.6 months for sequential chemotherapy and RT versus 38.5
months for concurrent chemoradiotherapy).
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 combinedmodality 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 platinumbased chemotherapy plus fulldose 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 with unresectable disease that has not progressed following concurrent platinumbased
chemotherapy and RT and who are candidates for immunotherapy, we offer the programmed death
ligand 1 (PDL1) antibody durvalumab. (See 'Immunotherapy' below.)
● For patients who are not candidates for a combinedmodality 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 platinumbased chemotherapy plus fulldose 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 singlestation 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 [35], results
which were similar to that of an earlier metaanalysis of seven small prospective and retrospective
studies [36]. 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 [3539].
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 [15,4047]. 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 (OS; fiveyear survival rate, 27
versus 20 percent; odds ratio [OR] 0.63, 95% CI 0.361.10) [43]. There was, however, a sevenfold increase in
the control of the primary tumors and an improvement in fiveyear progressionfree 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 [42,44]. 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 posthoc design, with patients treated with
pneumonectomy being more likely to have other adverse prognostic features.
The EORTC 08941 trial also suggested that there was no OS difference after induction chemotherapy for
those receiving surgery versus RT [45]. 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 [46].
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 [4851]. 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) [49]. 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 0.6630.996). 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 splitcourse thoracic
RT (two courses of 28 Gy in 2Gy 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 fiveyear survival rates (35 versus 27 percent and 16 versus 9 percent, respectively) [50,51].
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 [52].
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 [53]. With an average followup of 52 months, the three and fiveyear 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 [54,55].
(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 [56]. 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 followup of 73 months, those receiving cisplatin plus
etoposide had an improved threeyear survival rate (41 versus 26 percent; absolute difference 15 percent,
95% CI, 2 to 28 percent) and trend towards improved OS (23.3 versus 20.7 months; HR 0.76, 95% CI 0.55
1.05) [57]. 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 OS; 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 nonsquamous cell histology. In a phase III
trial of approximately 600 patients, pemetrexedcisplatin with RT and pemetrexed consolidation was
associated with similar survival as standard therapy, in this case cisplatinetoposide with RT and a non
pemetrexed consolidation treatment (median OS, 27 versus 25 months; HR 0.98, 95% CI 0.791.20), and a
lower incidence of drugrelated grade 3 to 4 adverse events (64 versus 77 percent) [58]. Although the trial
was closed early due to a lack of observed survival benefit, this combination is an acceptable alternative to
the regimens above.
Immunotherapy — Despite multimodality treatment, the prognosis for unresectable stage III NSCLC remains
poor, with fiveyear OS rates of approximately 15 percent [59,60]. Therefore, newer treatment paradigms
have evolved; for example, incorporation of immunotherapy. For patients with unresectable, stage III NSCLC
whose disease has not progressed following concurrent platinumbased chemotherapy and RT, we offer the
PDL1 antibody durvalumab, which is approved by the US Food and Drug Administration (FDA) for this
indication [61]. However, in the absence of mature OS data and the potential for toxicities associated with
immunotherapy, some experts may reasonably opt not to use durvalumab in this setting, pending further data.
The data regarding durvalumab in stage III NSCLC are discussed here, while immunotherapy for advanced
NSCLC and the investigational use of neoadjuvant immunotherapy are discussed elsewhere. (See
"Immunotherapy of advanced nonsmall cell lung cancer with immune checkpoint inhibition" and "Systemic
therapy in resectable nonsmall cell lung cancer", section on 'Neoadjuvant immunotherapy'.)
In a randomized phase III trial, over 700 patients with unresectable, stage III NSCLC without progression after
at least two cycles of platinumbased chemoradiotherapy were randomly assigned to up to 12 months of the
PDL1 antibody durvalumab every two weeks or placebo in a 2:1 ratio [62,63]. At a median followup of 25
months, durvalumab increased the median PFS (17.2 versus 5.6 months; HR for disease progression or
death 0.51, 95% CI 0.410.63) and OS (HR for death 0.68, 95% CI 0.540.86) [63]. The 12month survival
rates with and without durvalumab were 83 and 75 percent, respectively, and the 24month survival rates
were 66 and 56 percent, respectively. The benefit in PFS and OS with durvalumab was observed in both PD
L1 >25 or <25 percent subsets. An exploratory analysis observed that benefit with durvalumab was not
evident in patients with PDL1 expression <1 percent. Grade 3 or 4 adverse events occurred in 31 percent of
the patients who received durvalumab and 26 percent of those who received placebo, with the most common
severe adverse event being pneumonia. Adverse events of any grade that were of special interest, regardless
of cause, were reported in 66 percent of patients receiving durvalumab versus 49 percent of those receiving
placebo, most of which were grade 1 or 2. Such events for durvalumab versus placebo included diarrhea (18
versus 19 percent), pneumonitis (13 versus 8 percent), rash (12 versus 7 percent), and pruritus (12 versus 5
percent). Adverse events of special interest for which patients received concomitant treatment were reported
in 42 versus 17 of patients receiving durvalumab and placebo, respectively, with treatments typically including
steroids, endocrine agents, and occasionally other immunosuppressive agents. 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.
Administration of radiation — The standard dose fractionation regimen of RT with chemotherapy for stage
III NSCLC remains 60 Gy in 30 daily fractions. Intensitymodulated 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 [64], in which 544 patients with unresectable stage III A/B NSCLC were
randomly assigned in a twobytwo design to one of two systemic therapy regimens (carboplatin plus
paclitaxel with or without cetuximab) and to either standarddose (60 Gy/30 daily fractions) or highdose 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.
● Highdose (74 Gy) RT was associated with a shorter survival and an increased risk of death compared
with conventionaldose (60 Gy) RT (median, 20 versus 29 months; HR 1.38, 95% CI 1.091.76).
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 metastasisfree survival, and local failure rates between the two methods of delivery
[65]. 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 0.170.99).
● The addition of cetuximab to carboplatin plus paclitaxel did not significantly improve OS (median, 25
versus 24 months; HR 1.07, 95% CI 0.841.35) 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 higherdose
RT may be beneficial if chemotherapy cannot be given. In a metaanalysis of 21 trials including 3800 patients,
the majority of whom had stage III disease, higher than conventionaldose RT led to poorer survival in trials
where chemotherapy was used (median survival ratio for higher versus lower radiation doses, 0.83; 95% CI
0.710.97) but improved survival when chemotherapy was not used (median survival ratio for higher versus
lower radiation doses, 1.13; 95% CI 1.041.22) [36]. However, in practice, patients for whom chemotherapy
cannot be administered often have significant morbidity, raising the question of whether higherdose 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 1.101.64) [66]. 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.
Earlyphase data have also suggested efficacy of proton RT. In an openlabel, singlearm phase II study, 64
patients with unresectable stage III NSCLC received concurrent chemotherapy (carboplatinpaclitaxel) and
passively scattered proton RT (74Gy relative biological effectiveness) [67]. In this group, median OS was
26.5 months, fiveyear OS was 29 percent, and fiveyear 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 metaanalysis 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) [68]. 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 fiveyear 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 oncedaily 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) [69].
● Consolidation therapy – The administration of additional chemotherapy following the completion of a
