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Critical Review

Surgical Management of Early-Stage Non-small Cell LungCarcinoma and the Present and Future Roles of AdjuvantTherapy: A Review for the Radiation OncologistLaura Medford-Davis, MD,*Malcom DeCamp, MD,y Abram Recht, MD,z

John Flickinger, MD,x Chandra P. Belani, MD,k and John Varlotto, MD{

*Department of Emergency Medicine, Ben Taub General Hospital, Houston, TX; yDivision of Thoracic Surgery, Department

of Surgery, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois;zDepartment of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; xDepartment of

Radiation Oncology, Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; kDepartment of Medical Oncology, Penn State

Hershey Cancer Institute, and {Division of Radiation Oncology, Penn State Hershey Cancer Institute, Hershey,

Pennsylvania

Received Sep 20, 2011, and in revised form Jan 28, 2012. Accepted for publication Mar 16, 2012

We review the evidence for optimal surgical management and adjuvant therapy for patients with stages I and II non-small cell lung

cancer (NSCLC) along with factors associated with increased risks of recurrence. Based on the current evidence, we recommend

optimal use of mediastinal lymph node dissection, adjuvant chemotherapy, and post-operative radiation therapy, and make suggestions

for areas to explore in future prospective randomized clinical trials. 2012 Elsevier Inc.

Introduction

Patients present less often with early-stage (stage I and II)

non-small cell lung cancer (NSCLC) than with advanced-stage

disease. However, the increasing use of high-resolution

computerized tomography (CT) has resulted in the detection

of ever-smaller abnormalities, increasing the incidence of such

patients (1). New National Comprehensive Cancer Network

(NCCN) lung cancer screening guidelines recommending

routine low-dose CT screening for asymptomatic high-risk

individuals will likely cause an even sharper increase in the

incidence of early-stage NSCLC in the coming years (2).

Depending on staging procedures, 5-year overall survival (OS)

rates are just 45%-79% in stage I disease and 24%-57% in

stage II disease, indicating that current treatment approaches

are suboptimal (3-7) (Table 1). Even patients with pathologic

stage IA disease have 5-year OS rates of only 47%-79% (5,

7-10).

Perhaps because it is less frequent than advanced disease or

because such patients are perceived to have a favorable prognosis,

the treatment of early-stage NSCLC has not been as extensively

studied as that for patients with advanced-stage NSCLC. There is

substantial controversy regarding how best to treat these patients

with regard to both the details of surgery and the role of adjuvant

therapies.The main therapy for patients with early-stage NSCLC is

widely considered to be surgical resection. The historical standard

of care was to perform a lobectomy via thoracotomy, but newer

studies are exploring the potential advantages of video-assisted

thoracic surgery lobectomy (VATS) and sublobar resection (SLR).

NotedAn online CME test for this article can be taken at http://

astro.org/MOC.

Reprint requests to: John M. Varlotto, MD, Penn State Hershey Cancer

Institute, Radiation OncologyeCH63, 500 University Drive, PO Box 850,

Hershey, PA 17033-0850. Tel: (717) 531-8024; Fax: (717) 531-

0882; E-mail:[email protected]

Conflict of interest: none.

Int J Radiation Oncol Biol Phys, Vol. 84, No. 5, pp. 1048e1057, 2012

0360-3016/$ - see front matter 2012 Elsevier Inc. All rights reserved.doi:10.1016/j.ijrobp.2012.03.018

Radiation OncologyInternational Journal of

b iol og y p hy si cs

www.redjournal.org

CME
http://astro.org/MOChttp://astro.org/MOCmailto:[email protected]://dx.doi.org/10.1016/j.ijrobp.2012.03.018http://www.redjournal.org/http://www.redjournal.org/http://dx.doi.org/10.1016/j.ijrobp.2012.03.018mailto:[email protected]://astro.org/MOChttp://astro.org/MOC


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Whether and how thoroughly lymph nodes should be dissected has

also been hotly debated.

Trials exploring the role of adjuvant therapy in early-stage

disease have had mixed results. Postoperative adjuvant chemo-

therapy (ACT) is recommended for patients with stage II disease

to prevent recurrence by destroying residual disease. However, the

NCCN also makes a category 2B recommendation for ACT in

high-risk stage IB disease, whereas the American Society of

Clinical Oncology does not, and neither recommends its use in

patients with stage IA tumors despite relapse rates of 20%-25%

(2, 11, 12). Some research data suggest that it may be useful in all

stage IB cases(13).

