con trove rsi as en el manejo de estadio iiia

8/3/2019 Con Trove Rsi As en El Manejo de Estadio IIIA

1/18

191

Review

www expert-reviews com ISSN 1473-7140 2008 Expert Reviews Ltd10 1586/14737140 8 12 1913

Lung cancer is the number one cause o cancer-related mortality in the USA in both womenand men [101]. In 2008, the estimated cancerdeath rate increased in both genders. It is esti-mated that 215,020 new cases and 161,840deaths will occur as a result o lung cancerin the USA in 2008 [101]. To date, lung can-cer staging relies on a clinical classicationthat encompass the attributes o the tumorthat dene its behavior. The American Joint

Committee on Cancer (AJCC) classicationused today is based on the premise that, ingeneral, cancers that share the same anatomicsite and histology also have similar patterns ogrowth and outcomes. Thus, the T (size o theuntreated primary cancer), N (regional lymphnode involvement) and M (distant metastasis)system has been widely proposed by the AJCCto stage malignant diseases.

In lung cancer, early stages (I and II), whichencompass diseases such as T1 or T2 lesionswith or without metastasis to the ipsilateral

peribronchial and/or ipsilateral lymph nodes,

and intrapulmonary nodes, including involvment by direct extension o the primary tum(N1 disease) and T3 lesion without N1 diease, are considered to be candidates or sugery as a rst therapeutic option. It is whethe patient progresses to stage IIIA (N2 dease: metastasis to ipsilateral mediastinal anor subcarinal lymph nodes) that controverover management has occurred in recent yeaTraditionally, stage III (A and B) lung canc

has been considered unresectable and suiable or concurrent chemoradiation (CT/RTbased on several clinical trials that showed beter results than radiation therapy (RT) alonor rom sequential therapy[13]. NevertheleN2 with nodal disease involvement remaian area in which cancer physicians would lito be more aggressive and oer the patieimproved options. Improved RT technologsurgical interventions, supportive care, novtherapeutic agents, discovery o potential bimarkers and biological insights revealed b

gene-expression proling (GEP) in lung canc

Edgardo S Santos,Aurelio Castrellon,Marcelo Blaya andLuis E Raez

Author for correspondenceUniversity of Miami Miller

School of Medicine, Sylvester

Comprehensive Cancer Center,

1475 NW 12th Avenue,

Suite 3510, Miami,

FL 33136, USA

Tel.: +1 305 243 6554

Fax: +1 305 243 3289

[email protected]

New developments in the management o non-small-cell lung cancer, as well as recent proposaor changing the current lung cancer staging system, are posing a challenge in the therapeudecision making regarding this disease. For the last two decades, the management o stage II(N2) disease has been controversial and the target or clinical trials has been to determine thbest therapeutic approach that may result in better survival outcomes without increasing toxicit

For many years, combined modality treatment (systemic chemotherapy plus radiation therapbecame the standard o care in this setting. However, the poor outcomes seen with combinemodality or N2 has obligated us to explore other possibilities. In this sense, recent clinical triain the neoadjuvant setting using chemotherapy alone or combined modality are providing ruitresults and shiting the paradigm on this stage. A recent, large randomized multicenter trargues against what has slowly become a current practice in some centers the use preoperative modality or N2 disease. Another controversy that we will discuss here is thacceptance o adjuvant therapy or resected stage IBIIIA non-small-cell lung cancer. It was nlong ago that adjuvant radiation therapy was still the standard o care or patients who hapathological nodal disease. We will present the current data on these debatable issues and hoto implement this new knowledge into clinical practice.

Keywords: adjuvant chemotherapy concurrent chemoradiation induction chemotherapy lung cancer

N2 disease radiation therapy stage IIIA

Controversies in the

management of stage IIIAnon-small-cell lung cancerExpert Rev. Anticancer Ther. 8(12), 19131929 (2008)

For reprint orders, please contact [email protected]


2/18

Expert Rev Anticancer Ther 8(12) (2008)1914

Review Santos, Castrellon, Blaya & Raez

are some o the reasons why accurate diagnosis, proper stagingand patient selection in lung cancer has caught the attentiono researchers [414]. Although outside the scope o this review,GEP is providing new inormation on the behavior o this dis-ease and, perhaps, a molecular rather than an anatomic clas-

sication may oer better patient stratication and selection inthe near uture [8,11]. Certainly, there are biologic dierencesin each individual patient that must be recognized and takeninto consideration.

In this review, we discuss the management o N2 rom dierentperspectives: neoadjuvant versus adjuvant chemotherapy (CT)and single versus combined modality approach. Approximately20% o patients with newly diagnosed lung cancer present withlocally advanced N2 disease [15,16]. The TNM classicationdenes this group as having a potentially resectable tumor mass(T0 to T2) involving the ipsilateral mediastinal lymph nodes(N2), or a tumor invading the chest wall (T3) with hilar lymph

node (N1) involvement[17]

. Although complete resection orpatients with stage IIIA, bulky, N2-positive disease is techni-cally easible, the 5-year surviva l is only approximately 10% [15].The vast majority o recurrences are outside the eld o surgi-cal resection, accounting or the most common cause o deathater complete resection, suggesting that systemic approaches areneeded to improve the cure rate. These observations have high-lighted the need to develop combined modality approaches, suchas neoadjuvant CT ollowed by surgery and/or RT in attemptsto improve survival.

Clearly, N2 is a heterogeneous disease that can range romT3N1 disease to minimal N2 disease (microscopically oundater surgical resection) or bulky disease (with multistation

disease in the mediastinum). The burden o disease has beencorrelated with overall survival (OS) and the dierence betweenboth groups deserves attention [15]. Concurrent CT/RT and/orsequential therapy (CT ollowed by RT) were the most com-mon modalities used to treat N2 non-small-cell lung cancer(NSCLC) in the adjuvant setting until 2003. Controversy ariseswhen we consider that a clinica l N2 patient can be downstagedand, hence, become a potential candidate or surgical resec-tion. What should be oered in this case: single or combinedmodality as neoadjuvant approach? Herein, the assessment othe mediastinum becomes a crucial aspect prior to making adecision on resectability. Adding another actor to the com-

plexity o this management, surgery ater CT/RT (combinedmodality) remains controversial or patientswith N2 NSCLCater the report o the European Organisation or Researchand Treatment o Cancer (EORTC) 08941 trial, which willbe discussed later [18]. In 2007, the American College o ChestPhysicians (ACCP) updated its guidelines in which this organi-zation emphasized that preoperative induction treatment or N2disease should be done in the context o a clinical trial and is notrecommended as standard practice in the community[19].

The other topic that we will address is the actua l role o adju-vant therapy in N2 disease. Ater 30 years o adjuvant CT trials,we have nally ended up with the acceptance that this approach

prolong survival and improve cure rate in NSCLC. With the

publication o our randomized clinical trials showing survivaladvantage or patients who received adjuvant CT, oncologistsinitially started to adapt this modality o treatment or patho-logically stage IBIIIA NSCLC patients [2023]. Nonetheless, thebenet o this therapy seems to disappear or stage IB group and,

hence, adjuvant CT ater resection o stage IIIIIA is considerednow standard o care. To date, stage IB NSCLC (tumors at least4 cm in size) is the subject o ongoing clinica l research to addressthese controversial results [24].

Unortunately, data rom almost all clinical trials investigat-ing these particular questions are conusing due to heterogene-ity o patient population, including dierent stages, histology,diculty to assess volume or extent o nodal disease (bulky vsnonbulky N2) and others. Our current staging system does notdiscriminate among N2 disease patients (no subsets are consid-ered) and, hence, this crucial actor must be careully evaluatedwhen we analyze a clinical trial results prior to prescribing a

therapeutic approach. We have just recognized that we shouldstudy this particular stage using strict inclusion criteria and,hence, avoid other conounding actors that may not a llow us toget a conclusive answer. In this review, we ocus our attention onthe dierent clinical management or N2 nowadays.

Preoperative setting

Role of neoadjuvant chemotherapy alone for N2

The rationale or using induction CT in locally advancedNSCLC is based on the considerations that CT may preventthe growth o systemic disease and, at the same time, decreasethe locoregional micrometastatic burden, potentially achievingimproved complete resection rate, which may be translated into

better survival. The advantage o neoadjuvant CT lies in betterpatient compliance and tolerance.

Background of single-modality

neoadjuvant chemotherapy

Two important trials o neoadjuvant CT in NSCLC werereported by Roth et al. and Rosell et al. in the 1980s [25,26]. Inboth studies, patients with stage III NSCLC were randomized toeither surgery alone or chemotherapy ollowed by surgery. Bothstudies were small and closed early because o interim analysisdemonstrating improved survival in patients given preoperativeCT. Updated analysis continues to avor the neoadjuvant CT

in both studies [27]. A number o Phase III trials that comparedinduction CT to surgery alone have been conducted and resultso these trials are already reported (Table 1). The rst o these trialsconducted by the National Cancer Institute (NCI) randomized27 patients (all o whom had histologically conrmed metastasesto the ipsilateral mediastinal lymph nodes) to undergo surgicalexcision (n = 14) ollowed by mediastinal RT (5460 Gy) orto receive two 21-day cycles o cisplatin 80 mg/m2 on day 1and etoposide 120 mg/m2 on days 13 preoperatively, ollowedby our cycles o the same CT ater surgery (n = 13) [28]. Thestudy closed early due to poor accrual. The CT arm showed anonsignicant trend towards improved survival (median: 28.7

vs 15.6 months; p = 0.095) [28]. This study was ollowed by two


3/18

www expert reviews com 191

ReviewManagement of stage IIIA non-small-cell lung cancer

small randomized Phase III trials that reported striking resultswith neoadjuvant CT or N2 NSCLC. The rst o these twostudies was conducted at the MD Anderson Cancer Center,where 60 patients were randomly assigned to receive eitherinduction cisplatin/etoposide/cyclophosphamide three cycles

ollowed by surgery and then, three cycles o CT (n = 28) or sur-gery alone (n = 32) [25]. Al l patients with incompletely resecteddisease received additional RT. Overall response rate (ORR)to preoperative CT was 35%. The trial was terminated early,ollowing a single unplanned interim analysis. The decision toterminate the trial was based on ethical considerations, the mag-nitude o the treatment eect and the high degree o statisticalsignicance attained [25]. Patients who received CT obtained asignicant improvement in median survival (range : 64 monthsvs 11 months; p < 0.008) and a 3-year OS: 56 vs 15%, respec-tively. This increase in OS was maintained in a later analysiswith a median ollow-up o 82 months [29].

