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The Role of Surgery in Stage IIIA Non–Small Cell Lung Cancer
Hematol Oncol Clin N Am 19 (2005) 303 – 319
The Role of Surgery in Stage IIIA Non–Small Cell Lung Cancer Wilfried E.E. Eberhardt, Dr meda,*, Rodrigo Hepp, Dr medb, Georgios Stamatis, Prof Dr medc a Department of Internal Medicine (Cancer Research), West German Cancer Centre Essen, Universita¨tsklinikum of the University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany b Department of Radiation Therapy, Clinica Santa Maria, Hospital Padre Hurtado, Santiago, Chile c Department of Thoracic Endoscopy and Thoracic Surgery, Ruhrlandclinic, Tu¨schener Weg 40, 45239 Essen, Germany
Lung cancer is the leading cause of cancer-related deaths in North America and Europe [1,2]. More than 80% of patients can be classified as having non– small cell lung cancer (NSCLC) [3]. Although patients who have the early stages (I and II) of this disease are clear candidates for local treatments, in most cases— those who have advanced disease and proven distant metastases (stage IV)— up-front surgical resection is not considered and palliative systemic approaches consist of platinum-based combination chemotherapy protocols [3]. Stage III NSCLC subsumes a heterogeneous patient population that spans operable stage IIIA disease with minimal mediastinal lymph node involvement (‘‘minimal N2-disease’’) to extensive and diffuse bilateral mediastinal infiltration of lymphatic structures (‘‘N3-disease’’) or large and vital mediastinal organs (‘‘T4-disease’’); the last two are considered to be part of the inoperable IIIB stage group [3,4]. Surgery has an undisputed and overall accepted role only in that small group of patients that has minimal ipsilateral mediastinal lymph node involvement (‘‘minimal N2’’) found at surgical staging procedures or at up-front thoracotomy, especially in those situations when N2-disease is not suspected clinically [3]. For most patients who have stage III disease, a combination of chemotherapy and radiation is the current treatment of choice [5]. Recent de-
This work was supported in part by a grant from Deutsche Krebshilfe, Bonn, Germany. * Corresponding author. E-mail address: [email protected] (W.E.E. Eberhardt). 0889-8588/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.hoc.2005.02.002 hemonc.theclinics.com
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velopments include the use of adjuvant chemotherapy after up-front surgery in subgroups of stage III disease [6], as well as innovative ways to deliver concurrent chemoradiotherapy or combinations of chemotherapy with higherdose conformal radiotherapy techniques [7]. This article focuses on patients who have stage IIIA NSCLC and reviews the different possibilities for their treatment. Special emphasis is given to the inclusion of surgery into the different approaches to this disease stage. The current literature on this topic is reviewed and the different aspects of surgical treatment in the management of stage IIIA NSCLC are discussed.
Heterogeneity of stage IIIA non–small cell lung cancer Stage IIIA includes patients who have the following four TNM stages: T3N1, T1N2, T2N2, and T3N2. There is even further heterogeneity within this subgroup, however, because N2-disease can be based on several distinct extensions into the ipsilateral mediastinal lymph nodes [3,4,8]. There is a considerable clinical heterogeneity in the volume of lymph node disease (bulky versus nonbulky), amount of lymph node infiltration (microscopic versus macroscopic), number of involved lymph nodes (single versus multiple), and the biologic behavior of the disease within the mediastinum (lymphangitic spread versus nonlymphangitic and discontinuous spread) [9]. This differentiation does not cover the differences that are related to performance status, LDH, tumor location (upper lobe versus lower lobe), or existing comorbidities and their relevant clinical implications. There also may be further biologic variations based on molecular genetic variations of the tumors or differentially activated signal transduction pathways.
Results of surgery alone in patients in stage IIIA subgroups In patients who have pathologically proven N2-involvement at mediastinoscopy, long-term prognosis with surgical treatment alone is extremely poor [3,4,8]. Conversely, in patients who have negative mediastinoscopic findings, long-term survival rates are between 15% and 25% [3]. If mediastinal nodes are infiltrated with tumor cells, the 5-year survival rates following surgical resection are reduced to between 5% and 10% [3,4]. Another important discriminator is the clinical status of the patients at the time of diagnosis. With clinically evident mediastinal disease (bulky nodes or nodes N1.5cm) that can be confirmed at mediastinoscopy or thoracotomy, the cure rate decreases dramatically. A detailed retrospective French multicenter analysis looked at this issue and investigated 702 patients who had stage IIIA(N2) disease [9]. Five-year survival rates following surgery for patients who had clinical N2-disease and pathologic confirmation of involvement of multiple or a single mediastinal lymph node were 3% and 8%, respectively. Those patients who did not show clinical involvement
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of the mediastinal nodes in the up-front staging investigations—so-called ‘‘minimal N2-disease’’ in this evaluation—showed better 5-year survival rates of 11% (multiple nodes infiltrated) and 34% (a single mediastinal node pathologically involved). These data can represent baseline results against which future data sets can be compared. Besides surgical staging at mediastinoscopy, or alternatively at up-front thoracotomy, positron emission tomography (PET)-scanning has emerged as an important staging tool in this patient group [3,10]. Long-term prognosis is significantly better in patients who have PET-negative ipsilateral nodes compared with those who have PET-positive ipsilateral nodes. When analyzed critically, however, only the negative predictive value of PET is high; the positive predictive value of PET-scanning for the mediastinal nodes is less acceptable. Therefore, some investigators recommend that positive findings with the PET-scan should be confirmed pathologically at mediastinoscopy before a final stage can be assigned [10].