Adjuvant postoperative radiation therapy (PORT) to the tumor

bed and proximal nodal areas can reduce the risk of locoregional

recurrence (LR), but guidelines recommend against its use for

patients with disease stages earlier than stage IIIA(2, 11). This is

largely due to the well-publicized morbidity and mortality resulting

from now outdated PORT techniques (14). However, as ACT

becomes more effective and more widely used, the rationale that

patients will develop DR regardless of whether PORT is used has

become less compelling, and more patients may now be at risk for

local failure.We therefore have reviewed the evidence regarding the optimal

surgical management and adjuvant therapy for patients with

pathologic stages I and II NSCLC. Finally, we note how improved

understanding of new risk factors may lead to better definitions of

high-risk groups that should be studied in future trials of adjuvant

therapy.

Optimal Surgical Management

Pneumonectomy has a higher postoperative morbidity and

mortality than lobectomy (15-17). Since the early 1960s, lobec-

tomy has been considered the preferred operation when it issufficient to achieve complete resection. However, might even

more limited SLR comprising a segmentectomy or wedge resection

result in equivalent disease-free survival (DFS) and less morbidity?

Current NCCN guidelines recommend SLR only for patients with

limited pulmonary reserve unable to tolerate a larger operation, or

in patients with primary tumors smaller than 2 cm and at least one

of the following: pure adenocarcinoma in situ histology, a nodule

with > 50% ground glass on CT, and long doubling time (>400

days) confirmed on radiologic surveillance(2).

In 1995, the Lung Cancer Study Group performed a random-

ized trial of lobectomy vs SLR in patients with NSCLC smaller

than 3 cm, finding decreased OS and a 3-fold increase in LR for

patients in the SLR arm, regardless of actual tumor size. Addi-

tionally, the SLR group had no reduction in perioperative

complication rates or improvement in postoperative lung function

(18). Despite these negative findings for SLR, analysis of the

Surveillance, Epidemiology, and End Results (SEER) database

revealed that the percentage of patients with stage I NSCLC

treated with SLR remained constant at 16% from 1988-2000. The

reasons why this phase III multiinstitutional trial had so little

impact on SLR rates are not entirely clear, but one may be that

before 2000 there were few alternatives for patients with limited

pulmonary reserve, or that whereas there was significantly more

LR in the SLR group, the survival advantage for lobectomy was

only of borderline significance (PZ.08).

The proportion of SLR started to increase markedly in 2001,constituting more than 40% of resections performed in 2004 and

2005 (19) (Fig. 1). The reason for this is unclear. It should be

noted that in 2001, a prospective, multicenter Japanese experience

was published showing that none of the 68 patients treated with

SLR (segmentectomy) had LR, and their 5-year OS rate (87.1%)

was similar to that in 104 patients undergoing lobectomy (87.7%)

during the same time period at the same institution(20). A meta-

analysis published in 2005 seemed to support this finding of

equivalent outcome with SLR and lobectomy (21). However,

several more recent analyses of large retrospective databases

found that SLR resulted in an increased risk of LR (21), partic-

ularly at the staple line(19), and decreased OS(3, 4, 19).

The less invasive method of VATS lobectomy is also beingexplored (22, 23). The hope is that VATS will achieve equal

results to conventional lobectomy performed through open

thoracotomy, but with fewer postoperative complications (24). In

a prospective, randomized study performed in Japan in 1993-1994

Table 1 Five-year overall survival rates by stage

Cancer registry

of Norway,

1993-2002(3)

University of

Pittsburgh,

1990-2003(4)

MD Anderson Cancer Center,

1975-1988, and reference center for

anatomic and pathologic classification

of lung cancer, 1977-1982(6)

National Cancer Center

Hospital, Tokyo,

1961-1995(5)

IASLC lung cancer

staging project 7th

edition, SEER,

1998-2000(7)

Stage I 58.4%y 51%y

cIA* 61%* 70.8%* 47%-51%z

pIA# 67%* 79%*

cIB 38%* 44%* 45%z

pIB 57%* 59.7%*

Stage II 28.4%y

cIIA 34%* 41.1%* 31%z

pIIA 55%* 56.9%*

cIIB 24%* 36.9%* 26z

pIIB 39%* 45%*

Abbreviations: IASLC Z International Association for the Study of Lung Cancer; SEER Z Surveillance, Epidemiology, and End Results.

* Clinical stage.y Pathologic stage.z Pathologic stage was used when available, but clinical stage results are also included in the same calculations.