The second trial came rom another multicenter trial con-ducted in Spain, where 60 patients were randomized to undergoeither immediatesurgery (n = 30) or three cycles o CT givenat 3-week intervals (n = 30) ollowed by surgery [15]. The che-motherapeutic regimenconsisted o cisplatin (50 mg/m2), ios-amide (3 g/m2) and mitomycin (6 mg/m2). Both patientgroupsreceived mediastinal RT given to a cumulative dose o 50 Gy. An analysisater 24 months showed a signicant dierence

in survivaland enrollment was thereore stopped. There wesignicant dierences in disease-ree survival (DFS) and Obetween the two groups. The median period o DFS in the sugery group was 5 months compared with 20 months in the Cplus surgery group (p < 0.001) [26]. Similarly, the median O

in the surgery

group was 8 months

compared with 26 montin the CT plus surgery group (p < 0.001). The dierences survival between the two groupswere signicant, irrespectio the patients age, histology subtype, tumor size, location annumbero N2 levels involved. Interestingly, the prevalence mutated K-rasoncogeneswas 15% among the patients receivinneoadjuvant CT and 42% among those treated with surgealone (p = 0.05), which may account or the dierences seen this study because we know that the presence oK-rasconepoor prognosis nowadays [26].

Perhaps, one o the most infuential trials in this topic wthe Bimodality Lung Oncology Team (BLOT) Phase II tria

which showed good ecacy o two neoadjuvant cycles usinthe carboplatin/paclitaxel doublet with a avorable toxiciprole [30]. Owing to these results, the Southwest OncoloGroup (SWOG) launched a Phase III randomized trial (S9900Nonetheless, the S9900 study was also closed early due to thestablishment o adjuvant CT as the new standard o care, anthis highlighted the ethical issue o having a surgery-alone aras a result o these data [20]. At the time o closure, S9000 ha

Table 1. Selected randomized Phase III clinical trials o induction chemotherapy in stage IIIA non-small-celllung cancer.

Treatment Patients Response (%) Complete resection Outcome (months) Re

EtoposideCisplatin

EC 2 S + EC x 4

EC S = 13*

S = 14*ORR = 50 EC S = 84%

S = 85%MS: 28.7 vs 15.6; p = 0.095 [2

Cyclophosphamide

Etoposide

Cisplatin

CytxEC 3 S + CytxEC 3

Cyt x EC S = 28

S = 32ORR = 35 MS: 64 vs 11; p < 0.008

3-year OS: 56 vs 15

[2

Mitomycin

Iosamide

Cisplatin

MIC 3 S+ MIC 2

MIC S = 30

(N2: 83%)

S = 30 (N2: 63%)

ORR = 60

PR = 53

CR = 7

MIC S = 85%

S = 90%MS: 26 vs 8; p < 0.001

MDFS: 20 vs 5; p < 0.001

[2

Mitomycin

Iosamide

CisplatinMIC 2 S + MIC 2

MIC S = 176

75

S = 17992

ORR** = 64

PR** = 54

CR** = 11

MIC S = 92%

S = 86%

84%

pT3 or pN2

MS: 37 vs 26; p = 0.15

MDFS: 26.7 vs 12.9; p = 0.001

[2

Vindesine

Cisplatin

VC 3 S

VC x 3 S = 31S = 31

ORR = 28 VC S = 65%

S = 77%

MS: 17 vs 16; p = NS [3

Paclitaxel

Carb

P + Carb S = 180#S = 174#

ORR = 40 MS: 50 vs 47; p = 0.24

MDFS: 33 vs 21; p = 0.098

[3

*Stage IIIA with biopsy proo o N2.Received sequential radiation.Stage IIIA.Received postoperative chemotherapy.#30% Stage IIB/IIIA.**All groups.Carb: Carboplatin; CR: Complete radiographic response; EC: Etoposidecisplatin; MDFS: Median disease-ree survival; MIC: Mitomyciniosamidecisplatin;MS: Median survival; NS: Nonsignifcant; ORR: Overall response rate; OS: Overall survival; PR: Partial response; S: Surgical resection; VC: Vindesinecisplatin.


4/18



354 patients enrolled (30% o the patients had stage IIB/IIIA)and this early closure aected the statistical power o the resultso this trial. Patients were randomized to receive either neoad-juvant CT (carboplatin [AUC: 6] plus pacl itaxel at 225 mg/m2or three cycles) or surgery alone. The goal o the study was

to determine whether this drug combination (n = 180) couldimprove survival compared with surgery alone (n = 174). Majorradiographic response (40%) to neoadjuvant CT was observed.At the2005 Americal Society o Clinical Oncology(ASCO) meet-ing, a preliminary analysis did reveal a trend avoring progres-sion-ree survival (PFS), although there was no dierence inOS [31]. In a recent update, the S9900 trial revealed that therewas no statistical ly signicant PFS (33 vs 21 months; p = 0.098)as well as median survival (50 vs 47 months; p= 0.24); bothavored neoadjuvant CT [32].

Another trial, conducted by the French Thoracic CooperativeGroup, randomized 350 patients with clinical stage IBIIIA

disease (N2: 167 patients) to preoperative CT (n = 176) orsurgery a lone (n = 179) [33]. The CT consisted o two cycles oinduction cisplatin (30 mg/m2, days 13), iosamide (1.5 g/m2,days 13), and mitomycin (6 mg/m2, day 1), ollowed by twocycles postoperatively (consolidation). All patients with incom-pletely resected disease, pT3 or pN2 received additional RT(median: 60 Gy) [33]. ORR to neoadjuvant CT was 64%. Themedian survival was 37 versus 26 months, respectively; however,this di erence was not signicant (p = 0.15). The 4-year survivalrates were 44 and 35%, respectively. The only prognostic actorwas tumor staging, with a relative risk o death estimated at1.6 in N2 patients. Median DFS in the group treated with CTwas signicantly better compared with the surgery-alone group

(26.7 vs 12.9 months; p = 0.001) [33]. A subset analysis showeda signicant benet or CT in patients with N01 disease;however, that was not the case in the group with N2 disease(RR: 1.04; 95% CI: 0.681.60; p = 0.85) [33].

A study conducted in Japan also ailed to conrm benet rominduction CT [34]. In total, 62 patients with N2 NSCLC wererandomly assigned to receive either three cycles o inductionCT (cisplatin 80 mg/m2 and vindesine 3 mg/m2) ollowed bysurgery or surgery alone. Noteworthy, adjuvant treatment wasnot allowed and postsurgical RT was only given to incompletelyresected patients. O note, this trial was prematurely closed dueto a slow accrual rate, and hence, no survival dierence between

both arms was observed (17 vs 16 months) [34].In 2007, Gilligan et al. published the results o the MRC

LU22/NVALT 2/EORTC 08012 multicenter, randomized trialin which patients received either surgery alone or three cycles oplatinum-based CT ollowed by surgery [35]. The primary endpoint was OS, which was analyzed on an intention-to-treat basis.A total o 519 patients were randomized (surgery alone: n = 261;induction CT plus surgery: n = 258). The distribution by clinicalstage was: stage I : 61%, stage II : 31% and stage III: 7%. In thistrial, there was no evidence o a benet in terms o OS (hazardratio [HR]: 1.02; 95% CI: 0.801.31; p = 0.86). The impor-tance o this trial was that it added considerable weight to the

cumulative data on induction (preoperative) CT. By adding the

results o this trial, an updated systematic review suggested a 12%relative survival benet with the addition o neoadjuvant CT(1507 patients total; HR: 0.88; 95% CI: 0.761.01;p = 0.07),which is equivalent to an absolute improvement in survival o5% at 5 years [35]. From this study, we cannot draw any conclu-

sions with regard to stage III NSCLC due to the low number opatients with this clinical stage. Noteworthy acts rom this trialwere that neoadjuvant CT was easible, downstaging was seen in31% o the patients, it did not alter the type o surgical resection,and postoperative complications or impairment in quality o liewere not seen in this group.

Novel combinations in the neoadjuvant setting

The introduction o new agents or the treatment o lung can-cer has a lso brought with it the expectation or greater activity,which may also lead to a downstaging o bulky tumors andenable the improvement o the chance o complete resection.

Numerous Phase II clinical trials have evaluated combinationso these agents with platinum-based compounds. Nonetheless,comparison among these trials is not possible, again due to mul-tiple variables: inclusion criteria, pathologic documentation ostage III disease, number o subjects, addition o adjuvant RTand dierent therapy regimens, among others. Response ratesin the platinum-based CT trials have been reported as high as70%, with complete responses (CRs) ranging rom 0 to 8%.The percentages o surgical resections using neoadjuvant CThave exceeded 50%. Median survival has been reported to bebetween 14 and 36 months.

Among these studies, the combination o cisplatin plus gem-citabine has been shown to be synergistic in preclinical stud-

ies [36]. In patients with advanced NSCLC, this combinationhas produced ORR o more than 50% [37]. Table 2 shows theresults o selected Phase II trials using cisplatin/gemcitabinedoublet as induction CT ollowed by surgery in patients withstage IIIAIIIB NSCLC. Doses o gemcitabine and schedule odrug delivery has varied among these trials. Eligibility criteriaor study entry in all three trials included the ollowing: N2NSCLC [38] and stage III A and IIIB [39,40] with biopsy provenN2 disease. All trials selected patients with a perormance sta-tus (PS) o 01 according to the WHO. Ecacy o the drugcombination was high in a ll tria ls, with ORR or N2 over 65%and a CR o 06%. Complete surgical resection varied rom

4080%, mediastinal sterilization o aected lymph nodes wasseen in 53% o the patients that were randomized to surgery inthe study that exclusively included N2 disease [38]. Criteria orRT included nonresectable patients, lymph nodes or patientsthat could not undergo complete resection. The toxicity pro-le o cisplatin/gemcitabine combination has been avorable;thrombocytopenia has been the predominant hematologic toxic-ity, with grade III/IV toxicity seen in up to 60% o the patients.However, it has not been associated with an increased numbero bleeding events or platelet transusions [38].