Randomized trials of adjuvant chemotherapy in stage IIIA disease Although adjuvant chemotherapy for earlier stage disease (including stage IIIA subsets) in the postoperative setting had been without major success within multicenter randomized trials until 2002, the last 2 years have brought enormous progress in this respect [11]. The first large trial had been performed by an international multicenter cooperative group, including European Organization for Research and Treatment of Cancer (EORTC) centers, and was led by an Italian consortium (Adjuvant Lung Project Italy; ALPI) [12]. This trial showed a trend toward improved event-free survival rates at 4 and 5 years from randomization for patients who received postoperative chemotherapy; however, the result was not statistically significant. There also was no significant improvement in overall survival rates at 4 and 5 years in the adjuvant treatment arm. One of the major criticisms of this trial was the inclusion of a second-generation chemotherapy regimen, including mitomycin C, into the treatment protocol. Earlier experience with this regimen pointed to increased perioperative and postoperative toxicities that probably were the result of the pulmonary adverse effects of mitomycin [13]. It has to be mentioned within this context that the French cooperative trial on preoperative, neoadjuvant chemotherapy in early disease showed a comparable negative effect on the survival rates within the first 1.5 years, probably because of the same background of pulmonary toxicities [14]. Although this ALPI-trial was the first of the new generation of mega-trials on adjuvant chemotherapy, the second one was much larger; more than 3300 patients originally were planned to be included over several years of accrual. This International Adjuvant Lung Trial (IALT) led by a French Group and performed internationally in more than 130 treatment centers was the first large clinical study to show a statistically significant improvement in overall survival (in the range of 4%–5% at 5 years) and progression-free survival for adjuvant cisplatinbased chemotherapy [6]. There was no significant interaction between the
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covariates—including pathologic stage—and overall survival and progressionfree survival. Slow accrual led to an earlier than planned termination of patient inclusion at 1867 patients. Recently, the National Cancer Institute of Canada (NCIC) randomized trial on adjuvant chemotherapy in stage IB to IIB disease and the Cancer and Leukemia Group B (CALGB) trial in stage IB disease were presented at the American Society of Clinical Oncology (ASCO) 2004 annual meeting (Table 1) [15,16]. The trials showed a significant improvement in 5-year overall survival of 15% (NCIC) and in 4-year survival of 12% (CALGB); equally significant improvements in progression-free survival rates were demonstrated. If all current trials are analyzed together, we have strong evidence from more than 2500 patients with completely resected NSCLC that adjuvant chemotherapy significantly improves overall survival. A meta-analysis that is based on individual patient data is planned to look at subgroup analysis in a broader context. This is to identify subgroups of patients that show the most profits from such adjuvant chemotherapy protocols. A further analysis—The IALT Bio-initiative— is planning to look at molecular prognostic or predictive factors to identify subsets of patients who have increased or reduced benefits from the application of adjuvant platinum-based chemotherapy. One of the current conclusions to be drawn from the different trials is that for patients who have completely resected pathologic stage IIIA NSCLC, postoperative chemotherapy significantly prolongs overall survival and is indicated in patients who have good performance status and no contraindications based on the individual comorbidity profile. Therefore, up-front surgery that is followed by postoperative adjuvant chemotherapy (plus/minus sequential adjuvant radiotherapy) has become a valuable alternative treatment approach in patients who are not found to have stage III disease within initial staging investigations, but who turn out to have stage IIIA disease by detailed pathologic investigation of re-
Table 1 Adjuvant chemotherapy in non–small cell lung cancer: randomized studies Study [reference]
Stages
ALPI [12]
I–IIIA
IALT [6]
I–III
NCIC [15]
I–II
CALGB 9633 [16]
IB
Patients 603 606 935 932 243 239 173 171
Regimen M/V/P — P/E–P/Nav–P/Vbl–P/V — P/Nav — Tax/CP —
TC 69% — 74%b — 65%c — 85% —
5-y survival a
55.2 48a 44.5% 40.4% 69% 54% 71%d 59%d
P .59 b.03 .01 b.03
Abbreviations: CP, carboplatin; E, etoposide; M, mitomycin; Nav, navelbine; P, cisplatin; Tax, paclitaxel; TC, percent of patients receiving the planned number of chemotherapy cycles; V, vindesine; Vbl, vinblastine. a Overall median survival in months. b Percent of patients who received 240 mg/m2 cisplatin. c 65% received 3 to 4 cycles. 77% patients needed dose reductions. d 4-y survival.
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sected nodes [3]. This group, however, represents only a small subset (probably not more than 10%) of patients who have clinical stage IIIA disease. Different thoracic treatment centers initially consider these patients to have ‘‘operable IIIA’’ disease, or alternatively, ‘‘minimal IIIA’’ disease with only microscopic involvement of one lymph node level [3,9,17].
Induction chemotherapy followed by surgery in stage IIIA disease The first investigations to test induction chemotherapy before surgery in stage III NSCLC started before 1990 by the Lung Cancer Study Group [18]. The largest patient group since then was treated at the Memorial Sloan-Kettering Cancer Center in New York [13]. These early trials included second-generation chemotherapy protocols in the preoperative setting, such as a mitomycin-based regimen or cisplatin-based protocols. This first experience independently stimulated groups in Spain and at the M.D. Anderson Cancer Center to perform prospectively randomized trials that compared preoperative chemotherapy followed by surgery with surgery alone in patients who had stage III NSCLC [19,20]. Both trials showed significant survival benefits for a neoadjuvant chemotherapy approach; however, both trials had to be terminated early after accruing approximately 60 patients because of early stopping rules. A third trial of the National Cancer Institute also was terminated early (because of slow accrual) but showed some survival benefit for an induction protocol with cisplatin-based chemotherapy [21]. Although surgical staging of the mediastinum was not performed uniformly in all of those trials, one can speculate that most of the patients in these early randomized trials had more minimal mediastinal involvement, not the typical bulky IIIA disease that is found at mediastinal staging with CT-scan and mediastinoscopy. This rigid discrimination is of major importance because stage IIIA NSCLC includes a heterogeneous group of patients. Within recent years only one major randomized trial investigated neoadjuvant chemotherapy before surgery compared with local treatment only. This was a prospective randomized trial that was performed by a French intergroup consortium; however, this group included a second-generation chemotherapy combination in the preoperative setting and found a significantly increased perioperative mortality in the first 6 months after thoracotomy [14]. It was speculated that the inclusion of mitomycin C into this approach led to the increased deaths by contributing to pulmonary and cardiovascular events. This may have led to the finding that there was a clear trend for improved long-term survival rates only in the group that had preoperative chemotherapy application. None of these studies looked at end points of extent of resection or organ-sparing surgery in these patients who had locally advanced disease. ‘‘Downsizing’’ and ‘‘downstaging’’ of locally advanced tumors may be of major importance for the performance of complete resections or lobectomies, instead of pneumonectomies. Further investigation on this subject is needed urgently to reduce the rate of extended resections within this patient subset.