full course of cisplatinbased chemotherapy and radiation has not demonstrated a survival advantage
[55,70]. 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 [55,70]. 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 [59].
● 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 [7176]. 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 [73,74]. The
https://www.uptodate.com/contents/management-of-stage-iii-non-small-cell-lung-cancer/print?search=stage%20iii%20lung%20cancer&source=search_result… 10/23
incidence of brain metastases was significantly decreased with PCI compared with observation (oneyear
rate, 7.7 versus 18.0 percent). However, there was no difference in OS (fiveyear rate, 26 versus 25
percent for PCI and observation, respectively) [77].
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".)
Combinedmodality 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 [78]. RT consisted of 60 Gy
in 30 fractions over six weeks for both groups. At a median followup of 19 months, the combinedmodality
approach significantly prolonged overall survival (OS; median, 22 versus 17 months; hazard ratio [HR] 0.68,
95% CI 0.470.98). 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 as well as database studies also support
the use of concurrent chemoradiotherapy in carefully selected, fit patients [7981]. 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 [82]. 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 [83].
Comprehensive geriatric assessment may help to determine if older adult patients are fit enough to receive
combined chemoradiation. (See "Systemic chemotherapy for cancer in elderly persons", section on
'Comprehensive geriatric assessment' and "Systemic chemotherapy for cancer in elderly persons", section on
'Stage III disease'.)
Poor performance status — No standard approach exists for poorrisk patients who are not candidates for
standard combinedmodality therapy. Thoracic radiotherapy, preferably with sensitizing chemotherapy (eg,
singleagent), or sequential chemoradiotherapy are reasonable approaches in the absence of more definitive
data. For patients who are asymptomatic, we do not defer treatment. (See "Overview of the initial treatment of
advanced nonsmall cell lung cancer", section on 'Older adult patients'.)
The benefits of RT include palliation of tumorrelated 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 fiveyear survival rates of around 5 percent [8487]. Factors that have been
associated with an improved prognosis following definitive RT include small primary tumor and limited total
tumor volumes [87]. 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)
[88]. 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 [89].
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 "Radiationinduced lung injury".)
POSTTHERAPY SURVEILLANCE — Few if any data are available to support evidencebased 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 nonsmall cell lung cancer", section on 'Posttherapy 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 nonsmall 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 initial treatment of advanced nonsmall cell lung cancer".)
SOCIETY GUIDELINE LINKS — Links to society and governmentsponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and
management of lung cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easyto
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
indepth 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 email
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: Nonsmall cell lung cancer (The Basics)")
● Beyond the Basics topics (see "Patient education: Nonsmall cell lung cancer treatment; stage I to III
cancer (Beyond the Basics)" and "Patient education: Nonsmall cell lung cancer treatment; stage IV
cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Stage III nonsmall 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 "Systemic therapy in resectable nonsmall 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 singlestation 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 platinumbased chemotherapy plus fulldose 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 singlestation 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 patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent
platinumbased chemotherapy and RT, we recommend the programmed deathligand 1 (PDL1) antibody
durvalumab (Grade 1A). (See 'Immunotherapy' 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 poorrisk patients who are not fit enough to withstand the rigors of standard combinedmodality
therapy, we offer thoracic radiotherapy, preferably with sensitizing chemotherapy (eg, singleagent), or
sequential chemoradiotherapy, though data in this setting are limited. (See 'Poor performance status'
above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 4623 Version 65.0
GRAPHICS
T, N, and M descriptors for the eighth edition of TNM classification for lung cancer
T: Primary tumor
Tx Primary tumor cannot be assessed or tumor proven by presence of malignant cells in sputum or
bronchial washings but not visualized by imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor ≤3 cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic
evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus)*
T1a(mi) Minimally invasive adenocarcinoma ¶
T1a Tumor ≤1 cm in greatest dimension*
T1b Tumor >1 cm but ≤2 cm in greatest dimension*
T1c Tumor >2 cm but ≤3 cm in greatest dimension*
T2 Tumor >3 cm but ≤5 cm or tumor with any of the following features: Δ
Involves main bronchus regardless of distance from the carina but without
involvement of the carina
Invades visceral pleura
Associated with atelectasis or obstructive pneumonitis that extends to the hilar
region, involving part or all of the lung
T2a Tumor >3 cm but ≤4 cm in greatest dimension
T2b Tumor >4 cm but ≤5 cm in greatest dimension
T3 Tumor >5 cm but ≤7 cm in greatest dimension or associated with separate tumor nodule(s)
in the same lobe as the primary tumor or directly invades any of the following structures: chest
wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, parietal
pericardium
T4 Tumor >7 cm in greatest dimension or associated with separate tumor nodule(s) in a
different ipsilateral lobe than that of the primary tumor or invades any of the following
structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve,
esophagus, vertebral body, and carina
N: Regional lymph node involvement
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary
nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or
supraclavicular lymph node(s)
M: Distant metastasis
M0 No distant metastasis
M1 Distant metastasis present
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or
malignant pleural or pericardial effusion ◊
M1b Single extrathoracic metastasis §
M1c Multiple extrathoracic metastases in one or more organs
Stage groupings
Occult TX N0 M0
carcinoma
Stage 0 Tis N0 M0
Stage IA1 T1a(mi) N0 M0
T1a N0 M0
Stage IA2 T1b N0 M0
Stage IA3 T1c N0 M0
Stage IB T2a N0 M0
Stage IIA T2b N0 M0
Stage IIB T1a to c N1 M0
T2a N1 M0
T2b N1 M0
T3 N0 M0
Stage IIIA T1a to c N2 M0
T2a to b N2 M0
T3 N1 M0
T4 N0 M0
T4 N1 M0
Stage IIIB T1a to c N3 M0
T2a to b N3 M0
T3 N2 M0
T4 N2 M0
Stage IIIC T3 N3 M0
T4 N3 M0
Stage IVA Any T Any N M1a
Any T Any N M1b
Stage IVB Any T Any N M1c
NOTE: Changes to the seventh edition are in bold.
TNM: tumor, node, metastasis; Tis: carcinoma in situ; T1a(mi): minimally invasive adenocarcinoma.
* The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which
may extend proximal to the main bronchus, is also classified as T1a.
¶ Solitary adenocarcinoma, ≤3 cm with a predominately lepidic pattern and ≤5 mm invasion in any one focus.
Δ T2 tumors with these features are classified as T2a if ≤4 cm in greatest dimension or if size cannot be determined, and
T2b if >4 cm but ≤5 cm in greatest dimension.
◊ Most pleural (pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopic
examinations of pleural (pericardial) fluid are negative for tumor and the fluid is nonbloody and not an exudate. When
these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded
as a staging descriptor.
§ This includes involvement of a single distant (nonregional) lymph node.
Reproduced from: Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for
Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J
Thorac Oncol 2016; 11:39. Table used with the permission of Elsevier Inc. All rights reserved.
Graphic 109805 Version 1.0
Descriptors and T and M categories of the eighth edition with seventh edition for
comparison*
Descriptor N categories: 8th edition (7th edition)
Descriptor in 7th
in 8th Overall stage
edition
edition
N0 N1 N2 N3
T1 ≤1 cm T1a IA1 (IA) IIB (IIA) IIIA IIIB
T1 >1 to 2 cm T1b IA2 (IA) IIB (IIA) IIIA IIIB
T1 >2 to 3 cm T1c IA3 (IA) IIB (IIA) IIIA IIIB
T2 >3 to 4 cm T2a IB IIB (IIA) IIIA IIIB
T2 >4 to 5 cm T2b IIA (IB) IIB (IIA) IIIA IIIB
T2 >5 to 7 cm T3 IIB (IIA) IIIA (IIB) IIIB (IIIA) IIIC (IIIB)
T3 structures T3 IIB IIIA IIIB (IIIA) IIIC (IIIB)
T3 >7 cm T4 IIIA (IIB) IIIA IIIB (IIIA) IIIC (IIIB)
T3 diaphragm T4 IIIA (IIB) IIIA IIIB (IIIA) IIIC (IIIB)
T3 endobronchial: T2a IB (IIB) IIB (IIIA) IIIA IIIB