An important addition to lung cancer treatment was theintroduction o taxanes. The combination o taxanes with

platinum agents is well established in the rst-line treatment


5/18



o stage IIIBIV NSCLC. Two randomized Phase III clinicaltrials have evaluated docetaxel with cisplatin [41,42]. In the rsto these studies, the 2-year survival rate o cisplatin/docetaxelwas 21% compared with 14% demonstrated or cisplatin/vinore-lbine (p< 0.035). Table 3 shows results o Phase II clinical trialsevaluating the combination o taxanes and platinum agents inthe induction treatment o patients with mediastinoscopicallyproven N2 NSCLC. The ORR in both the EORTC 08958 andthe Swiss Group or Clinical Cancer Research (SAKK) trials was

over 60%, with CRs between 2 and 8%. Patients who receivedcarboplatin/paclitaxel were urther randomized to RT or sur-gery; complete resection was 80% in the group randomized tosurgery, with 17% o mediastinal lymph nodes ree o tumor(median survival o 20.5 months) [43]. In the trial o cispla-tin/docetaxel, participants who obtained a complete resectionreported a 19% complete pathological response, with 31% oresected patients having mediastinal lymph nodes ree o tumor.The median survival or the 90 patients included in the trialand those resected (n = 75) was 28 and 35 months, respectively[44]. Results o the cisplatin/docetaxel trial are among the bestresults obtained in pN2 NSCLC patients. The nal ana lysis

ater a longer ollow-up (median 5 years) demonstrated thatthe activity o CT on the tumor and on lymph nodes, as char-acterized by the amount o necrosis and brosis and clearanceo the malignant cells, respectively, was highly associated withoutcomes. Patients who attained a pathological response o 60%or over have a reduction on the risk o local relapse and distantmetastases by 56 and 64%, respectively[45].

Beore our discussion on novel chemotherapy regimens stud-ied as neoadjuvant approach, there are three meta-analyses donein this setting that also deserve our attention. The rst twoshowed a benecial eect o neoadjuvant CT in comparison withsurgery (with or without RT) [46,47]. The third study showed

that the dierences at 5-year postresection were not signicant

between the two groups (preoperative CT vs surgery alone) [4Berghmans et al. published a meta-analysis that included 2randomized studies (induction CT trial: n = 6 and adjuvaCT: n = 19) published in French or English between 1965 an2004 [46]. The overall meta-analysis showed that the HR the combined results was 0.66 (95% CI: 0.480.93) and 0.8(95% CI: 0.780.89) in avor o the addition o induction anadjuvant CT, respectively. Thus, the study showed a survivadvantage o induction and adjuvant CT in case o resectab

NSCLC. The eect was signicant or adjuvant CT in stagI and II (HR: 0.88; 95% CI: 0.830.94). For stage III diseasthe addition o CT was not statistically signicant or eithinduction (neoadjuvant) or adjuvant CT; however, there wastrend in avor o CT (adjuvant: HR = 0.85, 95% CI: .691.0neoadjuvant: HR = 0.65; 95% CI: 0.411.04). In this metanalysis, the authors commented on the need to separastage III disease rom earlier stages [46]. It is important emphasize that or resectable stage III (mainly N2 diseasethis study only documented a trend in avor o CT (either neoadjuvant or adjuvant). Burdett et al. perormed a systematreview and meta-analysis to assess the ecacy o preoper

tive (neoadjuvant) CT in NSCLC [47]. Ater exclusion o triathat deviate rom the objective o the study, seven randomizeclinical trials were considered (with a total o 988 patients) the analysis. Preoperative CT was ound to improve surviv(HR: 0.82; 95% CI: 0.690.97; p = 0.02). This is equivaleto an absolute benet o 6%, increasing OS across all stages disease rom 14 to 20% at 5 years [47]. Making the data mocontroversial, Nakamura et al. published a meta-analysis thincluded ve randomized clinical trials with the goal o esmating the HR o patients who underwent preoperative CT dierent timerames: 1, 3 and 5 years postsurgical resectio[48]. This study included patients with stage IBIIIA (n = 56

N2 = 122 patients only); 281 patients received preoperati

Table 2. Phase II clinical trials o gemcitabine in combination with cisplatin as induction treatment orstage IIIAIIIB non-small-cell lung cancer.

Treatment Patients(n)

Response (%) Complete resection posteriorradiation (%)

MS (months) and1-year survival rate

Ref

G 1000 mg/m2 on days 1, 8 and 15C 100 mg/m2 on day 2

Every 28 days x 3 cycles

53* ORR = 70.2PR = 56

CR = 6

7253 mediastinal lymph nodes ree

o tumor

MS = 18.969%

[3

G 1250 mg/m2 on days 1 and 8

C 70 mg/m2 on day 2


47*

23ORR* = 68

CR* = 6

OR = 35

CR = 0

40 (33*, 7)

Tumor-downstaging rate: 20%

68

MS = 14.5

67%

[3


C 70 mg/m2 on day 8


14*

29ORR* = 78

CR* = 0

ORR = 52

CR= 8

81#

72NR [4

*Stage IIIA with biopsy proo o N2 disease.Stage IIIB with biopsy proo o N2 disease.Received sequential radiation.17 patients randomized to surgery.#16 patients eligible or surgery beore induction.C: Cisplatin; CR: Complete response; G: Gemcitabine; MS: Median survival; NR: Not reported; ORR: Overall response rate; PR: Partial response.


6/18



CT, while 283 underwent surgery. The combined HRs at 1, 3and 5 years a ter surgery were 0.65, 0.83 and 0.85, respectively(preoperative CT compared with surgery alone). A signicantsurvival benet o induction (preoperative) CT was seen inNSCLC patients at 1 and 3 years postsurgery. However, thecombined survival dierence at 5-year postresection was notstatistically signicant. The authors concluded that the beneto preoperative CT or patients with NSCLC is unclear, espe-cially or N2 patients where the analysis did not detect anybenet [48]. We need to consider that the number o patientswith N2 was too small in this study. In addition, the study hadconsiderable heterogeneity between the ve studies selected,

such as the percentage o squamous cell carcinomas in eachstudy (range: 22.274.1%), the percentage o men in each study(range: 44.498.3%) and the therapeutic regimens used amongthe studies.

Platinum-based triplets as neoadjuvant

Phase II clinical trials with three-drug combinations have beenconducted in N2 NSCLC (Table 4). The rationale or these trialsis to improve response rate, leading to a better complete resectionrate, with the goal o improving survival. Two Italian trials haveevaluated the activity o the triplet cisplatin/paclitaxel/gemcit-abine. Inclusion criteria were dierent, as one trial included only

N2 NSCLC and the other include both stage IIIA and IIIB [49,50].In general, both trials had similar ORR and median survival.A better complete pathological response to induction chemo-therapy o 23% was observed in the trial that only includedN2 disease. The toxicity o this schedule was mild and mainlyhematological (grade III/IV neutropenia reported in almost 30%o patients in both studies).

Recently, the Spanish Lung Cancer Group clinical trial 9901reported the long-term survival data associated with completeresection [51]. Participants were N2 disease and selected stage IIIB(T4, N0-1) NSCLC patients. The triplet consisted o cisplatin/docetaxel/gemcitabine. The median OS and 3- and 5-year sur-

vival rates were 15.9 months and 36.8 and 21.1%, respectively.

There were no signicant dierences in surviva l between N2 andIIIB patients. Completely resected N2 and IIIB patients (68.9%o those eligible or surgery) had an impressive median surviva ltime o 48.5 months, with a 5-year survival rate o 41.4% [51].For completely resected stage IIIB patients, median survivaltime was 60.6 months and the 5-year survival rate was 53.2%.In the absence o mediastinal lymph nodes, median survivaltime or these patients was not reached and 5-year survival ratewas 57%. Neutropenia was the predominant hematologic toxic-ity. Grade III or IV neutropenia was observed in 62.5% o thepatients and 35.8% o the cycles; however, only nine patients(6%) had ebrile neutropenia [51].

The Radiation Therapy Oncology Group (RTOG) 8901trial, a Phase III randomized trial, was designed to show theequivalency o CT plus RT compared with CT plus surgeryin patients with N2 NSCLC [52]. All patients received con-solidation CT ater completion o arm 1 and arm 2. In thistrial, T1T3 and N2 NSCLC patients were enrolled between1990 and 1994 by RTOG and ECOG. Documentation o N2disease was done by mediastinoscopy or anterior mediastino-tomy. In total, 73 out o 75 patients enrolled were evaluable.Preoperative CT consisted o cisplatin, vinblastine and mito-mycin C. The latter was dropped rom induction regimen dueto toxicity. Patients were then randomized to surgery or RT

(64 Gy in 7 weeks) ollowed by cisplatin and vinblastine (orboth arms) [52]. In total, 12 patients who received preoperativeCT were not randomized to surgery or RT thereater. A totalo 45 patients were randomized to RT (postinduction chemo-therapy) or surgery. A total o 54% o evaluable patients hadbulky N2 disease. The distribution o bulky N2 disease wasuniorm among the treatment arms. The incidence o grade IVtoxicity was 56% in patients receiving mitomycin C and 29%in those who did not, and long-term toxicity was equivalentacross the arms. Three treatment-related mortalities (TRMs)occurred: two patients in the surgical arm (one late pulmonarytoxicity and one pulmonary embolus) and one patient in the

RT arm (radiation pneumonitis) [52]. Induction or neoadjuvant

Table 3. Phase II clinical trials o taxanes combined with platinum agents as induction treatment orstage IIIA non-small-cell lung cancer.

Treatment Patients

(n)

Response (%) Complete resection/posterior

therapy (%)

MS/EFS (months) and

13-year survival rate

Ref.

T 85 mg/m2 on day 1C 4050 mg/m2 on days 1 and 2

Every 21 days 3 cycles

90* ORR = 66CR = 8

PR = 58

7567

19 pCR

31 mediastinal LNs ree o tumor

36

MS = 35EFS = 15

3-year:36%

[42]

P 200 mg/m2 on day 1

Cb (AUC = 6) on day 1


52 ORR = 64

CR = 2

PR = 61

15

80%

17% mediastinal LNs ree o tumor

20.5

1-year: 68.5%

[43]

*Stage IIIA with biopsy proo o N2 potentially respectable.Underwent surgical excision o primary tumor.Received sequential radiation.Stage IIIA with biopsy proo o N2 judged as irresectable.C: Cisplatin; Cb: Carboplatin; CR: Complete response; EFS: Event-ree survival; LN: Lymph node; MS: Median survival; NR: Not reported; ORR: Overall response rate;P: Paclitaxel; pCR: Complete pathological response; PR: Partial response; T: Docetaxel.


7/18



CT was completed in 78% o the patients. Complete resectionwas perormed in 73% o 26 patients who underwent surgery.Consolidation CT was completed in 75% o the patients. Nostatistically signicant dierence was ound among the treat-ment arms. The overall PFS rate was 53 and 17% at 1 and 3years, respectively. The median PFS was 14 months. No dier-

ence in the 1-year survival rate (70 vs 66%) or median survivaltime (19.4 vs 17.4 months) between the surgery and RT armswas observed [52]. The median survival in the patients receivinginduction CT only was 8.9 months. No statistically signicantdierence was noted in the time to local ailure between thesurgical and RT arms. Unortunately, the patient accrual to thistrial was poor due to a large Phase II trial, which demonstratedthe easibility o preoperative concurrent CT/RT in N2 NSCLCand led to the initiation o the US Intergroup 0139 study wherepatients received neoadjuvant combined modality (CT/RT)and were then randomized to either surgery or consolidationRT (up to 61 Gy). Thus, the results o RTOG 8901 were non-

conclusive. Nonetheless, important observations were drawnrom this study: N2 histological conrmation in both armseliminated biases and local control, and survival was essentiallyequal between the surgical and RT arms.