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Within recent years there have been phase II trials that tested third-generation chemotherapy combinations as induction therapy protocols in mediastinoscopically-proven stage IIIA(N2) disease (Table 2) [14,22–30]. These combinations included carboplatin and paclitaxel, cisplatin and paclitaxel, cisplatin and docetaxel, carboplatin and docetaxel, cisplatin and gemcitabine, and cisplatin and vinorelbine. The largest trial was reported by the Swiss Schweizerisches Institut fu¨r Angewandte Krebsforschung Trials Group [25]. They used three cycles of a combination of cisplatin and docetaxel as induction therapy and found a resection rate of approximately 45% of all patients who were included in the protocol based on an intent-to-treat analysis. Treatment with these newer drug regimens resulted in significantly reduced rates of morbidity and mortality in the perioperative setting; this also may be based on learning effects within the hands of more and more experienced multimodality treatment groups. Surgery in this setting has generated fewer and fewer toxic events and, therefore, indications of surgery may be much more appropriate compared with those in former studies with treatment-related death rates of between 5% and 12%. Recent data on surgical morbidity and mortality come from the large, multicenter, EORTC-study that randomized patients who had IIIA(N2) disease following a response to three cycles of induction chemotherapy to surgery or definitive radiation [31]. Because an induction chemotherapy–only approach was chosen within this trial, the morbidity and mortality define a baseline with which to compare future approaches. Although the toxicity profile of the surgical arm has been reported, the final survival data of this randomized trial have not been published. Further long-term follow-up of this study is needed to reach the necessary number of events to give a valid statistical comparison. Two major arguments against this trial have been: (1) the comparator arm was based on a sequential chemotherapy and radiotherapy–only approach without a modern chemoradiation protocol included and (2) patients who had stable disease were not randomized. With the final results of this study awaited, however, this trial could generate a new standard of care for the multicenter setting in this stage.
Chemoradiotherapy without surgery in stage IIIA disease When discussing the role of surgery in stage IIIA NSCLC, it has to be taken into account that for most patients who are within this stage (~70%–85%), combined chemotherapy and radiotherapy is a valid and generally accepted treatment strategy [5,8,9]. Recently, concurrent chemoradiotherapy protocols represent the most active approach with 5-year survival rates in stage IIIA disease that range from 12% to 25%, based on the patients selected in the treated population [5,9]. Although chemoradiotherapy has its own typical toxicity profile (esophagitis, radiation pneumonitis), treatment-related deaths rarely are observed following this therapy and do not exceed 1% to 2%. Newer strategies to give postoperative consolidation chemotherapy (taxane-based) can add to the postoperative morbidity and mortality in this treatment schema, however. From
Table 2 Selected phase II–III studies of induction chemotherapy followed by surgery Stages
Patients
Regimen
ORR
R0
TRD
OMS
1-y OS
5-y OS
Depierre et al [14]
I-IIIA
179 176
2 P/I/MMC + S F P/I/MMC S
64% —
86% 85%
9% 5%
— —
77% 73%
44%a 35%a
Van Kooten et al [22] Mattson et al [23]
IIIAB IIIAB
JCOG 9209 [24]
IIIA
Betticher et al [25] Cigolari et al [26] EORTC 08958 [27]
IIIA IIIB IIIA
29 134 140 31 31 90 30 52
62% 28% — 28% — 66% 60% 64%
— — — 10% 22% — — —
129 42 131
3% 2% 0% 0% 0% 3% 0% 0% 0% 0% 0% b1%
61% 59% 51% 68% 65% 65% — 68.5%
IIIAB IIIAB IIIA
48% 13% 16% 65% 77% 48% 37% 13% — 29% 38% 47%
17 14.8 12.6 16 17 28 23 20.5
Cappuzzo et al [28] Cappuzzo et al [29] Lorent et al [30]
2 P/Gem + S or RT Doc 3 + S or RT S or RT 2 P/V + S versus S alone 3 P/Doc + S F RT (33 patients) 3 P/V + S 3 Tax/CP + S (15 patients) versus 3 Tac/CP + RT 4 P/Gem + S F postoperative RT 3 P/Gem/Tax + S or RT 3 P/I/V + S
19.4 21.7 24
74% 92% —
— — 21%
62% 71% 54%
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Study [reference]
Abbreviations: Doc, docetaxel; Gem, gemcitabine; I, ifosfamide; MMC, mitomicin C; OMS, overall median survival; ORR, overall response rate; R0, microscopically complete resection rate; RT, radiotherapy; S, surgery; TRD, treatment-related death rate. a 4-y survival.
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analysis of competing risks for this patient group it is clear that adequate systemic treatment with platinum-based chemotherapy is necessary to reduce the risk of systemic relapse outside the brain (Fig. 1). Therefore, alternative ways to add this systemic therapy include induction chemotherapy before chemoradiation or consolidation chemotherapy following concurrent chemoradiotherapy.
Induction chemoradiotherapy followed by surgery in stage IIIA disease To optimize preoperative downsizing and downstaging, different groups used chemoradiotherapy protocols before definitive surgery in stage IIIA NSCLC. The largest experience comes from the Southwest Oncology Group (SWOG); cisplatin and etoposide were given concurrently with 45 Gy conventionally fractionated radiotherapy before definitive surgery (Table 3) [32–44]. In this experience, 75 patients who had stage IIIA disease were treated with concurrent chemotherapy and radiotherapy. Overall, 85% of these patients’ disease could be resected. Long-term survival rates were promising although the treatment-related death rate seemed to be high (10%). Since then, many prospective phase II trials have been performed with different patient selection criteria (including IIIA and selected IIIB subsets) and different chemotherapy protocols (second-generation versus third-generation protocols) [32–44]. Most investigations showed a clear learning curve in the morbidity and mortality analysis; fewer adverse events usually appeared in the second half of the trial. The treatment-related death rate ranged from 2% to 10%, with the newer studies showing a reduced rate of approximately 4% to 6%. Different ways to combine chemotherapy and radiotherapy were used in the different investigations. Hyperfractionated accelerated radiotherapy was used in some of the trials [33,34,39,40,42,43], whereas conventionally fractionated radiation was used in others [32,35–38,41]. Generally, clinical response rates and complete resection rates (R0) were approximately 55% to 85% or 50% to 75%; these were increased treatment related events local relapse loco-regional relapse
competing risks
systemic relapse outside the brain brain relapse events due to co-morbidities natural death hazard
Fig. 1. Competing risks in patients who have stage IIIA disease.