Volume 84 Number 5 2012 Adjuvant therapy for early-stage NSCLC 1049


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for patients with clinical stage 1A disease, the 5-year OS in 48

patients treated with VATS lobectomy with mediastinal lymph

node dissection (MLND) was at least equivalent to that of open

lobectomy with MLND (24). Two meta-analyses suggest that

patients treated with VATS lobectomy may have even higher 4- to

5-year OS rates than those undergoing traditional open lobectomy

(25, 26). However, because most of the data in both meta-analyses

were from case series and observational studies, large multi-

institution prospective randomized trials are needed for better

evaluation of this promising surgical technique. If these initially

encouraging results continue to be validated, VATS lobectomy

may challenge open lobectomy as the preferred standard of care.

The presence of disease in mediastinal nodes is an adverse

prognostic factor. Subclinical nodal involvement was found in

about 20% of patients with peripheral adenocarcinomas smaller

than 2 cm and clinically normal nodes in 1 study, and it was

associated with a 24% absolute decrease in the 5-year OS in this

group(27). Other studies show that patients with pathologic stage

I tumors have survival rates as much as 21% higher than patients

with clinical stage I disease (5, 6) (Table 1), suggesting that

clinical staging misses subclinical nodal disease that would

upstage these patients. A newly published analysis of American

College of Surgeons Oncology Group (ACOSOG) Z0040

discovered occult disease with cytokeratin immunohistochemistry

in 22.4% of histologically negative resected lymph nodes (28).

These data suggest that when searched for, subclinical nodal

involvement is present even in early-stage disease with higher than

anticipated prevalence. When nodal disease is unresected and

hence undiscovered, patients shown to benefit from adjuvant

therapies to treat nodal disease are not offered those therapies.

In addition to yielding more accurate information for staging

and adjuvant treatment options, MLND might also directly

improve survival by excising more of the cancer burden. The

degree to which the improvement in OS in patients undergoingMLND is due to staging being more accurate when more nodes

were removed, rather than reduced recurrence rates from

increased resection of occult nodal disease, is uncertain. A

Cochrane systematic review of 3 randomized controlled trials

(RCTs) concluded that MLND offered a 37% relative reduction in

the risk of death and a borderline-significant 22% relative

reduction in the risk of DR when compared with mediastinal

lymph node sampling (MLNS), with no difference in LR (29).

Interestingly, the trials that show a benefit for SLR or VATS

lobectomy also performed an adequate MLND (19, 24). A

randomized study by Wu et al (30)of 471 patients with stage I-

IIIA NSCLC revealed an absolute benefit in 5-year OS of 11% for

patients undergoing MLND, compared with MLNS. However, the

Table 2 Major randomized controlled trials of adjuvant chemotherapy

Trial # Pts Median F/U (y) Stage % pneumo Chemo

ANITA(37) 840 6.4 IB-IIIA: IB 36%, II 24%,

IIIA 39%

36% control arm,

38% ACT arm

Cisplatin/vinorelbine

JBR10(38) 482 9.3 IB-II: IB 45%, II 55% 22% control arm,

25% ACT arm

Cisplatin/vinorelbine

IALT(36, 40) 1867 7.5 I-III: I 36%, II 24%,

40% III

34.6% control arm,

34.8% ACT arm

Cisplatin with vinca

alkalide or etoposide

26.8% Cisplatin/

vinorelbine

CALGB 9633(39) 344 6.1 IB 100% 11% control arm,

12% ACT arm

Paclitaxel/carboplatin

Abbreviations:ACT Z adjuvant chemotherapy; ANITA Z Adjuvant Navelbine International Trialist Association; Chemo Z chemotherapy; CT Z

computed tomography; CXR Z chest radiograph; DFS Z disease-free survival; DR Z distant recurrence; F/U Z follow-up; IALT Z International

Adjuvant Lung Cancer Trial; CALGBZ

Cancer and Leukemia Group B trial; JBR10Z

National Cancer Institute of Canada Clinical Trials GroupJBR10 trial; LR Z local recurrence; OS Z overall survival; Pneumo Z pneumonectomy; PORT Z postoperative radiation therapy; Pts Z patients.

Fig. 1. Types of surgical resection for stage I patients 1988-

2006.

Medford-Davis et al. International Journal of Radiation Oncology Biology Physics1050


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MLNS group had removal of only suspicious-appearing nodes,

rather than a thorough sampling; this likely explains why 48% of

the MLND group has pathologic stage IIIA disease after surgery,

compared with only 28% of the MLNS group. The increased

identification of N2 disease presumably led more patients in the

MLND group to receive adjuvant treatment, which may have also

resulted in better survival in the MLND arm.

However,the ACOSOGZ0030 trial foundno difference in 6-year

OS, 5-year DFS, local recurrence, regional recurrence, or DR rates

between patients randomized to MLND or MLNS. This investiga-

tion also demonstrated that an equally efficacious MLNS was ach-

ieved with either VATS, mediastinoscopy, or thoracotomy, thereby

eliminating concerns about adequate lymph node staging with less

invasive procedures(31). The technique for performing MLNS in

this trial (unlike in the earlier trial by Wu et al) was a rigorously

defined procedure that evaluated at least 4 different lymph node

stations tailored to the location of the primary tumor(32).