Role of combined modality (chemoradiation) as

neoadjuvant therapy

This modality is more appropriate to patients whose tumor bur-den will preclude a survival advantage ater initial resection oror whom surgery is not technically easible at the beginning.To date, the current standard o treatment is concurrent CT/RTalone. Nonetheless, we recognized that this group has a high

rate o locoregional and systemic ailures with this standard

approach. Thus, it is hypothesized that by resecting residudisease postinduction therapy, a number o these patients mattain a better disease-ree survival. RT does not have any roin the preoperative setting as single modality since it does nimprove survival [53].

The role o neoadjuvant CT/RT in stage III NSCLC w

initially examined in the SWOG 8805 trial [54,55]. One o tworthy pieces o inormation ound in this study was that nodstatus at the time o surgery was the best predictor o OS. Thopatients who had N2 or N3 disease prior to concurrent CT/Rand became pathologically negative in the mediastinum had improved survival over those who remained with microscopdisease. Another important nding was a lack o correlatiobetween radiological response with survival and pathologicresponse. This study became the platorm or uture trials locally advanced NSCLC.

In 2005, the North American Intergroup updated results rothe INT 0139 trial, with a longer ollow-up (2.5 years p

patient) [56]. This is the largest Phase III tria l that prospectiveaddresses this question. In this trial, NSCLC patients who hPS 01 and T13, pN2 and M0 were randomized providinresection was technically easible. All patients received cisplatat 50 mg/m2 on days 1, 8, 29 and 36 and etoposide at 50 mg/mon days 15 and days 2933 plus RT to 45 Gy starting oday 1. With regards to randomization, arm 1 (202 patienthad resection ino progression ollowed by consolidation C(cisplatin/etoposide) or two cycles and arm 2 (194 patientcompleted consolidation RT (to 61 Gy) ollowed by CT (cplatin/etoposide) or two cycles [56]. TRM was 7.9 and 2.1on arms 1 and 2, respectively. There were 16 deaths on th

surgical arm: ten o them occurred within 30 days o surger

Table 4. Neoadjuvant Phase II clinical trials o platinum-based triplet regimens.

Treatment Patients(n)

Response (%) Complete resection rateposterior treatment

MS/EFS (months)15-year survival rate

Re


P 125 mg/m2

on days 1 and 8C 50 mg/m2 on days 1 and 8


49* ORR = 73

PR = 71CR = 2

27 100%

63%: LNs ree o tumor26%: pCR

51%

MS: 23

1 year: 85%

[5


P 125 mg/m2 on days 1 and 8

C 50 mg/m2 on days 1 and 8


26*

16ORR = 71

PR = 69

CR = 2

21

76%

7%: pCR

MS: 21.7

EFS: 17.4

1 year: 92%

[4


T 20 mg/m2 on days 1, 8 and 15

C 75 mg/m2 on day 1


69*

67ORR = 56

PR = 54

CR = 2

90

24%*

20%*

10% LNs ree o tumor

8% pCR

13%#

23%

MS: 15.7 months

EFS: 9.9 months

1 year: 62%

3 year: 36%

5 year: 21%

[5

*Stage IIIA with biopsy proo o N2 potentially respectable.Underwent surgical excision o primary tumor.Received sequential radiation.Stage IIIB.#Received adjuvant chemotherapy.C: Cisplatin; CR: Complete response; EFS: Event-ree survival; G: Gemcitabine; LN: Lymph nodes; MS: Median survival; NR: Not reported; ORR: Overall response rate;P: Paclitaxel; pCR: Complete pathological response; PR: Partial response; T: Docetaxel.


8/18



and nine o these ten deaths were in patients who underwentpneumonectomy. Arm 1 (n = 164): pathology showed 29 (18%)patients had T0N0 and 76 (46%) achieved TanyN0. The PFSo arm1 was superior (median 12.8 vs 10.5 months; p= 0.017;HR: 0.77). Although more patients survived without PD in

arm 1 (p = 0.008), more died without PD also (p = 0.021).OScurves overlap or 2 years but separate late, avoring arm 1(median OS: 23.6 vs 22.2 months; p = 0.24; HR: 0.87; 5-yearOS: 27.2vs 20.3%; p = 0.10).Interestingly, the 5-year OS inarm 1 or those who achieved pN0 at surgery was 41%, pN13:24% and no surgery: 8% (p < 0.0001) [56]. Thus, this longerollow-up conrmed that PFS was improved when surgery ol-lows concurrent CT/RT in pN2 NSCLC patients. In terms oOS, there was a trend in avor o a trimodality approach. Otherrelevant conclusions were that pathologically N0 disease at sur-gery predicts better survival and, perhaps, i pneumonectomy isneeded, then this trimodality approach will not be optimal due

to a high mortality rate seen in those patients[56]

.Based on the results o the INT 0139 trial, SWOG andRTOG opened a clinical trial which was planned to evalu-ate the survival benet o concurrent CT/RT (using cisplatin/docetaxel combination) prior to surgical resection versus pre-operative CT (cisplatin/docetaxel) alone or avorable progno-sis N2 NSCLC patients [102]. Both arms were also planned toreceive consolidation docetaxel postsurgery. In this randomizedstudy, 574 patients were planned to be enrolled. Unortunately,in December 2006, this trial was closed due to not meetingits accrual goals. An ongoing Phase II trial conducted by theKorean National Cancer Institute (NCI) is evaluating this con-cept only in patients who have biopsy-proven N2 disease [103].

All patients will also receive consolidation CT. Arm 1 (pre-operative chemotherapy) consists o paclitaxel (90 mg/m 2) andcisplatin (40 mg/m2), both administered on days 1 and 8 every3 weeks or two cycles; arm 2 (preoperative CT/RT) consistso paclitaxel (50 mg/m2) and cisplatin (20 mg/m2) both givenon days 1, 8, 15, 22 and 29 plus RT at 1.8 Gy daily (ve times/week) or 5 weeks (45 Gy target dose). The postoperative con-solidation CT will consist o paclitaxel (90 mg/m2) and cispla-tin (40 mg/m2) on days 1 and 8 every 3 weeks or two cycles.Results on this trial are eagerly awaited [103].

In the 2008 ASCO meeting, Bonnet et al. presented two di-erent induction modalities [57]. Arm 1 consisted o induction

CT ollowed by concurrent CT/RT, and arm B was completelythe opposite sequential (concurrent CT/RT ollowed by induc-tion CT). Both arms had the same dosing; arm 1: paclitaxel at225 mg/m2 and carboplatin AUC 6 on day 1 (two to three cycles)ollowed by hyperractionated RT at 1.5 Gy two-times per day(total 45 Gy) with concurrent paclitaxel at 50 mg/m2 and carbo-platin AUC 2 on days 1, 8 and 15. Arm 2 consisted o hyper-rac-tionated RT concurrent with carboplatin/paclitaxel, ollowed bysame CT regimen [57]. In this study, all patients had biopsy-provenstage III and PET (prerandomization and at restaging). A total o210 patients were randomized and 207 were evaluable. Both armswere well balanced. Median ollow-up was 35 months. The eature

distribution between arms 1 and 2 was 106 versus 104 patients;

N2: 34 versus 39%; stage IIIB 64 versus 60%; primary technicaloperability 24 versus 23%; perormance status (PS) 0: 19 versus18% and PS 1: 29 versus 29%. The median OS (primary endpoint) was 543 versus 550 days (p = 0.73) and median PFS was326 versus 343 days (p = 0.86). Grade III and IV nonhematologic

toxicities were not signicantly dierent between treatment arms.There were no dierences in N2 in terms o median OS and PFSin both arms, however, a trend avored arm 2. The authors con-cluded that this multimodal induction approach does not aectOS and PFS in stage III NSCLC [57]. In a Phase II trial, Masset al. reported at the 2008 ASCO annual meeting a combinationo cisplatin/docetaxel concurrently with involved-eld thoracicRT (IFRT) ollowed by surgery or patients with stage IIIA/BNSCLC [58]. The primary end point was radiologic response toconcurrent CT/RT. Secondary end points included toxicity, e-cacy o surgery, postoperative morbidity and mortality, time toprogression and OS [58]. In total, 42 out o 45 enrolled patients

were evaluable. Patients received both cisplatin and docetaxel at20 mg/m2 on days 1, 8, 15, 22, 29 and 36 plus RT once-dailyractions at 1.8 Gy (ve ractions/week to a total dose o 45 Gyduring days 836). Restaging consisted o noninvasive test, andthose who achieved mediastinal downstaging underwent surgicalresection to achieve radical resection. The median ollow-up timewas 26.2 months (95% CI: 24.627.7). N2 disease was present in25 patients, and 17 patients had N2 (cT4N2 = 10; cT4N0/N1 = 4and cN3 = 3). A radiologic response was seen in 20 patients (48%)and eight (19%) showed PD. Toxicity was mild. A total o 20out o 23 operated patients (48%) underwent a radical resectionwithout residual mediastinal malignant disease and ten pneumo-nectomies were perormed [58]. For those who underwent surgical

resection, the mean survival time was 20.3 versus 16 months orthose without operation (p= 0.068). The 30-day mortality waslow (4%). However, 21 out o 42 patients showed progressionand 16 o these developed distant metastasis. Weekly cisplatin/docetaxel concurrent with IFRT has limited toxicity and inducesa good radiological response, and almost hal o the patients wereable to undergo radical surgical resection [58].

In another Phase II trial, de Santis et al. evalu-ated sequential induction with a chemotherapy triplet(cisplatin/docetaxel/gemcitabine) ollowed by concurrentCT/RT, and then surgical resection or stage III NSCLC [59].Chemonaive patients who had N2 and IIIB (T4, N1-N2 only)

NSCLC were eligible. In total, 43 enrolled patients receivedcisplatin at 35 mg/m2, docetaxel at 30 mg/m2 and gemcitabine1000 mg/m2 on days 1 and 8 every 21 days or up to two cyclesollowed by concurrent CT/RT: or N2 nonbulky, cisplatin at50 mg/m2 on days 1 and 8 every 21 days or two cycles, anddocetaxel 20 mg/m2/week 5; or N2 bulky and IIIB, the regi-men consisted o cisplatin at 50 mg/m2 on days 1 and 8, andetoposide 50 mg/m2 on day 15 every 28 days or two cycles.At restaging, i a patient had resectable disease (by 45 Gy on Tand N elds), they underwent surgical resection. Otherwise, thepatient completed RT (uninterrupted) to 61.2 Gy. The patientsdistributions were N2 nonbulky: 6; N2 bulky: 14 and IIIB:

23 [59]. A total o 25 out o 42 evaluable patients (60%) had


9/18



an objective response ater induction. A total o 19 respondingpatients underwent radical surgery (N2: 10 and stage IIIB: 9).Interestingly, pathologic CR (pCR) rate in the mediastinal lymphnodes was 58%. In total, 14 patients (33%) were not resectableand received the ull RT dose. Seven patients progressed during

induction. The study concluded that this induction modality isactive and well tolerated. The study needs to mature to reportPFS and median survival time [59].