Table 3 Selected phase II–III studies of induction chemoradiotherapy followed by surgery Stages
Patients
Regimen
ORR
R0
TRD
OMS
1-y OS
5-y OS
SWOG 8805 [32] Choi et al [33] Eberhardt et al [34] RTOG 89-01 [35]
IIIAB IIIA IIIAB IIIA
126 42 94 73
59% 74% 64%
Pisch et al [36]
IIIAB
80
—
83% 81% 53% 73% — —
10% 7% 6% 8% 5% 0%
— 25 20 19.4 17.4 28
— — — 70% 66% 68%
26%a 37% 26% — — —
Kuten et al [37] De Candis et al [38] DeCamp et al [39] Trodella et al [40] Machtay et al [41] Gauler et al [42] Friedel et al [43]
IIIAB IIIAB IIIAB IIIAB IIIA IIIAB IIIAB
37 43 105 92 53 64 114
P/E/RT 45 Gy + S F boost P/Vbl/FU/HFRT 42 Gy + S F boost 3 P/E + P/E/HFRT 45 Gy + S P/V/MMC + S (26 patients) versus P/V/MMC + RT 64 Gy (19 patients) P/Tax/HFRT 45 Gy + S or (28 patients) P/Tax/HFRT 60 Gy (52 patients) Tax/CP/RT 50.4 Gy + S or RT boost 4 Tax/CP + S + RT or RT/P P/Tax/HFRT + S + boost P/Tax/HFRT CP/RT or P/FU/HFRT + S P/E or CP/Tax + RT 45–54 Gy + S 3 P/Tax/HFRT 45 Gy + S 2 CP/Tax + CP/Tax/HFRT 45 Gy + S
52% 45% 62% 69% — 84% 60%
49% 29% 79% 61% 72% 52% 52%
3% 2% 9% 8% 9% 5%
22 15 27 17.2 21 25 22
— 51% 67% 59% — —
— — 30% 15% 31% 28%a 37%a
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Study [reference]
Abbreviations: FU, 5-Fluorouracil; HFRT, hyperfractionated RT; IIIAB, stages IIIA and IIIB. a 3-y survival.
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in comparison with induction chemotherapy–only trials. The optimal schedule for chemotherapy and radiotherapy is not known in this preoperative setting.
Trimodality including surgery versus bimodality: implications of Intergroup Trial 0139 Based on two major phase II pilots within SWOG, the phase III trial was aimed at testing trimodality versus bimodality strategies in stage IIIA(N2) disease [44]. The SWOG pilot had tested surgery following chemoradiation in 125 patients who had stage IIIA(N2) and IIIB disease [32]. Seventy-five patients of this subset were classified and pathologically proven as having stage IIIA(N2) disease. Surgery turned out to be feasible following chemoradiation and could be performed in this setting with acceptable morbidity and mortality. A follow-up phase II study piloted a definitive chemoradiation protocol with radiation doses of 61 Gy followed by consolidation chemotherapy; the 5-year survival rate was approximately 20% in a patient population of comparable (pathologically proven) patients who had IIIB disease [45]. The results of both consecutive trials led to the development of the randomized phase III Intergroup 0139 study design (Table 4) [44]. This trial randomized 429 patients to test chemoradiation followed by surgery (trimodality) versus a definitive chemoradiation protocol. Three-hundred and ninety-two patients were evaluable for the final analysis. The results of this trial were presented at ASCO 2003 and updated at the International Association for the Study of Lung Cancer World Conference on Lung Cancer in Vancouver in the fall of 2003 [44,46]. Although a significant improvement was observed in the progression-free survival results for the arm that included surgery, this did not translate into a significant overall survival benefit. Longer follow-up of this study will give more detailed information, including whether there also is a small survival benefit for selected patient subgroups following the inclusion of surgery in such a multimodality approach. One of the major findings of this prospective randomized trial was that surgery turned out to be safe and feasible, even after an intensive chemoradiation protocol in the multicenter setting. Learning effects showed reduced treatment-related mortality in the progress of the trial. This is a typical and constant finding within multicenter randomized trials, including surgical arms in the setting of stage III disease. After the logistics of such an approach have been set up and the multimodality groups have become more experienced with these protocols, the treatment-related death rate decreases to comparable rates as in settings with surgical treatment up-front, without any preoperative induction therapy.
Other randomized trials in stage IIIA disease including surgery The survival analysis is awaited for the large, randomized phase III trial that is being performed by the EORTC Lung Cancer Cooperative Group. Following
Table 4 Randomized trials including surgery in stage IIIA disease Stage
Patients
Regimen
R0
PnR
TRD
PFS (mo)
3-y survival
P
Albain et al [44]
IIIA (N2)
429a 558b
Eberhardt et al [50]
IIIA IIIB IIIA (min)
EORTC 08941 [31]
IIIA
167e NA
R0333/SS0332 [48]f
IIIA
84% — 45% 45% 60% 71% 44% — —
— — 35% 33% 20% 43% 41% — —
7% — 6% 6% 5% 2% 4% — —
14 11.7 10 10 29 15 — — —
38% 33% 24% 23% 38% 35% — — —
NS
Thomas et al [47]
P/E 2 + 45 Gy + S + P/E 2 P/E 2 + 61 Gy + P/E 2 P/E 3 + 45 Gy/bid/CP/V + S + 24 Gyc P/E 3 + S + 54 Gy F 24 Gy P/E 3 + 45 Gy/bid/P/E + PCI + S S + 45 Gy 3 C/X or 3 CP/X + S F RT 3 C/X or 3 CP/X + RT 2 P/Doc/RT 45 Gy + S + 3 P/Doc 2 P/Doc + S + 3 P/Doc
112d
NS NS — — —
Abbreviations: bid, twice daily; C/X, cisplatin and partner regimen; CP/X, carboplatin and partner regimen; Min, minimal; NS, not significant; PCI, prophylactic cranial irradiation; PFS, progression-free survival; PnR, pneumonectomy rate. a Data on 392 patients. b Data on 526 patients. c Additional dose on patients with R1/R2 resection. d Data on 106 patients. e Only data on patients randomized to surgery. f Ongoing trial.