So, how many nodes should be removed? Several studies have

shown poorer OS and increased DR when fewer than 10 nodes are

recovered at the time of resection (33, 34). An examination of

SEER data for all patients undergoing resection of stage I NSCLC

from 1992-2002 revealed better OS and DFS for patients who had11-16 N1 nodes and 7-10 N2 nodes examined. However, there was

an increase in the 90-day mortality rate when 11 or more N2 nodes

were removed, suggesting that overly aggressive dissection may

be hazardous(1).The authors of ACOSOG Z0040 recommend that

at least 12 mediastinal nodes be removed. ACOSOG Z0040 trial

demonstrated no increase in morbidity and only a slight increase

in operative mortality (2.0% vs 0.76%) in the MLND group.

However, unlike the retrospective SEER review, all participating

Thoracic Surgeons were board-certified in thoracic surgery and

properly trained for this investigation. In light of actual practice

patterns revealing that only 57.8% of NSCLC surgical patients

receive any mediastinal node sampling during surgery(35)despite

national guidelines(2), the results of both ACOSOG Z0030 and

Wu et al should be an impetus to perform a thorough (or any)

MLNS in the other 42.2% of surgical patients who currently

receive none. When adequate MLNS of at least 4 stations is

performed and the nodes are found to be negative, it might

preclude the need for a full MLND because only 4% of patients in

ACOSOG-Z0030 were upstaged to N2 after receiving such an

adequate MLNS(32).

Adjuvant Chemotherapy

The rationale for early-stage ACT is to treat residual locoregional

or distant metastases that are left behind after surgical resection to

prevent recurrence. The NCCN recommends ACT as the standard

of care for all patients with pathologic stage II NSCLC and patients

with high-risk stage IB disease(2). Although research continues to

evaluate whether ACT could also improve outcomes for stage I

disease, significant evidence has been lacking. Recent ACT trials

are detailed in Table 2. Several RCTs that showed a benefit for

ACT used cisplatin in combination with a second agent(36-38). A

prospective, randomized trial that did not demonstrate a survival

benefit for ACT used a carboplatin-containing combination instage IB(39); however, the subset of patients with tumors larger

than 4 cm did have an improvement in survival. Given that

cisplatin doublets have been more extensively evaluated, it is

likely best to use cisplatin combinations in early-stage ACT.

The International Adjuvant Lung Cancer Trial reported

improved OS and DFS for all early-stage patients, with no

difference according to stage at 5 years (36); however, a subse-

quent study with a median follow-up time of 7.5 years discovered

a reversal of benefit whereby those receiving ACT had worse DFS

and OS after 5 years(40). The Adjuvant Navelbine International

Trialist Association (ANITA) trial found statistically significant

increased OS up to 7 years in all patients combined, but with

a trend toward no benefit in the stage IB subgroup (37). The

Trial PORT Type of F/U LR definition %LR & DR OS results

ANITA(37) 33% control arm, 22%

ACT arm

LR, DR by clinical

exam or CT, CXR

Ispilateral

mediastinum

18% control arm, 12%

ACT arm

5-y and 7-y OS better

with ACT by 8.6%,

8.4% subgroup II,

IIA benefit but not

IB

JBR10(38) No RT Clinical exam and

CXR

? ? 5-y OS 11% better for

ACT, confined to

N1 diseaseIALT(36, 40) 30.8% control arm,

30.4% ACT arm

1.9%, Stage I 33.7%,

Stage II, 64.3%

Stage III

? ? 4.4% and 6.2% LR

benefit at 5 & 8 yr

ACT

Improved 5-y DFS and

OS

CALGB 9633

(39)

None ? ? ? Trend toward improved

DFS and OS, but

statistically

significant only for T

>4 cm group

Table 2 (continued)



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Cancer and Leukemia Group B (CALGB) 9633 study, which

included only stage IB patients, initially had promising results, but

ACT was of equivocal benefit with longer follow-up times (39).

Whether the failure of this trial to find an OS benefit was due to the

use of carboplatin instead of cisplatin, or to the possibility that it

may have been underpowered compared with other ACT trials(36-

38), is presently uncertain. Nonetheless, an exploratory analysis of

CALGB 9633 suggested that patients with tumors larger than 4 cm

maintained a significantly better OS(39). Similarly, a statistically

significant survival benefit was found for stage IB and stage II

patients treated with ACT in the National Cancer Institute of

Canada Clinical Trials Group JBR10 trial, although subgroup

analysis was not significant for stage IB patients alone (38).