location/atelectasis 3 to 4
cm
T3 endobronchial: T2b IIA (IIB) IIB (IIIA) IIIA IIIB

location/atelectasis 4 to 5
cm
T4 T4 IIIA IIIA IIIB IIIC (IIIB)
M1a M1a IVA (IV) IVA (IV) IVA (IV) IVA (IV)
M1b single lesion M1b IVA (IV) IVA (IV) IVA (IV) IVA (IV)
M1c multiple lesions M1c IVB (IV) IVB (IV) IVB (IV) IVB (IV)
* Where there is a change, the resultant stage groupings for the eighth edition are in bold, and the stage in the seventh
edition is given in parenthesis.
Original figure modified for this publication. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging
Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification
for Lung Cancer. J Thorac Oncol 2016; 11:39. Table used with the permission of Elsevier Inc. All rights reserved.
Graphic 109806 Version 3.0
Contributor Disclosures
Steven E Schild, MD Nothing to disclose Suresh S Ramalingam, MD Consultant/Advisory Boards:
AbbVie; AstraZeneca; Bristol-Myers Squibb; Boehringer Ingelheim; Celgene; Lilly; Merck; Novartis;
Genentech [Lung cancer (Pemetrexed)]. Eric Vallières, MD, FRCSC Nothing to disclose Rogerio C
Lilenbaum, MD, FACP Consultant/Advisory Boards: AstraZeneca [Non-small cell lung cancer
(Osimertinib)]. Joseph S Friedberg, MD Nothing to disclose Sadhna R Vora, MD Nothing to disclose
Contributor disclosures are reviewed for conﬂicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
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Stage IVA Any T Any N M1a