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Study [reference]
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three cycles of platinum-based induction chemotherapy, patients with objective response (complete response [CR], partial response, or minor response) were randomized to receive surgical resection or definitive radiotherapy [31]. Accrual to this study has been finished and the final survival analysis probably will be presented at one of the upcoming oncology meetings next year. A prospectively randomized phase III study by the German Lung Cancer Cooperative Group included patients who had inoperable stages IIIA and IIIB disease [47]. Patients were randomized to: (1) induction chemotherapy with cisplatinum and etoposide followed by chemoradiation with weekly carboplatin and vindesine and hyperfractionated accelerated radiotherapy of 45 Gy leading to definitive surgery, if possible, or (2) the same induction chemotherapy protocol with cisplatin and etoposide followed by surgery, if possible, and postoperative radiotherapy up to 68 Gy. The analysis of this study was presented at ASCO 2004; there were no differences in complete resection rate, overall survival, and progression-free survival between the two randomization arms [47]. There is major criticism of the design of this trial because there is no evidence for the efficacy of weekly carboplatin and vindesine in concurrent chemoradiotherapy protocols. Also, both study arms were given radiotherapy in this setting—one arm before surgery, the other postoperatively. Furthermore, more than two thirds of patients had more advanced stage IIIB disease. It also may be that the patient selection included a heterogeneous population. As a consequence of the North American Intergroup Trial 0139, the follow-up phase III trial recently started accrual. The purpose of that trial is to compare induction chemoradiotherapy followed by surgery and consolidation chemotherapy with induction chemotherapy followed by surgery and consolidation chemotherapy (see Table 4) [48]. This study is a high priority North American Intergroup Trial that is led by SWOG and the Radiation Therapy Oncology Group (RTOG). This trial most likely will include more patients who have early and operable stage IIIA disease, not the bulky and multilevel N2 disease that also had been included in the earlier 0139 study.
Toxicity considerations of surgery in stage IIIA disease Although the early trials that included surgery in the setting of multimodality protocols for stage IIIA disease showed considerable morbidity and mortality, recent investigations proved that surgery can be performed safely by experienced multimodality treatment teams. Perioperative mortality has been reduced to approximately 1% to 2% for lobectomies and less than 4% for pneumonectomies with this strategy [49]. Therefore, surgery has become a safe means to achieve definitive local control at the location of the primary tumor. These mortalities no longer are significantly different from up-front surgery in the same setting. Moreover, it can be speculated that in selected patients, induction protocols of combination chemotherapy or concurrent chemoradiation can induce downsizing and downstaging, and thus, lead to increased complete resection rates and organ-
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sparing surgical approaches [50]. A randomized German Krebshilfe Trial that was performed by the West German Cancer Center Consortium was the first to demonstrate an organ-sparing effect of induction chemoradiotherapy (bimodality) before surgery when compared with local treatment alone (surgery followed by radiation) in a prospectively randomized trial [50]. More data on a reduction of the rate of pneumonectomies following induction therapy have not been reported. Therefore, the dogma of ‘‘oncologic resection within the boundaries of the initial tumor volume’’ still remains to be challenged. Experience from several other solid tumors, including breast cancer, cervical cancer, and esophageal cancer, however, has taught us that downstaging can be effective, especially when concurrent radiation therapy is added. With a further reduction of morbidity and mortality being realistic by taking into account the comorbidity profiles of the patients, and with a positive selection strategy of patients for the performance of surgery, organ-sparing surgery based on the postinduction disease may become even more attractive as a routine treatment in this patient group.
Surgery as a tool to evaluate pathologic response to new treatment principles New treatment principles may be added to induction protocols; their overall activity on the biology of the tumors may be monitored by pathologic examination of the resected specimen. Epithelial growth factor receptor targeting agents and vessel endothelial growth factor receptor (VEGF-R) acting drugs could be of interest for induction chemotherapy and concurrent chemoradiation protocols. The rate of pathologic CR at the time of surgery may be a good surrogate of biologic activity of such an innovative combination strategy. Therefore, surgery may be a good and valuable diagnostic tool in this clinical model of locally-advanced stage IIIA NSCLC when testing new induction therapies (eg. thyrosine kinase inhibitors, monoclonal antibodies, VEGF-R inhibitors).
Competing risks of patients who have stage IIIA disease When discussing possible treatment options for the management of stage IIIA NSCLC, the different competing risks of these patients must be taken into account. Surgery can only aim at the local disease at the location of the primary tumor (T1,T2) and some parts of the regional disease in the loco-regional structures (T3) or the mediastinal nodes (N2). The systemic disease outside the brain and the risk to develop disease within the brain are not controlled readily by surgery. Systemic chemotherapy can reduce that rate of relapse outside the brain significantly, but may not be active prophylactically on the risk of brain relapse. The risk of brain relapse may be reduced significantly by the introduction of prophylactic cranial irradiation (PCI) into this setting; however, its overall value
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has not been determined within this context [51]. Ongoing randomized trials on the role of PCI continue, including RTOG 0214 in locally advanced NSCLC. New molecular-targeted agents also may be active on the systemic disease outside the brain, but their ability to reduce brain relapse is not probable. It may be projected that the importance of surgery for definitive local control may become more important if and when systemic risk outside the brain and within the brain can be reduced significantly by inclusion of chemotherapy, molecular-targeted agents, and PCI. In this respect, careful selection of patients in whom the inclusion of surgery for definitive local control might lead to a real survival benefit must be guided by scientific and clinical evidence. These principles have to be developed within carefully planned prospectively randomized phase III trials. Also, the development of clinical and molecular prognostic or predictive factors has to be a major focus of research. This may lead eventually to a more adequate treatment individualization. The prognostic and clinical heterogeneity of stage IIIA disease has been pointed out and needs to be addressed properly to achieve this ultimate goal.
Summary Surgery has a definitive role in the subset of patients that has microscopic N2-disease—single level involvement without bulky or multilevel mediastinal infiltration shown at mediastinoscopy. This small group of patients that has ‘‘operable IIIA(N2)’’ or ‘‘minimal N2-disease’’ represents less than 15% of all patients who have stage IIIA disease. Following the IALT results, surgery followed by adjuvant chemotherapy with or without sequential radiotherapy represents a valid treatment strategy for this small and selected group of patients. All other subsets of stage IIIA disease are treated at most thoracic centers within concurrent chemoradiation protocols. Surgery following a bimodality induction is feasible and has an overall comparable toxicity profile to definitive bimodality (dose-escalated chemoradiation) or to surgery following induction chemotherapy alone. Recent results from single center or multicenter experiences demonstrated that the overall morbidity and mortality following surgery have decreased remarkably, probably as a result of improved supportive measures and learning effects. Long-term follow-up reports of bimodality protocols without surgery versus bimodality followed by surgical resection are awaited, including the North American Intergroup Trial (0139). These results will help to define the standards of care for the group of patients that has stage IIIA(N2) disease. The preliminary follow-up of this trial could demonstrate significantly increased rates of progression-free survival at 4 years; however, these data have not translated yet into a significant improvement of overall survival rates at 4 and 5 years. Further follow-up is awaited to give final conclusions on this issue. Induction chemotherapy that is followed by surgery represents another strategy in stage IIIA disease that was investigated by other cooperative groups. Future decision-making will have to take into account treatment morbidity and mortality and parameters of
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organ-sparing surgery following induction, probably best represented by rates of pneumonectomy or rates of lobectomy in the different patient groups.