An ongoing Phase II clinical tria l conducted by Wakelee et al.is investigating the combination o carboplatin/docetaxel withRT ollowed by surgery in locally advanced (stage III A/B)NSCLC patients. The study is also looking at how PET scanscan assesses response to CT/RT and GEP patterns related topatient outcomes [104].

Responders after postinduction therapy: do they really

need surgery?

A large Phase III randomized multicenter trial (EORTC 08941)conducted by van Meerbeecket al. concluded that surgical resec-tion ater response to induction CT in selected N2 patients didnot improve OS or PFS compared with RT alone [18]. This studyadds more controversy to the management o this specic group.Herein, 579 patients who had histologic- or cytologic-provenN2 and were considered to be unresectable were eligible or theanalysis. They received three cycles o platinum-based inductionCT. Responders were subsequently randomized to either surgeryor RT. There was a 61% response rate to induction CT; aterrandomization, 154 patients were entered into each arm (surgicalresection and RT) [18]. Postoperative RT was given to 62 (40%)patients. Median and 5-year OS or patients randomly assigned

to surgery and RT were 16.4 versus 17.5 months and 15.7 versus14%, respectively (HR: 1.06; 95% CI: 0.841.35). The impor-tance o this study lies on a clear-cut patient selection (only N2

disease) and then, only responders were randomized, making robust data. Furthermore, the results o this trial also contradiroutine practices seen in some centers, where induction CT olowed by surgery is based on some trials suggesting that surgealone (or this specic group, IIIAN2) is inerior to a bimodali

approach [25,26,28] . Another interesting aspect on this trial was thpersistent mediastinal involvement ater induction CT may prclude any benet rom surgical approach, and corroborated resuhave been seen in other studies [44,60]. Hence, whether patienwho reach a clearance in the mediastinum should be oered sugery is an unanswered question that will require a powered stuto randomize these patients into RT alone versus surgery. Thconcept is being considered by the EORTC-LCG group.

In conclusion, the question o what is the best inductioapproach or N2 disease continues to be debated.

Postoperative phase

Adjuvant chemotherapy for N2 NSCLC

Adjuvant CT has been shown to improve survival in a wivariety o cancers, particularly in breast, colon and in othtumor types. But what benet does adjuvant CT provide in luncancer? Unortunately, the therapeutic ecacy o adjuvant Cor early-stage NSCLC has been less clear. Four trials o adjuvaCT in NSCLC have shown improved survival: Internation Adjuvant Lung Cancer Trial Collaborative Group (IALTthe North American Intergroup Study JBR.10 (led by thNational Cancer Institute o Canada), the Adjuvant NavelbiInternational Trialist Association (ANITA) study and thJapan Lung Cancer Research Group on Postsurgical AdjuvaChemotherapy(Table 5) [2023]. It is important to note, howeve

that neither JBR.10 nor the Japan Lung Cancer Research Groustudy included N2 patients among their patient populationthus, we will limit our comments on these studies.

Table 5. Selected studies in adjuvant therapy or non-small-cell lung cancer.

Study n Gender Stage IIIA Chemotherapy regimen Pneumonectomy(%)

Radiotherapy(%)

Re

Male (%) Female (%)

ALPI 1088 937 (86) 151 (14) 310 (28) Mitomycin C (8 mg/m2 day 1),

Vindesine (3 mg/m2 on days 1 and

8) and cisplatin

(100 mg/m2 on day 1) or 3 cycles

274 (25) 470 (43) [6

IALT 1867 1502 (80) 365 (20) 549 (29) Cisplatin-based combinations

(cisplatin 80120 mg/m2)

combined with vindesine,

vinblastine, vinorelbine

or etoposide

648 (35) 572 (31) [2

BIG 381 261 (69) 120 (31) 133 (35) Cisplatin-based combination

(MIC, MVP, CV and NC)

or 3 cycles

NR 52 (14) [6

ANITA 840 721 (86) 115 (14) 325 (39) Vinorelbine 30 mg/m2/week,

16 administrations, plus cisplatin

100mg/m2 every 4 weeks or

4 cycles

310 (37) 201 (24) [2

CV: Cisplatin plus vindesine; MIC: Mitomycin Ciosamidecisplatin; MVP: Mitomycin Cvindesinecisplatin; NC: Vinorelbinecisplatin.


10/18



In NSCLC, survival ater resection is most closely relatedto the pathologic stage o the disease. At 5-years, N2 NSCLChas a survival rate o 1923% [17,6164]. The initial interest oradjuvant CT in NSCLC began in the 1960s, with the study oalkylating agents and cisplatin. However, this treatment era was

fooded by the lack o support to address the cytotoxic eectsderived rom CT. Furthermore, these studies oten compriseda heterogeneous patient population as well as a limited samplesize. Nonetheless, or that reason, the Non-Small-Cell LungCancer Collaborative Group conducted a meta-analysis to bet-ter assess the eect o conventional CT on survival in patientswith NSCLC [65]. This meta-analysis collected updated datarom 9387 patients included in 52 randomized clinical trials;it suggested that cisplatin-based adjuvant CT could yield anabsolute OS advantage at 5 years; specically, cisplatin-basedCT ater surgery or stage IIII NSCLC had a 13% reductionin the risk o death and an absolute improvement in survival o

5% at 5 years compared with those treated with surgery a lone.This led to the planning and execution, by several cooperativegroups, o randomized, prospective clinical trials in order tovalidate these results.

The Adjuvant Lung Project Italy (ALPI) trial was the rstlarge randomized controlled trial o platinum-based adjuvantCT to be published [66]. Over 1200 patients with stages IIIIAwere randomized to receive three postoperative CT cycles usinga triplet regimen: mytomycin C at 8 mg/m 2 on day 1, vindesine3 mg/m2 on days 1 and 8, and cisplatin at 100 mg/m2 on day 1every 3 weeks (MVP regimen) and no CT (Table 5). PostoperativeRT was permitted and 43% o the patients in each arm receivedit. In total, 27% o the patients in this study had N2 disease

(120 patients in the MVP arm and 111 patients in the controlarm). This prospective randomized trial ai led to conrm a sta-tistically signicant role or adjuvant CT in completely resectedNSCLC [66]. There was signicant toxicity derived rom thetriplet regimen as well as patient compliance. Only 9% o thepatients assigned to receive CT never began therapy, primarilydue to consent withdrawal [66].

The Big Lung Trial (BLT) was a multicenter trial led by theBritish Medical Research Council [67]. In this trial, surgery (withor without RT) alone (arm A) was compared with surgery (with orwithout RT) plus chemotherapy (arm B). A total o 381 patientswere randomized to arm A (n = 189) and B (n = 192), respectively

(Table5). There were three variations in the CT regimens used: three3-weekly cycles o either

Mitomycin C/vinblastine/cisplatin (MVbP)

Mitomycin/iosamide/cisplatin (MIC)

Cisplatin/vinorelbine or cisplatin/vindesine

The chemotherapy regimen distribution was as ollow: 42%o the patients received the MVbP regimen, 33% received theMIC regimen, 22% received the cisplatin/vinorelbine regimenand 3% received the cisplatin/vindesine regimen. A minority(14%) o patients received RT. There were six treatment-related

deaths and there was no survival benet observed with the use

o adjuvant CT [67]. The small sample size and heterogeneity opatients included somewhat limited the conclusions that could bedrawn rom this study. With regard to N2, there were 99 patientsincluded in the study with this particular stage (47 patients inarm A and 52 in arm B) [67].

One o the most important studies assessing adjuvant CT inpatients with NSCLC was the IALT study[20]. This was a largeinternational study in which patients were recruited rom 148centers around the world, comparing the e ect o adjuvant CT(cisplatin-based doublet) versus no CT in patients with com-pletely resected stage IIII NSCLC. The therapeutic agentscombined with cisplatin were etoposide, vinorelbine, vinblast-ine and vindesine. The number o cycles or cisplatin were threeor our and the dosing range was 80120 mg/m2. The totalnumber o randomized patients on the study was 1867, makingit the largest single study evaluating adjuvant CT in NSCLC [20].The patients assigned to CT had a signicantly higher survival

rate than those assigned to observation (HR: 0.86; p < 0.03). Atotal o 734 patients (39%) had stage III disease and a subsetanalysis suggested that these were the patients with the greatestimprovement in OS. From the 549 patients who had N2 disease,274 received CT and 275 were randomized to the control arm[20]. Finally, the ANITA trial was an open-label, randomizedmulticenter controlled study that also evaluated whether adjuvantCT using the cisplatin/vinorelbine combination was superior toobservation in patients with completely resected stage IIIIANSCLC [22]. This tria l included 840 patients rom 101 centers in14 countries. Patients assigned to the CT arm received cisplatinat 100 mg/m2 and vinorelbine at 30 mg/m2. Postoperative RTwas not mandatory and was given depending on the centers

preerence. The primary end point was OS [22]. In the ANITAtrial, 325 patients (39%) had N2 NSCLC. The ANITA trialconrmed the benet shown in the NCI o Canada JBR.10 studyor stage II disease and provided new data or patients with N2disease [21,23]. The trial also showed important data that werepreviously suggested in the Postoperative Radiation Therapy(PORT) meta-analysis: postoperative RT appeared to have anadverse eect on OS. Recently, the Lung Adjuvant CisplatinEvaluation (LACE) Collaborative Group published the resultso a meta-analysis that included ve large trials [2022,66,67] con-ducted ater 1995 and where cisplatin-based CT was used asadjuvant therapy[68]. A total o 4584 patients were included in

the meta-analysis. The overall HR o death was 0.89 (95% CI:0.820.96; p = 0.005) at a median ollow-up o 5.2 years. ThisHR corresponds to a 5-year absolute benet o 5.4% rom CT.The benet was superior or stage II and III (HR: 0.83; 95% CI:0.730.95 and HR: 0.83; 95% CI: 0.720.94, respectively).Importantly, the eect o CT did not vary signicantly with thecombined drugs, such as vinorelbine, etoposide or vinca alkaloid.The meta-analysis concluded that cisplatin-based CT signi-cantly improves survival in patients with NSCLC [68]. In sum-mary, no single randomized prospective study has been designedto include only N2 disease and address adjuvant CT and/orconcurrent modality benet in this heterogeneous group. Data

are derived rom large studies and subset analyses. Given the


11/18



heterogeneity o this population, adjuvant CT remains challeng-ing. Another conounding actor is the ample variation in CTregimens used previously and, perhaps, this may play a key role inthe lack o benet seen in some o these studies [66,69]. However,there is cumulative evidence avoring the cisplatin-based doublet

as the preerred adjuvant CT or resected NSCLC patients.