Any T Any N M1b

Stage IVB Any T Any N M1c

T1 ≤1 cm T1a IA1 (IA) IIB (IIA) IIIA IIIB

T1 >1 to 2 cm T1b IA2 (IA) IIB (IIA) IIIA IIIB

T1 >2 to 3 cm T1c IA3 (IA) IIB (IIA) IIIA IIIB

T2 >3 to 4 cm T2a IB IIB (IIA) IIIA IIIB

T2 >4 to 5 cm T2b IIA (IB) IIB (IIA) IIIA IIIB

T2 >5 to 7 cm T3 IIB (IIA) IIIA (IIB) IIIB (IIIA) IIIC (IIIB)

T3 structures T3 IIB IIIA IIIB (IIIA) IIIC (IIIB)

T3 >7 cm T4 IIIA (IIB) IIIA IIIB (IIIA) IIIC (IIIB)

T3 diaphragm T4 IIIA (IIB) IIIA IIIB (IIIA) IIIC (IIIB)

T3 endobronchial: T2a IB (IIB) IIB (IIIA) IIIA IIIB

T3 endobronchial: T2b IIA (IIB) IIB (IIIA) IIIA IIIB

T4 T4 IIIA IIIA IIIB IIIC (IIIB)

M1a M1a IVA (IV) IVA (IV) IVA (IV) IVA (IV)

M1b single lesion M1b IVA (IV) IVA (IV) IVA (IV) IVA (IV)

M1c multiple lesions M1c IVB (IV) IVB (IV) IVB (IV) IVB (IV)

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