The LACE meta-analysis of the 5 largest cisplatin-based

regimens tested in randomized trials against no-ACT control

arms found a nonsignificant trend toward improved survival in

stage IB patients and a significant improvement for stage II and III

patients, but decreased survival in stage IA patients (41). Another

meta-analysis supported the role of ACT in patients with stage IB

disease(13). Survival thus far continues to be decreased in stage

IA patients, presumably because the lower risk of recurrence

outweighs the impact of chemotherapy on the rest of the body,which is why it will be important for future research to find the

subgroups of IA patients with higher rates of recurrence in whom

the benefits of ACT might outweigh its risks.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy (NACT) has been studied less exten-

sively than ACT. One trial confirmed a decreased risk of DR but no

improvement in LR and a nonsignificant trend toward improved

OS, but it also added ACT to those in the NACT group whose

tumors responded to NACT(42). The Southwest Oncology Group

(SWOG) trial (S9900) closed early because of emerging evidencedemonstrating a stronger survival benefit for ACT. Nevertheless,

the trends toward better OS and PFS noted with NACT may not

have reached statistical significance because of the trials prema-

ture termination (43). A systematic review and meta-analysis

found a significant benefit for OS in all stages, ranging from

4%-7% more patients alive at 5 years in stages I and II regardless

of whether cisplatin or carboplatin was used(44, 45). However, 5

of the 7 RCTs analyzed also gave some form of ACT, and 6 of the

7, like SWOG, closed early, making it difficult to draw any

unbiased conclusions about NACT. In a head-to-head comparison,

despite seeing higher compliance for NACT, the NATCH

(Neoadjuvant or Adjuvant Chemotherapy in Patients With Oper-

able Non-Small Cell Lung Cancer) trial found no significantdifference in outcomes for ACT vs NACT(45). Given this result, it

is possible that ACT would be more efficacious than NACT if

equal compliance could be achieved. A Chinese study is currently

recruiting stage IB-IIIA patients to receive 1 standard regimen of

chemotherapy, randomized to be given either preoperatively or

postoperatively (www.cancer.gov, CSLC0501). The results should

provide more insight into which timing is more efficacious.

Postoperative Radiation Therapy

The PORT meta-analysis published in 1998 found a detrimental

effect of PORT on survival in patients with stage I and II, N0 orN1 disease(14). However, it has been heavily criticized because it

analyzed trials dating as far back as 1965, with 7 of the 9 trials

delivering at least some treatment with cobalt-60 units rather than

linear accelerators, and many of the trials also irradiated large

volumes to high doses (46). For example, 1 trial that contributed

over 30% of the patients to the meta-analysis used doses that are

known today to increase toxicity and treatment-related deaths

(47). Therefore, this meta-analysis may be unrepresentative of the

outcomes achieved with the current standard of practice, because

the efficacy and safety profile of PORT have advanced signifi-

cantly in recent decades.

The results of 2 phase III trials of PORT have been published

since 1997. A trial of stage I patients conducted in Italy by Tro-

della et al in the late 1980s found a 9% improvement in 5-year OS

and a 21% reduction in LR in the PORT arm with acceptable

levels of treatment toxicity, compared with surgery alone (48).

Although this result is promising, recruitment was interrupted by

the publication of the PORT meta-analysis, and the sample size of

only 104 is too small to enable strong conclusions to be drawn.

Using similar modern techniques, Mayer et al demonstrated that

PORT significantly reduced LR, with nonsignificant improve-

ments in DFS and OS in patients with T1-3N0-2 NSCLC (49).

Two large retrospective trials have also shown a survival benefitof PORT for N2 disease. The Mayo Clinic found a 43% absolute

decline in LR and a 21% absolute increase in survival at 4 years

with PORT compared with surgery alone (50). A study using the

SEER database of patients who received diagnoses between 1988

and 2002 founda decrease in OS in patients with stage II N0 and N1

disease treated with PORT, but increased survival in N2 disease

(51). (This mirrored results from a much earlier randomized trial of

patients with stage II-III squamous NSCLC, where PORT

decreased LR in the ipsilateral lung and mediastinum, and

decreased overall recurrence rates in an N2 subgroup analysis (52)).

In stages earlier than N2, there is not yet enough evidence to

recommend PORT. However, given the risks associated with PORT

suggested by current, albeit poor-quality, evidence (14), thequestion arises whether or not to treat positive margins, which have

high recurrence rates. Recommendations coming out of the PORT

trial place a dose limit at 45 Gy(53), and Machtay et al found an

excess risk for death at radiation doses higher than 54 Gy (54).