Radiation therapy as adjuvant treatment for NSCLC

The question i there is a role or RT in stage III NSCLC patientswho had undergone surgery has been controversial or long time.In act, beore the CALGB 8433 trial, high-dose RT was thestandard o care or locally or regionally advanced NSCLCpatients, albeit with a 5-year surviva l o only 310% ater suchtherapy. The data are not clear because the question o adju-vant RT has been addressed encompassing in a single group oearly-stage NSCLC patients (stages I, II and IIIA), causing moreconusion when the data are presented or the group as a whole.

It is well-known that patients who have earlier stage (I or II)NSCLC have a much better prognosis than those with a moreadvanced disease (IIIA), and proving the benet o adjuvantstrategies is much harder.

One o the oldest studies that discussed the option o adju-vant RT was rom the Lung Cancer Study Group (LCSG). Theydesigned the second in a series o adjuvant trials (LCSG 791) orpatients who had an incomplete resection o their primary tumor[70]. A total o 172 patients with locally advanced disease (positivemargins or positive highest mediastinal node sampled) were ran-domized to either RT alone or in combination with CT (cisplatin,doxorubicin and cyclophosphamide). The combined CT andRT arm had a signicantly longer recurrence-ree survival and a

decrease in the incidence o distant metastases [70].Although the above trial showed an advantage to combine

CT and RT ollowing resection, two other subsequent largetrials ailed to show the same results. In a French CooperativeGroup trial, 267 patients (most o them stage III) were randomlyassigned to RT (60 Gy over 6 weeks) or three cycles o adjuvantCT (cyclophosphamide, doxorubicin, cisplatin, vincristine andlomustine) ollowed by a similar RT protocol [71]. This studyailed to demonstrate any dierence in terms o DFS or OS. Therisk o distant metastases was lower in the group that receivedCT, but there was no dierence in the local relapse rates, makingthe role o RT more controversial.

In a similar trial, ECOG randomly assigned 488 patientswith completely resected stage II or IIIA NSCLC to RT alone(50.4 Gy) or our cycles o cisplatin/etoposide in addition tothe same dose o RT [72]. This study also ound no dierencein the median survival or rate o local recurrence. Furthermore,the concurrent modality arm has an increased incidence andseverity o adverse events compared with the RT-alone arm [72].Based on the results o these randomized studies, adjuvant com-bined modality (CT/RT) was not recommended outside o aclinical trial.

To date, the most important published meta-ana lysis wasthe PORT trial, which reviewed data on individual patients

rom all available randomized trials on postoperative RT versus

surgery alone [73]. Data on 2128 patients, rom nine randomized trials, both published and unpublished, were analyzed bintention-to-treat. There were 707 deaths among 1056 patienassigned to postoperative RT and 661 among 1072 assigned surgery alone. Median ollow-up was 3.9 years or survivin

patients. The results showed a signicant adverse eect o posoperative RT on survival (HR: 1.21; 95% CI: 1.081.34). Th21% relative increase in the risk o death is equivalent to aabsolute detriment o 7% (311) at 2 years, reducing OS ro55 to 48% [73]. A subgroup analysis o this study suggested ththe adverse eect o postoperative RT was greatest or patienwith stage I/II, N0 and N1 disease. Thereore, postoperatiRT was thought to be detrimental to patients with early-stacompletely resected NSCLC and should not be used routineor such patients. Nonetheless, the study did not address throle o postoperative RT in the treatment o N2 tumors anhence, this setting may warrant urther research. Moreove

the PORT meta-analysis was criticized because it had somproblems. First, the PORT researchers state that they exhaustivesearched or all published and unpublished data. Nonetheless,twrandomized trialswere excluded rom their meta-analysis [74,7interestingly, neither o these excluded trials showed evideno a detrimental survival eect o PORT and they actualsuggesteda trend toward a benet or node-positive patientAnother important problem was the large number o patien(~26% o the entire sample) who underwent resection (winegative margins) andwere ound to have negative regionlymph nodes (stage I disease). There did not appear to be, there is not now, any scienticbasis or PORT in these patienas they are known to have a low risk o loca lregional recurren

compared with patients with positive mediastinal nodes (Ndisease) who have a high risk o locoregional recurrence anare more likely to benet rom PORT [7680]. A third problerom this meta-analysis was the act that old radiation sourc(cobalt-60) and outdated radiation elds (lateral elds) weused,both o which would be expected to increase the radition exposureto normal lung tissue and, hence, cause complications. Cobalt-60 irradiation used in many (i not moso the patients in the PORT meta-ana lysishas been shown have unacceptable complications ater pneumonectomy, ansome trials used a large daily radiation raction size or higtotal radiation doses,which are known to increase the risks

complications [8183].Recently, the ANITA trial showed that the addition o C

ollowing complete resection o stage IBIIA NSCLC improvOS by 8.6% at 5 years [22]. In this study, the use o PORT lymph node-positive disease was not randomized or requirebut each institution had to decide on an individual poliregarding PORT and adhere to this policy beore initiatioo the trial. Radiation doses ranged rom 45 to 60 Gy in 2-Gractions, all delivered using high-energy linear acceleratorSince postoperative RT was not randomized, only a descritive analysis was perormed. Patients with N2 disease in thobservation arm who received postoperative RT had a bett

5-year survival: (21% PORT vs 17% no RT). Patients with N


12/18



disease in the CT arm who had PORT also had a better 5-yearsurvival (47% PORT vs 34% no RT) [22]. Being a retrospectiveana lysis, these dierences do not carry statistical signicance,but are provocative observations.

Expert commentaryThe management o clinical N2 poses a challenge today dueto novel therapeutic agents with a better toxicity prole, bet-ter RT-delivery methods and extensive data with provocativeand controversial results rom our clinical tria ls. The latter issuecauses diculty in interpreting trial results that do not subdividepatients appropriately. Thus, what is better: to oer neoadjuvanttherapy (single or combined modality) ollowed by surgery orpostoperative (adjuvant) CT? To date, we have not reached a nalanswer. We have meta-analyses, subanalyses and provocativeobservations that served as the platorm or the new generation oclinical trials. A new lung cancer staging classication has been

proposed (IASLC Lung Cancer Staging Project) and, i accepted,it means that we will be more aggressive in the management othis disease, and exhaust al l possibilities to consider a patient apotential surgical candidate.

To answer the question o what is better, neoadjuvant or adju-vant CT in NSCLC, perhaps we will need to wait or the nalresults o the NATCH trial initially presented at the World LungCancer Congress in Seoul, Korea [84]. This three-arm trial willaddress the question o whether DFS is improved with the useo neoadjuvant or adjuvant CT compared with surgery alone inearly-stage NSCLC. Unortunately, this trial does not includeN2 disease, only clinical stages I (> 2 cm), II and T3N1. Patientsare randomized to surgery a lone or three cycles o neoadjuvant

carboplatin/paclitaxel or surgery ollowed by three cycles oadjuvant carboplatin/paclitaxel (at the same schedule). Thisprospective, randomized trial planned to include 624 patientsand mature survival data are expected in 2009.

Is single modality superior to combined modality or N2?To date, the ACCP does not recommend the use o combinedmodality (or downstaging) outside the context o clinical trials[19]. Although this approach has shown clinical ecacy, there isconcern in terms o toxicity and long-term results, and we stil ldo not know what is the best CT combination and RT dosingand schedule. The vast majority o the data avored neoadju-vant CT (at least three cycles) rather than combined modality

[30,32,85] . When CT has been used as a single modality, the rateo progression was low or those who underwent neoadjuvanttreatment and surgical results were also comparable to thoserandomized to surgery alone [32,85]. A caveat on these stud-ies [30,32] is that they did not include N2 disease (stage IIIAwas dened as T3N1). A systematic review that included sevenclinical trials comparing preoperative CT ollowed by surgeryversus surgery alone avored the neoadjuvant arm (HR: 0.82)[86]. When the EORTC 08012 was added to this population,the HR still avored neoadjuvant CT but to a lesser extent (HR:0.88) [85]. In terms o preoperative concurrent CT/RT, a sub-ana lysis rom the INT 0139 suggested that, i pneumonectomy

is planned ahead, perhaps this approach (trimodality) is not

recommended due to the high mortality rate seen in this group;hence, the importance o a multidisciplinary approach amongthe treating physicians.

Presently, we consider there to be enough data to avoid theuse o postoperative RT in patients with pathologic early-

stage NSCLC. These patients are well served with cisplatin-based doublet adjuvant CT. As mentioned previously, we lackstrong evidence or pN2 disease. However, a subset analysis romthe ANITA trial showed that sequential adjuvant CT ollowedby RT results in a better outcome or these subjects [22]. Thus,in this regard, we consider that the use o RT in this setting willbe at the discretion o the treating physician.

The trimodality option studied in the INT 0139 trial needslonger ollow-up to analyze the morbidity and mortality, espe-cially when a pneumonectomy is perormed. A concern or thetrimodality approach is that those patients who are not candi-date or surgical resection ater induction will ace a subopti-

mal treatment since RT is restarted ater several weeks takenor restaging or possible surgery. This gap in the treatmentdelivery is associated with poor outcomes [87,88]. Thus, thisapproach is better served in a multidisciplinary approach anda case-by-case basis.

Five-year view

Thus ar, the management o clinical and pathologic N2 diseaserepresents a challenge and debate in oncology. Several ongoingclinical trials will, in the near uture, dene the best combinationo conventional and/or targeted agents either as a single modalityor in combination with RT. We are waiting or the impact thattargeted agents may have in early-stage NSCLC. The positive

results ound in ECOG 4599 in the metastatic setting createdthe background to move this agent into the adjuvant setting [89].Such a study (ECOG 1505) is already ongoing or stage IBIIIANSCLC. The results o the NATCH trial are eagerly anticipatedand we hope that it will dene the role o neoadjuvant versusadjuvant treatment or NSCLC.