References [1] Levi F, Lucchini F, Negri E, et al. Cancer mortality in Europe, 1995–1999, and an overview of trends since 1960. Int J Cancer 2004;110:155 – 69. [2] Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54(1):8 – 29. [3] Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th edition. Philadelphia7 Lippincott; 1997. p. 858 – 911. [4] Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111:1710 – 7. [5] Johnson DH, Turrisi AT, Pass HJ. Combined modality treatment for locally advanced non-small cell lung cancer. In: Pass HJ, Mitchell J, Johnson DH, et al, editors. Lung cancer: principles and practice. Philadelphia7 Lippincott-Raven; 1996. p. 863 – 73. [6] International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350:351 – 60. [7] Socinski MA, Morris DE, Halle JS, et al. Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial. J Clin Oncol 2004;22:4341 – 50. [8] Eberhardt W, Gauler T, Hepp R, et al. The role of chemoradiotherapy in the treatment of stage III non small cell lung cancer. Ann Oncol 2004;15(Suppl 4):71 – 80. [9] Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non–small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000;18:2981 – 9. [10] Vansteenkiste J, Fischer BM, Dooms C, et al. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol 2004;5:531 – 40. [11] Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899 – 909. [12] Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95:1453 – 61. [13] Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993;55:1365 – 73. [14] Depierre A, Millerron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002;20:247 – 53. [15] Winton TL, Livingston R, Johnson D, et al. A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage IB and II non-small-cell lung cancer (NSCLC) Intergroup JBR.10 [abstract]. Proc Am Soc Clin Oncol 2004;40. [16] Strauss GM, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) Protocol 9633 [abstract]. Proc Am Soc Clin Oncol 2004;40. [17] Grunenwald D, LeChevalier T. Stage category of non-small cell lung cancer: a new proposal. J Natl Cancer Inst 1997;89:88 – 9. [18] Weiden PL, Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small cell lung cancer. A phase 2 study of the LCSG. Chest 1994;106: S344 – 7.
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[19] Rosell R, Gomez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA nonsmall-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 1999; 26:7 – 14. [20] Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 1998;21:1 – 6. [21] Pass HI, Pogrebniak HW, Steinberg SM, et al. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992;53(6):992 – 8. [22] Van Kooten M, Rosenberg M, Orlando M, et al. Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer. Invest New Drugs 2002;20:439 – 46. [23] Mattson KV, Abratt RP, ten Velde G, et al. Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomised phase III study. Ann Oncol 2003;14:116 – 22. [24] Nagai K, Tsuchiya R, Mori T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003;125:254 – 60. [25] Betticher DC, Hsu Schmitz SF, Totsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial. J Clin Oncol 2003;21: 1752 – 9. [26] Cigolari S, Curcio C, Maiorino A, et al. Cisplatin plus vinorelbine as induction chemotherapy followed by surgery in the treatment of stage IIIB non-small cell lung cancer. Final results of a multicenter phase II study. Anticancer Res 2003;23:1803 – 9. [27] O’Brien ME, Splinter T, Smit EF, et al. Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer. An EORTC phase II study (EORTC 08958). Eur J Cancer 2003;39:1416 – 22. [28] Cappuzzo F, De Marinis F, Nelli F, et al. Phase II study of gemcitabine-cisplatin-paclitaxel triplet as induction chemotherapy in inoperable, locally-advanced non-small-cell lung cancer. Lung Cancer 2003;42:355 – 61. [29] Cappuzzo F, Selvaggi G, Gregorc V, et al. Gemcitabine and cisplatin as induction chemotherapy for patients with unresectable stage IIIA-bulky N2 and stage IIIB nonsmall cell lung carcinoma: an Italian Lung Cancer Project Observational Study. Cancer 2003;98:128 – 34. [30] Lorent N, De Leyn P, Lievens Y, et al. Long-term survival of surgically staged IIIA-N2 nonsmall-cell lung cancer treated with surgical combined modality approach: analysis of a 7-year prospective experience. Ann Oncol 2004;15:1645 – 53. [31] Van Schil P, Van Meerbeeck JP, Kramer G, et al. Surgery after induction chemotherapy: morbidity in the first 100 patients of the surgery arm of EORTC 08941 trial [abstract]. Lung Cancer 2003;41:S45. [32] Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880 – 92. [33] Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol 1997;15:712 – 22. [34] Eberhardt W, Wilke H, Stamatis G, et al. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial. J Clin Oncol 1998;16:622 – 34. [35] Johnstone DW, Byhardt RW, Ettinger D, et al. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-smallcell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2002;54:365 – 9. [36] Pisch J, Moskovitz T, Esik O, et al. Concurrent paclitaxel-cisplatin and twice-a-day irradiation in
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The Role of Surgery in Stage IIIA Non–Small Cell Lung Cancer Wilfried E.E. Eberhardt, Dr meda,*, Rodrigo Hepp, Dr medb, Georgios Stamatis, Prof Dr medc a Department of Internal Medicine (Cancer Research), West German Cancer Centre Essen, Universita¨tsklinikum of the University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany b Department of Radiation Therapy, Clinica Santa Maria, Hospital Padre Hurtado, Santiago, Chile c Department of Thoracic Endoscopy and Thoracic Surgery, Ruhrlandclinic, Tu¨schener Weg 40, 45239 Essen, Germany
Lung cancer is the leading cause of cancer-related deaths in North America and Europe [1,2]. More than 80% of patients can be classified as having non– small cell lung cancer (NSCLC) [3]. Although patients who have the early stages (I and II) of this disease are clear candidates for local treatments, in most cases— those who have advanced disease and proven distant metastases (stage IV)— up-front surgical resection is not considered and palliative systemic approaches consist of platinum-based combination chemotherapy protocols [3]. Stage III NSCLC subsumes a heterogeneous patient population that spans operable stage IIIA disease with minimal mediastinal lymph node involvement (‘‘minimal N2-disease’’) to extensive and diffuse bilateral mediastinal infiltration of lymphatic structures (‘‘N3-disease’’) or large and vital mediastinal organs (‘‘T4-disease’’); the last two are considered to be part of the inoperable IIIB stage group [3,4]. Surgery has an undisputed and overall accepted role only in that small group of patients that has minimal ipsilateral mediastinal lymph node involvement (‘‘minimal N2’’) found at surgical staging procedures or at up-front thoracotomy, especially in those situations when N2-disease is not suspected clinically [3]. For most patients who have stage III disease, a combination of chemotherapy and radiation is the current treatment of choice [5]. Recent de-
This work was supported in part by a grant from Deutsche Krebshilfe, Bonn, Germany. * Corresponding author. E-mail address: [email protected] (W.E.E. Eberhardt). 0889-8588/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.hoc.2005.02.002 hemonc.theclinics.com
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velopments include the use of adjuvant chemotherapy after up-front surgery in subgroups of stage III disease [6], as well as innovative ways to deliver concurrent chemoradiotherapy or combinations of chemotherapy with higherdose conformal radiotherapy techniques [7]. This article focuses on patients who have stage IIIA NSCLC and reviews the different possibilities for their treatment. Special emphasis is given to the inclusion of surgery into the different approaches to this disease stage. The current literature on this topic is reviewed and the different aspects of surgical treatment in the management of stage IIIA NSCLC are discussed.