However, extrapolating from research in other cancers, positive

margins require a dose of at least 60 Gy, which is potentially toxic

to large lung volumes(55). Therefore, we recommend that PORT

for positive margins must be given via a small boost field with the

elimination of as much normal heart and lung as possible after an

initial field that is treated to 50 Gy, but no boost field when there is

great uncertainty about the location of the positive margin.

One way to improve the therapeutic ratio of PORT for patients

with early-stage NSCLC may be to limit the treatment volume. Ouranalysis of 60 patients with N1 disease found that two-thirds of

local recurrences would have been included in fields that covered

the bronchial stump/staple line, the ipsilateral hilum, ipsilateral and

contralateral mediastinum, and subcarinal areas(56). Although one

rationale for the de-emphasis of PORT is that metastatic disease is

less salvageable and more deadly, so when patients are likely to

succumb to DR they should not risk treatment toxicity to prevent

LR alone (57), our retrospective review also demonstrated that

receiving ACT was the only factor significantly associated with the

risk of LR, suggesting that ACT is now delaying or eliminating DR

so that patients manifest LR as the first site of recurrence(56, 57).

Another approach is to use intraoperative brachytherapy to treat

high-risk areas. Single-institution series have published promisingreductions in stump recurrences by placing mesh containing

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radioactive iodine seeds along the suture line, with 1 report

describing an improvement in LR rate from 18.6% in the SLR-alone

series at a median follow-up time of 24-29 months, to just 4.1% in

the second series at 38.3 months with the addition of iodine-125

brachytherapy to SLR (58, 59). The preliminary results of the

ACOSOG Z4032 phase III trial (www.cancer.gov,NCT00107172),

which randomized SLR candidates to standard SLR alone or SLR

plus intraoperative brachytherapy at the resection margin, showed

no difference in severe or life-threatening adverse events at 30 and

90 days(60), but we await publication of the long-term outcomes.

Trimodality Therapy

With ACT recognized as the standard of care for patients with stage

II and possibly stage IB disease, it remains to be determined

whether PORT should be integrated with ACT to further improve

outcomes. Recent RCTs have included PORT and have still found

a positive result for ACT (36, 37). A retrospective review of the

ANITA trial suggested that PORT may result in further survival

improvement for patients with pN2 disease treated both with and

without ACT (61). However, we areunaware of anydata on whetherPORT is most effective if given concurrently with, before, or after

ACT. ACT with cisplatin and etoposide in addition to adjuvant

radiation therapy did improve intrathoracic recurrence and overall

survival in completely resected stage II or IIIA NSCLC (62). We

think that it may be best to treat a positive surgical margin with

radiation therapy given concomitantly or before chemotherapy,

rather than wait until after ACT. The importance of timing radiation

therapy in close proximity to surgery in the setting of positive or

close margins has been previously shown in breast cancer(63).

Identifying High-Risk Groups for Targeted

Adjuvant Therapy

Personalized medicine has already entered NSCLC treatment with

the discovery of epidermal growth factor receptor mutations.

Patients with such mutations have significantly better DFS rates

when treated with tyrosine kinase inhibitors such as erlotinib and

gefitinib compared with conventional chemotherapeutic agents

(64). More recent discoveries of new biomarkers that predict

chemotherapy response are promising for a new era of targeted

chemotherapy. The presence of a 15-gene mRNA signature in

surgically resected early-stage lung cancer was able to separate

patients who did not receive adjuvant therapy into high and low-

risk groups and was predictive of improved survival in high-risk,

but not low-risk patients treated with ACT. Likewise, the presence

of excision repair cross-complementation group 1 (ERCC-1)

predicted for worse survival in patients treated with adjuvant

chemotherapy, but better survival in patients who had surgical

resection of lung cancer without ACT(65, 66). More recently, the

oncogenic fusion genes EML4-ALK have been found in a small

subset of lung cancer patients. A recent phase II trial demonstrated

a high response rate of 57% to an ALK inhibitor in the subgroup

with EML4-ALK rearrangement even though most patients had

already received previous systemic chemotherapy (67). As we

discover more of these biomarkers, testing for them will become

increasingly important to designing future clinical trials to deter-

mine optimal treatment regimens.