There are a lot o expectations o what changes may occur ithe lung cancer staging system is modied in the near uture.Several studies have shown that our current staging system doesnot discriminate sucient among lung cancer patients withinthe same stage [90,91]. N2 disease encompasses a large hetero-geneity, and it will be very important or uture trials to better

dene and measure this specic disease stage. Certainly, the useo PET, re-mediastinoscopy and endoscopic ultrasound will playa more important role in the restaging process o patients aterinduction treatments, and perhaps will replace the conventionalcomputed tomography or this purpose [92].

Many questions remain unanswered. Unortunately, the NorthAmerican Intergroup trial (S0332/RTOG 0412) was closedprematurely, and hence, has let us without an answer or thecontroversial IIIA (N2) disease in terms o best induction treat-ment: CT alone versus combined modality. Thus, the results oa Phase II trial conducted by the Korean NCI: (looking at thesame concept) are eagerly awaited or the signicant importance

that they have to better understand this disease [103].


13/18



Key issues

Treatment o stage IIIA non-small cell lung cancer remains controversial and it is better addressed ater a multidisciplinary group

(tumor board) gets together and decides the best therapy or each patient.

No single randomized prospective study has been designed to include only stage II IA (N2) disease and address neoadjuvant

chemotherapy versus concurrent modality in this heterogeneous group.

Adjuvant chemotherapy or stage IIIA is standard o care based on survival data rom our large randomized clinical trials; however,

more needs to be learn about what to do i the patient already got neoadjuvant chemotherapy beore (no need o adjuvant longer?

give adjuvant chemotherapy to complete a total o our cycles o chemotherapy?).

Radiation therapy is not considered standard therapy in the induction setting and it is recommended in the context o a clinical trial

or in some specifc situations where the Tumor Board considers that the amount o N2 disease justifes its use until more defnitive

evidence becomes available.

There is good clinical evidence that patients with stage IIIA (N2) with bulky disease are better served with concomitant modality

approach instead o surgery rom the beginning.Although defnitive conclusions cannot yet be drawn, several Phase II trials and some published randomized studies suggest that

induction chemotherapy ollowed by complete resection o primary tumor may improve the long-term survival rate.

Results rom two recent randomized clinical trials o induction chemotherapy, the S9900 and the French Thoracic Cooperative Grou

demonstrate an improvement in disease-ree survival avoring the chemotherapy group, but have ailed to improve overall survival.

Identifcation o predictive/prognostic actors to select patients who would derive the greatest beneft rom combined modality

therapy will help clariy the most appropriate clinical use o neoadjuvant chemotherapy, particularly or patients with

stage IIIA disease.

ReerencesPapers o special note have been highlighted as :

ofinterest

ofconsiderableinterest

Dillman RO, Herndon J, Seagren SL,1Easton WL Jr, Green MR. Improvedsurvival in stage III NSCLC: seven yearollow-up o CALGB 8433.J. Natl CancerInst. 88(17), 12101215 (1996).

Le Chevalier T, Arrigada R, Quoix E2 et al.Radiotherapy alone versus combinedchemotherapy and radiotherapy innon-resectable non-small cell lung cancer:rst analysis o a randomized trial o353 patients.J. Natl Cancer Inst. 83(6),417423 (1991).

Non-Small Cell Lung Cancer Collaborative3Group. Chemotherapy in non-small celllung cancer: a meta-analysis using updateddata on individual patients rom52 randomized clinical trials. Br. Med. J.311, 899909 (1995).

Olaussen KA, Dunant A, Fouret P4 et al.DNA repair by ERCC1 in non-small-celllung cancer and cisplatin-based adjuvantchemotherapy. N. Engl. J. Med. 355(10),983991 (2006).

Zheng Z, Chen T, Li X, Haura E, Sharma A,5Bepler G. DNA synthesis and repair genesRRM1 and ERCC1 in lung cancer. N. Engl.J. Med. 356(8), 800808 (2007).

Tsao MS, Aviel-Ronen S, Ding K6 et al.Prognostic and predictive importance op53 and RAS or adjuvant chemotherapyin non small-cell lung cancer.J. Clin.Oncol. 25(33), 52405247 (2007).

Potti A, Mukherjee S, Petersen R7 et al.A genomic strategy to rene prognosis inearly-stage non-small-cell lung cancer.N. Engl. J. Med. 355(6), 570580 (2006).

Inamura K, Fujiwara T, Hoshida Y8 et al.Two subclasses o lung squamous cellcarcinoma with dierent gene expressionproles and prognosis identied byhierarchical clustering and non-negativematrix actorization. Oncogene24(47),71057113 (2005).

Raponi M, Zhang Y, Yu J9 et al. Geneexpression signatures or predicting

prognosis o squamous cell andadenocarcinomas o the lung. Cancer Res.66(15), 74667472 (2006).

Beer DG, Kardia SL, Huang CC10 et al.Gene-expression proles predict survivalo patients with lung adenocarcinoma.Nat. Med. 8(8), 816824 (2002).

Bhattacharjee A, Richards WG, Staunton11J et al. Classication o human lungcarcinomas by mRNA expressionproling reveals distinct adenocarcinomasubclasses. Proc. Natl Acad. Sci. USA98(24), 1379013795 (2001).

Potti A, Dressman HK, Bild A12 et al.Genomic signatures to guide the use ochemotherapeutics. Nat. Med. 12(11),12941300 (2006).

Chen HY, Yu SL, Chen CH13 et al.

A ve-gene signature and clinical outcomin non-small cell lung cancer. N. Engl. J.Med. 356(1), 1120 (2007).

Tsao MS,C. Zhu, K. Ding, D14 et al.A 15-gene expression signature prognosticor survival and predictive or adjuvantchemotherapy benet in JBR.10 patients.Presented at: 44th Annual Meeting o theAmerican Society o Clinical Oncology.Chicago, IL, USA, 30 May3 June 2008(Abstract 7510).

Andre F, Grunenwald D, Pignon JP15 et al.Survival o patients with resected N2

non-small-cell lung cancer: evidence or asubclassication and implications.J. ClinOncol. 18(16), 29812989 (2000).

Emphasizes the heterogeneity seen in

stage IIIA (N2) disease and describes tw

distinct homogeneous subgroupsand

proposes dierent therapeutic approache

Fosella FV, Rivera E, Roth JA. Pre-16operative chemotherapy or stage IIIAnon-small cell lung cancer. Curr. Opin.Oncol. 8(2), 106111 (1996).

Mountain CF. The international system 17staging lung cancer. Semin. Surg. Oncol.

18(2), 106115 (2000).

Financial & competing interests disclosure

The authors have no relevant aliations or nancial involvement with

any organization or entity with a nancial interest in or nancial confict

with the subject matter or materials discussed in the manuscript. This

includes employment, consultancies, honoraria, stock ownership

options, expert testimony, grants or patents received or pending,

royalties.

No writing assistance was utilized in the production o this manuscr ip


14/18



van Meerbeeck JP, Kramer GW, van Schil18PE et al. Randomized controlled trial oresection versus radiotherapy aterinduction chemotherapy in stage IIIAN2non-small-cell lung cancer.J. Natl CancerInst. 99(6), 442 450 (2007).

Randomized trial wh ich has questioned

the role o surgery versus rad iotherapy in

proven biopsy N2 disea se.

Robinson LA, Ruckdeschel JC,19Wagner H Jr, Stevens CW; AmericanCollege o Chest Physicians. Treatment onon-small cell lung cancer-stage IIIA :ACCP evidence-based clinical practiceguidelines (2nd edition). Chest132(3 Suppl.), 243S265S (2007).

Arriagada R, Bergman B, Dunant A,20Le Chevalier T, Pignon JP, VansteenkisteJ; International Adjuvant Lung Cancer

Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patientswith completely resected non-small-celllung cancer. N. Engl. J. Med. 350(4),351360 (2004).

Cisplatin-based adjuvant chemotherapy

improves survival in lung cancer

patients.

Winton T, Livingston R, Johnson D21 et al.Vinorelbine plus cisplatin vs. observationin resected non-small-cell lung cancer.N. Engl. J. Med. 352(25), 25892597(2005).

Douillard JY, Rosell R, De Lena M22 et al.Adjuvant vinorelbine plus cisplatin versusobservation in patients with completelyresected stage IBIIIA non-small-celllung cancer (Adjuvant NavelbineInternational Trialist Association[ANITA]): a randomized controlled trial.Lancet Oncol. 7, 719727 (2006) .

Adjuvant vinorelbine plus cisplatin

extends surviva l in resected non-small-

cell lung cancer (NSCLC) patients; 39%

o these patients were N2 NSCLC.

Kato H, Ichinose Y, Ohta M23 et al.

A randomized trial o adjuvantchemotherapy with uraciltegaur oradenocarcinoma o the lung. N. Engl. J.Med. 350(17), 17131721 (2004).

Wakelee HA, Schiller JH, Gandara DR.24Current status o adjuvant chemotherapyor stage IB non-small cell lung cancer:implications or the New IntergroupTrial. Clin.Lung Cancer8(1), 1821(2006).

Roth JA, Fossella F, Komaki R25 et al.A randomized trial comparingperioperativechemotherapy and surgerywith surgery alone in respectable stage

IIIA non small c ell lung cancer.J. NatlCancer Inst. 86(9), 673680 (1994).

Clinical investigation showing the

easibility and efcacy o neoadjuvant

chemotherapy in N2 NSCLC.

Rosell R, Gomez-Codina J, Camps C26 etal . A randomized trial comparingpre-operative chemotherapy plus surgerywith surgery alone in patients withnon-small cell lung cancer. N. Engl. J.Med. 330(3), 153158 (1994).

Rosell R, Felip E . Role o multimodality27treatment or lung cancer. Semin. Surg.Oncol. 18(2), 143151 (2000 ).

Pass HI, Pogrebniak HW, Steinberg SM,28Mulshine J, Minna J. Randomized trial oneoadjuvant therapy or lung cancer:interim analysis.Ann. Thorac. Surg.53(6), 992998 (1992).

Roth JA, Atkinson EN, Fossella F29 et al.Long-term ollow-up o patients enrolledin a randomized trial comparingperioperative chemotherapy and surgerywith surgery alone in resectable stage IIIAnon-small-cell lung cancer. Lung Cancer21(1), 16 (1998).

Pisters KM, Ginsberg RJ, Giroux DJ30 et al.Induction chemotherapy beore surgeryor early-stage lung cancer: a novelapproach. Bimodality Lung OncologyTeam.J. Thorac. Cardiovasc. Surg. 119(3),429439 (2000).

Pisters KM, Vallieres E, Bunn P31 et al.S9900: a Phase III trial o surgery aloneor surgery plus pre-operative (preop)paclitaxel/carboplatin (PC) chemotherapyin early stage non small lung cancer:Preliminary results. Presented at: 41stAnnual Meeting o the American Society oClinical Oncology. Orlando, FL, USA,1317 May 2005 (Abstract LBA7012).