Heterogeneity of stage IIIA non–small cell lung cancer Stage IIIA includes patients who have the following four TNM stages: T3N1, T1N2, T2N2, and T3N2. There is even further heterogeneity within this subgroup, however, because N2-disease can be based on several distinct extensions into the ipsilateral mediastinal lymph nodes [3,4,8]. There is a considerable clinical heterogeneity in the volume of lymph node disease (bulky versus nonbulky), amount of lymph node infiltration (microscopic versus macroscopic), number of involved lymph nodes (single versus multiple), and the biologic behavior of the disease within the mediastinum (lymphangitic spread versus nonlymphangitic and discontinuous spread) [9]. This differentiation does not cover the differences that are related to performance status, LDH, tumor location (upper lobe versus lower lobe), or existing comorbidities and their relevant clinical implications. There also may be further biologic variations based on molecular genetic variations of the tumors or differentially activated signal transduction pathways.
Results of surgery alone in patients in stage IIIA subgroups In patients who have pathologically proven N2-involvement at mediastinoscopy, long-term prognosis with surgical treatment alone is extremely poor [3,4,8]. Conversely, in patients who have negative mediastinoscopic findings, long-term survival rates are between 15% and 25% [3]. If mediastinal nodes are infiltrated with tumor cells, the 5-year survival rates following surgical resection are reduced to between 5% and 10% [3,4]. Another important discriminator is the clinical status of the patients at the time of diagnosis. With clinically evident mediastinal disease (bulky nodes or nodes N1.5cm) that can be confirmed at mediastinoscopy or thoracotomy, the cure rate decreases dramatically. A detailed retrospective French multicenter analysis looked at this issue and investigated 702 patients who had stage IIIA(N2) disease [9]. Five-year survival rates following surgery for patients who had clinical N2-disease and pathologic confirmation of involvement of multiple or a single mediastinal lymph node were 3% and 8%, respectively. Those patients who did not show clinical involvement
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of the mediastinal nodes in the up-front staging investigations—so-called ‘‘minimal N2-disease’’ in this evaluation—showed better 5-year survival rates of 11% (multiple nodes infiltrated) and 34% (a single mediastinal node pathologically involved). These data can represent baseline results against which future data sets can be compared. Besides surgical staging at mediastinoscopy, or alternatively at up-front thoracotomy, positron emission tomography (PET)-scanning has emerged as an important staging tool in this patient group [3,10]. Long-term prognosis is significantly better in patients who have PET-negative ipsilateral nodes compared with those who have PET-positive ipsilateral nodes. When analyzed critically, however, only the negative predictive value of PET is high; the positive predictive value of PET-scanning for the mediastinal nodes is less acceptable. Therefore, some investigators recommend that positive findings with the PET-scan should be confirmed pathologically at mediastinoscopy before a final stage can be assigned [10].
Randomized trials of adjuvant chemotherapy in stage IIIA disease Although adjuvant chemotherapy for earlier stage disease (including stage IIIA subsets) in the postoperative setting had been without major success within multicenter randomized trials until 2002, the last 2 years have brought enormous progress in this respect [11]. The first large trial had been performed by an international multicenter cooperative group, including European Organization for Research and Treatment of Cancer (EORTC) centers, and was led by an Italian consortium (Adjuvant Lung Project Italy; ALPI) [12]. This trial showed a trend toward improved event-free survival rates at 4 and 5 years from randomization for patients who received postoperative chemotherapy; however, the result was not statistically significant. There also was no significant improvement in overall survival rates at 4 and 5 years in the adjuvant treatment arm. One of the major criticisms of this trial was the inclusion of a second-generation chemotherapy regimen, including mitomycin C, into the treatment protocol. Earlier experience with this regimen pointed to increased perioperative and postoperative toxicities that probably were the result of the pulmonary adverse effects of mitomycin [13]. It has to be mentioned within this context that the French cooperative trial on preoperative, neoadjuvant chemotherapy in early disease showed a comparable negative effect on the survival rates within the first 1.5 years, probably because of the same background of pulmonary toxicities [14]. Although this ALPI-trial was the first of the new generation of mega-trials on adjuvant chemotherapy, the second one was much larger; more than 3300 patients originally were planned to be included over several years of accrual. This International Adjuvant Lung Trial (IALT) led by a French Group and performed internationally in more than 130 treatment centers was the first large clinical study to show a statistically significant improvement in overall survival (in the range of 4%–5% at 5 years) and progression-free survival for adjuvant cisplatinbased chemotherapy [6]. There was no significant interaction between the
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covariates—including pathologic stage—and overall survival and progressionfree survival. Slow accrual led to an earlier than planned termination of patient inclusion at 1867 patients. Recently, the National Cancer Institute of Canada (NCIC) randomized trial on adjuvant chemotherapy in stage IB to IIB disease and the Cancer and Leukemia Group B (CALGB) trial in stage IB disease were presented at the American Society of Clinical Oncology (ASCO) 2004 annual meeting (Table 1) [15,16]. The trials showed a significant improvement in 5-year overall survival of 15% (NCIC) and in 4-year survival of 12% (CALGB); equally significant improvements in progression-free survival rates were demonstrated. If all current trials are analyzed together, we have strong evidence from more than 2500 patients with completely resected NSCLC that adjuvant chemotherapy significantly improves overall survival. A meta-analysis that is based on individual patient data is planned to look at subgroup analysis in a broader context. This is to identify subgroups of patients that show the most profits from such adjuvant chemotherapy protocols. A further analysis—The IALT Bio-initiative— is planning to look at molecular prognostic or predictive factors to identify subsets of patients who have increased or reduced benefits from the application of adjuvant platinum-based chemotherapy. One of the current conclusions to be drawn from the different trials is that for patients who have completely resected pathologic stage IIIA NSCLC, postoperative chemotherapy significantly prolongs overall survival and is indicated in patients who have good performance status and no contraindications based on the individual comorbidity profile. Therefore, up-front surgery that is followed by postoperative adjuvant chemotherapy (plus/minus sequential adjuvant radiotherapy) has become a valuable alternative treatment approach in patients who are not found to have stage III disease within initial staging investigations, but who turn out to have stage IIIA disease by detailed pathologic investigation of re-
Table 1 Adjuvant chemotherapy in non–small cell lung cancer: randomized studies Study [reference]
Stages
ALPI [12]
I–IIIA
IALT [6]
I–III
NCIC [15]
I–II
CALGB 9633 [16]
IB
Patients 603 606 935 932 243 239 173 171
Regimen M/V/P — P/E–P/Nav–P/Vbl–P/V — P/Nav — Tax/CP —
TC 69% — 74%b — 65%c — 85% —
5-y survival a
55.2 48a 44.5% 40.4% 69% 54% 71%d 59%d
P .59 b.03 .01 b.03
Abbreviations: CP, carboplatin; E, etoposide; M, mitomycin; Nav, navelbine; P, cisplatin; Tax, paclitaxel; TC, percent of patients receiving the planned number of chemotherapy cycles; V, vindesine; Vbl, vinblastine. a Overall median survival in months. b Percent of patients who received 240 mg/m2 cisplatin. c 65% received 3 to 4 cycles. 77% patients needed dose reductions. d 4-y survival.