Classic pathologic factors such as the presence of lympho-

vascular invasion(33, 69), poorly differentiated histology(34, 68),

and larger T size(10, 33, 69)also increase the rates of DR and LR

and are associated with decreased OS in patients with resected

early-stage NSCLC (Table 3). However, the risk factors for LR

may be different than those for DR (17). In addition to theseclassic factors, a retrospective analysis of 373 NSCLC patients

undergoing definitive surgical resection has revealed diabetes

mellitus comorbidity as another risk factor for local recurrence,

independent of body mass index or metabolic syndrome, with

a larger hazard ratio than either tumor size or lymphovascular

invasion (17). This finding was confirmed in an additional cohort

of 168 patients (70). Another investigation compiled data from

820,900 patients in 97 prospective studies and also found that

diabetes significantly increased the risk of death resulting from

lung cancer (hazard ratio, 1.27) independent of adiposity (71). All

these findings are intriguing and will require validation through

prospective assessment.

Conclusions

Surgery remains the mainstay of treatment of patients with early-

stage NSCLC. Although open lobectomy has been the gold stan-

dard, we believe that it is preferable to perform a minimally

invasive lobectomy such as VATS whenever possible. A phase III

trial in China will compare this approach directly with axillary

thoracotomy (www.cancer.gov, NCT01102517). Sublobar

Table 3 Prognostic factors for overall survival, local recurrence, and distant recurrence

Prognostic factors Overall survival Local recurrence Distant recurrenceLVI (17, 19, 56, 72) (17, 69, 72) (17)

Grade (poorly differentiated) (19, 71) (19)

Sublobar resection (3, 4, 72) (72)

ACT (36, 37, 38, 41) (17, 51)

Diabetes (71) (17, 70)

LOS (19) (19)

T size (3, 29, 69, 72) (19, 29, 72) (72)

Histology (nonsquamous) (17, 19) (17, 72)

No. of nodes positive (17, 56) (56)

No. of nodes resected (56) (56)

Pneumonectomy (3, 16) (17, 56)

Abbreviations:ACT Z adjuvant chemotherapy; LOS Z length of postoperative hospital stay; LVI Z lymphovascular invasion.

Numbers refer to references.

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resection should be used only in patients with small, peripheral

tumors of less than 2 cm with ground-glass appearance (2),

pending the results of the CALGB14053 trial, which will comparelobectomy with SLR in stage IA patients with peripheral tumors

smaller than 2 cm. Patients should also undergo a thorough MLNS

(at least 12 nodes recovered from should be 5 or 6 stations for right

(stations 2R, 4R, 7, 8, and 9) or left-sided lesions (stations 4L, 5, 6,7, 8, and 9), respectively).

Table 4 Ongoing adjuvant chemotherapy clinical trials*

Trial, phase Institution Surgical stage Interventions Primary outcome

Completion

date

NCT00863512

CALGB-

30506, phase

III

USA and

Australia, 94

sites

I-IIA, N0 ACT vs observation OS 1/2014

NCT00923637,

phase II

Guangdong,

China

IB-IIIA ACT pemetrexed followed by

pemetrexed/oxaliplatin

Clinical feasibility rate 6/2015

NCT00675597,

phase I

Memorial Sloan-

Kettering

IA-IIIB ACT docetaxel/vinorelbine 4

cycles (with/without PORT

after ACT for N2 disease)

Docetaxel/vinorelbine

tolerability for increased

no. of cycles

5/2012

NCT00478699,

phase III

Alicante, Spain II-IIIA ACT docetaxel

gemcitabine/cisplatin and

docetaxel/cisplatin vs

docetaxel/cisplatin alone

5-y OS 6/2012

NCT00321334 Guangzhou,

China

pIB-IIIA NACT vs ACT docetaxel/

carboplatin

3-y DFS 3/2012

NCT01258127 Sichuan, China IB-IIIA ACT pemetrexed/carboplatin

vs vinorelbine/carboplatin

8/2015

NCT00324805 USA and Canada,

649 locations

IB-IIIA (>4 cm) ACT with/without

bevacizumab

OS 7/2015

NCT01410214,

phase II

China (multiple

centers)

IIIA EGFR

mutations

ACT with erlotinib vs

vinorelbine/cisplatin

2-y DFS 7/2017

NCT01407822,

phase II

Guangdong,

China

IIIA, N2 NACT and ACT with

erlotinib vs cisplatin/

gemcitabine

Objective response rate 3/2016

NCT00462995,

phase II

Toronto I-IIB NACT oral erlotinib Ki67

Immunohistochemistry

expression

11/2012

NCT00455572 Belgium, Canada,

France,

Germany, Italy,

UK

IB-III ACT with Glaxo-Smith-Kline

immunotherapy agent

with/without cisplatin/

vinorelbine (4 arms)

Anti-MAGE-A3

seroconversion, anti-

protein D seroconversion,

MAGE-A3 T cellresponse, adverse events

4/2012

NCT00775385,

phase II/III

France (multiple

centers)