Pisters KM, Vallteres E, Bunn P32 et al.S 9900 surgery alone or surgery plusinduction paclitaxel carboplatin (PC)chemotherapy in early stage non-smallcell lung cancer (NSCLC): ollow up on aPhase II trial. Presented at: 43rd AnnualMeeting o the American Society o ClinicalOncology. Chicago, IL, USA,15 June 2007 (Abstract 7520).

Depierre A, Milleron B, Moro-Sibilot D33et al. Pre-operative chemotherapyollowed by surgery compared withprimary surgery in resectable stage I(except T1N0), II and IIIA non-small-celllung cancer.J. Clin. Oncol. 20(1),247253 (2002) .

Randomized Phase III trial o

neoadjuvant chemotherapy,

demonstrating disease-ree survival

advantage, but ailing to demonstrate

overall survival in N2 disease.

Nagai K, Tsuchiya R, Mori T34 et al. LungCancer Surgical Study Group o the JapanClinical Oncology Group. A randomizedtrial comparing induction chemotherapyollowed by surgery with surgery alone orpatients with stage IIIA N2 non-small celllung cancer (JCOG 9209).J. Thorac.Cardiovasc. Surg. 125(2), 254260(2003).

Gilligan D, Nicolson M, Smith I35 et al.Pre-operative chemotherapy in patientswith resectable non-small cell lungcancer: results o the MRC LU22/NVALT 2/EORTC 08012 multicentrerandomised trial and update o systematicreview. Lancet369(9577), 19291937

(2007).Peters GJ, Ruiz van Haperen VW,36Bergman AM et al. Preclinicalcombination therapy with gemcitabineand mechanisms o resistance. Semin.Oncol. 23(5 Suppl. 10), 1624 (1996).

Abratt RP, Bezwoda WR, Goedhals L,37Hacking DJ. Weekly gemcitabine withmonthly cisplatin: eective chemotherapyor advanced non-small cell lung cancer.J. Clin. Oncol. 15(2), 744749 (1997).

Van Zandwijk N, Smit EF, Kramer GW38et al. Gemcitabine and cisplatin asinduction regimen or patients withbiopsy-proven stage IIIA N2 non-small-cell lung cancer.J. Clin. Oncol. 18(14),26582664 (2000 ).

Migliorino MR, De Marinis F, Nelli F39et al. A 3-week schedule o gemcitabineplus cisplatin as induction chemotherapyor stage III non-small cell lung cancer.Lung Cancer35(3), 319327 (2002).

Santo A, Pedersini R, Pasini F40 et al.A Phase II study o inductionchemotherapy with gemcitabine (G) andcisplatin (P) in locally advancednon-small cell lung cancer: interim

analysis. Lung Cancer. 34(Suppl. 4),S15S20 (2001).

Schiller JH, Harrington D, Belani CP41 etal . Comparison o our chemotherapyregimens or advanced non-small-celllung cancer. N. Engl. J. Med. 346(2),9298 (2002).

Fossella F, Pereira JR, von Pawel J42 et al.Randomized, multinational, Phase IIIstudy o docetaxel plus platinumcombinations versus vinorelbine pluscisplatin or advanced non-small-cell lungcancer: the TAX 326 study group. J. Clin.

Oncol. 21(16), 30163024 (2003).


15/18



OBrien ME, Splinter T, Smit EF43 et al.Carboplatin and paclitaxel (Taxol) as aninduction regimen or patients withbiopsy-proven stage IIIA N2 non-smallcell lung cancer. An EORTC Phase IIstudy (EORTC 08958). Eur. J. Cancer

39(10), 14161422 (2003) .Betticher DC, Hsu Schmitz SF, Totsch M44et al. Mediastinal lymph node clearanceater docetaxelcisplatin neoadjuvantchemotherapy is prognostic o survival inpatients with stage IIIA pN2 non-small-celllung cancer: a multicenter Phase II trial.J. Clin. Oncol. 21(9), 17521759 (2003).

Betticher DC, Hsu Schmitz SF, Ttsch M45et al. Swiss Group or Clinical CancerResearch (SAKK ). Prognostic actorsaecting long-term outcomes in patientswith resected stage IIIA pN2 non-small-

cell lung cancer: 5-year ollow-up o aPhase II study. Br. J. Cancer. 94(8),10991106 (2006) .

Berghmans T, Paesmans M, Meert AP46et al. Survival improvement in resectablenon-small cell lung cancer with (neo)adjuvant chemotherapy: results o ameta-analysis o the literature. LungCancer49(1), 1323 (2005).

Burdett S, Stewart LA, Rydzewska L.47A systematic review and meta-analysis othe literature: chemotherapy and surgeryversus surgery alone in non-small celllung cancer.J. Thorac. Oncol. 1(7),

611621 (2006).

Nakamura H, Kawasaki N, Taguchi M,48Kabasawa K. Role o pre-operativechemotherapy or non-small-cell lungcancer: a meta-analysis. Lung Cancer54(3), 325329 (2006).

Cappuzzo F, Selvaggi G, Gregorc V49 et al.Gemcitabine and cisplatin as inductionchemotherapy or patients withunresectable stage III A bulky N2 andstage IIIB nonsmall cell lung carcinoma.Cancer98(1), 128134 (2003).

De Marinis F, Nelli F, Migliorino MR50

et al. Gemcitabine, paclitaxel, andcisplatin as induction chemotherapy orpatients with biopsy-proven stageIIIA(N2) nonsmall cell lung carcinoma: aPhase II multicenter study. Cancer98(8),17071715 (2003).

Garrido P, Gonzlez-Larriba JL, Insa A51et al. Long-term survival associated withcomplete resection ater inductionchemotherapy in stage IIIA (N2) and IIIB(T4N0-1) non small-cell lung cancerpatients: the Spanish Lung Cancer GroupTrial 9901.J. Clin. Oncol. 25(30),47364742 (2007).

Provocative results seen or t riplet

regimens used as induction

chemotherapy or N2 and stage IIIB

NSCLC.

Pisters KM, Mirkovic N, Pass HI, Albain52KS. Pre-operative chemotherapy/radiationtherapy or early stage and locallyadvanced non small cell lung carcinoma.In: Lung Cancer: Principles and Practice(3rd Edition). Pass HI, Carbone DP,Johnson DH, Minna JD, Turrisi AT(Eds). Lippincott Williams & Wilkins,PA, USA 626649 (2004).

Warram J. Pre-operative irradiation o53cancer o the lung: nal report o atherapeutic trial. A collaborative study.Cancer36(3), 914925 (1975).

Albain KS, Rusch VW, Crowley JJ54 et al.Concurrent cisplatin/etoposide plus chest

radiotherapy ollowed by surgery orstages IIIA (N2) and IIIB non small celllung cancer: mature results o SouthwestOncology Group Phase II study 8805.J. Clin. Oncol. 13(8), 18801892 (1995).

Albain K, Rusch V, Crowley J55 et al.Long term survival ater concurrentcisplatin/etoposide (PE) plus chestradiotherapy (RT) ollowed by surgery inbulky, stages IIIA (N2) and IIIB nonsmall cell lung cancer (NSCLC): 6 yearoutcomes rom Southwest OncologyGroup Lung Committee 8805. Proc. Am.Soc. Clin. Oncol. 18, 467a (1999).

Albain KS, Swann RS, Rusch VR56 et al.Phase III study o concurrentchemotherapy and radiotherapy (CT/RT)vs CT/RT ollowed by surgical resectionor stage IIIA(pN2) non-small cell lungcancer (NSCLC): outcomes update oNorth American Intergroup 0139 (RTOG9309). Presented at: 41st Annual Meetingo the American Society o ClinicalOncology. Orlando, FL, USA, 1317 May2005 (Abstract 7014).

Bonnet R, Schneider CP, Wendt TG57 et al.Paclitaxel/carboplatin (PC) ollowed by

twice daily chemoradiation (hRT/PC)versus hRT/PC ollowed by PC asinduction to surgery in stage IIInon-small cell lung cancer (NSCLC): arandomized Phase III trial o the LungCancer Study Group Mitteldeutschland.Presented at: 44th Annual Meeting o theAmerican Society o Clinical Oncology.Chicago, IL, USA, 30 May3 June 2008(Abstract 7541).

Maas KW, Sharouni SY, Phernambucq58EC et al. A Phase II study o weeklydocetaxel/cisplatin and concurrentradiotherapy ollowed by surgery in

patients with stage III non-small cell luncancer (NSCLC). Presented at: 44thAnnual Meeting o the American Society oClinical Oncology. Chicago, IL,USA, 30 May3 June 2008(Abstract 7586).

de Santis S, Donato V, Caruso C59 et al.Induction (Ind), gemcitabine (G),docetaxel (D) and cisplatin (C) plusconcurrent (Con) chemotherapy withthoracic radiotherapy (TRT) in stage IIInon-small cell lung cancer (NSCLC).Presented at: 44th Annual Meeting o theAmerican Society o Clinical Oncology.Chicago, IL, USA, 30 May3 June 2008(Abstract 7589).

Bueno R, Richards WG, Swanson SJ60 et Nodal stage ater induction therapy orstage IIIA lung cancer determines patien

survival.Ann. Thorac. Surg. 70(6),18261831 (2000) .

van Rens MT, de la Riviere AB, Elbers61HR, van Den Bosch JM. Prognosticassessment o 2,361 patients whounderwent pulmonary resection ornon-small cell lung cancer, stage I, II anIIIA. Chest117(2), 374379 (2000 ).

Naruke T, Tsuchiya R, Kondo H,62Asamura H. Prognosis and survival a teresection or bronchogenic carcinomabased on the 1997 TNM classication:the Japanese experience.Ann. Thorac.Surg. 71(6), 17591764 (2001).

Fang D, Zhang D, Huang G, Zhang R,63Wang L, Zhang D. Results o surgicalresection o patients with primary lungcancer: a retrospective analysis o 1,905cases.Ann. Thorac. Surg. 72(4), 11551159 (2001).

Goya T, Asamura H, Yoshimura H64 et alPrognosis o 6644 resected non-small-celung cancers in Japan: a Japanese lungcancer registry study. Lung Cancer50(2227234 (2005).

Non-Small-Cell Lung Cancer65Collaborative Group. Chemotherapy in

non-small-cell lung cancer: a meta-analysis using updated data onindividual patients rom 52 randomizedclinical trials. BMJ311(7010), 899909(1995).

Scagliotti GV, Fossati R, Torri V66 et al.Adjuvant Lung Project Italy/EuropeanOrganization or Research Treatment oCancer-Lung Cancer Cooperative Grou

con trove rsi as en el manejo de estadio iiia

Documents