II-IIIA non-N2, non

squamous

ACT pemetrexed/cisplatin

regular schedule vs tailored

to ERCC1 status

Feasibility 12/2014

NCT01405079,

phase III

China (multiple

centers)

II-IIIA with EGFR

mutation

ACT gefitinib vs vinorelbine/

cisplatin

3-y DFS 8/2018

NCT00775307,

phase II/III

France (multiple

centers)

I ACT with pazopanib vs

placebo

Feasibility (phase II); DFS

(phase III)

12/2013

NCT01066234,

phase III

Seoul, Korea IIIA (microscopic

N2)

Adjuvant chemoradiation

therapy paclitaxel/cisplatin

vs ACT only-paclitaxel/

carboplatin

3-y DFS 3/2014

NCT01209520 University ofMiami, Florida

I-IIIA with tumorsuppressor gene

hypermethylation

ACT (any regimen) followedby 5-azacitidine

Presence of methylatedtumor suppressor genes in

tumor tissue and serum;

grade of demethylation

induced by 5-azacitidine

and duration of effect

7/2014

Abbreviations:ACT Z adjuvant chemotherapy; DFS Z disease free survival; ERCC1 Z excision repair cross-complementation group 1; NACT Z

neoadjuvant chemotherapy.

* www.clinicaltrials.gov, accessed 1/10/2012.

http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/


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Stage II patients should routinely receive ACT, preferably with

a cisplatin doublet based on the results of the ANITA and JBR10

trials, and this ACT regimen also should be strongly considered

for high-risk stage IB patients. CALGB 30506 is currently

randomly allocating stage I and stage IIA-N0 patients to ACT or

observation (www.cancer.gov,CALGB-30506). However, because

this trial allows the use of multiple different ACT regimens, we

believe that a prospective trial in patients with pathologic stage I

disease that chooses regimens based on either patient or tumor

characteristics such as NCT00775385 (Table 4) is warranted. This

trial as well as all current investigations concerning the adjuvant

treatment of lung cancer are enclosed in (Table 4) for reference.

There is still insufficient evidence to recommend the use ofPORT in early-stage NSCLC. However, the encouraging results of

2 recent prospective trials in early-stage NSCLC, which demon-

strated positive outcomes when modern radiotherapeutic tech-

niques were used, suggest that this may change in the future

(49, 50). We greatly encourage prospective evaluation of failure

patterns so that patients can be treated using modern techniques

that confine radiation delivery to the highest-risk recurrence areas.

We propose that the bronchial stump, the staple line, and the nodes

of the ipsilateral hilum and mediastinum as defined by Trodella

et al (49) should be evaluated as potential site that could benefit

from PORT in resected N0 NSCLC and that factors associated

with recurrence in this area be prospectively determined; (Fig. 2a)

and that this same area with the addition of the subcarinal and

contralateral mediastinum should be similarly investigated for

patients with N1 to N2 disease (Fig. 2b)(72). More phase II trials,

such as RTOG 9705, using concurrent PORT and ACT, are needed

to determine the optimal timing to integrate ACT and PORT

(www.cancer.gov, RTOG-9705).

Finally, evaluation of the risk factors that determine LR and

DR, and their impact on the value of adjuvant therapy, are needed

to optimize the use of ACT, PORT, and targeted therapies.

Although extensive evidence links TNM stage to survival (7),

there is no proof that TNM is associated with recurrence risk.Although N stage is currently used to determine whether or not

PORT should be given, N stage may not be related to, and has

never been proven prospectively to be associated with, LR, and it

may only be a risk factor for DR (17). Early evidence indicates

that risk stratification beyond T and N stage affects outcomes

(Table 3) and should also have an impact on treatment decisions.

Although staging and treatment of lung cancer have traditionally

relied on histopathologic risk factors, we greatly encourage

prospective assessment of genetic, metabolic, as well as treatment

and patient-related factors to ultimately determine the risk of local

and distal recurrence and to optimally tailor treatment algorithms.

We believe that N stage may be best used to determine treatment

areas for prospective evaluation of risk factors as shown in Fig. 2,but not as the sole determinant of the decision of whether to

administer PORT.

Proper trials evaluating the role of PORT will not be

possible until risk factors for local recurrence and recurrence

areas are defined through prospective investigations. At that

time, proper patients stratification for prospective, randomized

studies evaluating PORT can then be ultimately determined.

The failure of past prospective, randomized trials may not only

have been due to poor radiation technique, but also due to

improper patient randomization for risk factors associated with

local recurrence.

Choosing a treatment strategy based on patient and tumor

characteristics will be an appropriate future strategy to improveoverall outcome.

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