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sected nodes [3]. This group, however, represents only a small subset (probably not more than 10%) of patients who have clinical stage IIIA disease. Different thoracic treatment centers initially consider these patients to have ‘‘operable IIIA’’ disease, or alternatively, ‘‘minimal IIIA’’ disease with only microscopic involvement of one lymph node level [3,9,17].
Induction chemotherapy followed by surgery in stage IIIA disease The first investigations to test induction chemotherapy before surgery in stage III NSCLC started before 1990 by the Lung Cancer Study Group [18]. The largest patient group since then was treated at the Memorial Sloan-Kettering Cancer Center in New York [13]. These early trials included second-generation chemotherapy protocols in the preoperative setting, such as a mitomycin-based regimen or cisplatin-based protocols. This first experience independently stimulated groups in Spain and at the M.D. Anderson Cancer Center to perform prospectively randomized trials that compared preoperative chemotherapy followed by surgery with surgery alone in patients who had stage III NSCLC [19,20]. Both trials showed significant survival benefits for a neoadjuvant chemotherapy approach; however, both trials had to be terminated early after accruing approximately 60 patients because of early stopping rules. A third trial of the National Cancer Institute also was terminated early (because of slow accrual) but showed some survival benefit for an induction protocol with cisplatin-based chemotherapy [21]. Although surgical staging of the mediastinum was not performed uniformly in all of those trials, one can speculate that most of the patients in these early randomized trials had more minimal mediastinal involvement, not the typical bulky IIIA disease that is found at mediastinal staging with CT-scan and mediastinoscopy. This rigid discrimination is of major importance because stage IIIA NSCLC includes a heterogeneous group of patients. Within recent years only one major randomized trial investigated neoadjuvant chemotherapy before surgery compared with local treatment only. This was a prospective randomized trial that was performed by a French intergroup consortium; however, this group included a second-generation chemotherapy combination in the preoperative setting and found a significantly increased perioperative mortality in the first 6 months after thoracotomy [14]. It was speculated that the inclusion of mitomycin C into this approach led to the increased deaths by contributing to pulmonary and cardiovascular events. This may have led to the finding that there was a clear trend for improved long-term survival rates only in the group that had preoperative chemotherapy application. None of these studies looked at end points of extent of resection or organ-sparing surgery in these patients who had locally advanced disease. ‘‘Downsizing’’ and ‘‘downstaging’’ of locally advanced tumors may be of major importance for the performance of complete resections or lobectomies, instead of pneumonectomies. Further investigation on this subject is needed urgently to reduce the rate of extended resections within this patient subset.
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Within recent years there have been phase II trials that tested third-generation chemotherapy combinations as induction therapy protocols in mediastinoscopically-proven stage IIIA(N2) disease (Table 2) [14,22–30]. These combinations included carboplatin and paclitaxel, cisplatin and paclitaxel, cisplatin and docetaxel, carboplatin and docetaxel, cisplatin and gemcitabine, and cisplatin and vinorelbine. The largest trial was reported by the Swiss Schweizerisches Institut fu¨r Angewandte Krebsforschung Trials Group [25]. They used three cycles of a combination of cisplatin and docetaxel as induction therapy and found a resection rate of approximately 45% of all patients who were included in the protocol based on an intent-to-treat analysis. Treatment with these newer drug regimens resulted in significantly reduced rates of morbidity and mortality in the perioperative setting; this also may be based on learning effects within the hands of more and more experienced multimodality treatment groups. Surgery in this setting has generated fewer and fewer toxic events and, therefore, indications of surgery may be much more appropriate compared with those in former studies with treatment-related death rates of between 5% and 12%. Recent data on surgical morbidity and mortality come from the large, multicenter, EORTC-study that randomized patients who had IIIA(N2) disease following a response to three cycles of induction chemotherapy to surgery or definitive radiation [31]. Because an induction chemotherapy–only approach was chosen within this trial, the morbidity and mortality define a baseline with which to compare future approaches. Although the toxicity profile of the surgical arm has been reported, the final survival data of this randomized trial have not been published. Further long-term follow-up of this study is needed to reach the necessary number of events to give a valid statistical comparison. Two major arguments against this trial have been: (1) the comparator arm was based on a sequential chemotherapy and radiotherapy–only approach without a modern chemoradiation protocol included and (2) patients who had stable disease were not randomized. With the final results of this study awaited, however, this trial could generate a new standard of care for the multicenter setting in this stage.
Chemoradiotherapy without surgery in stage IIIA disease When discussing the role of surgery in stage IIIA NSCLC, it has to be taken into account that for most patients who are within this stage (~70%–85%), combined chemotherapy and radiotherapy is a valid and generally accepted treatment strategy [5,8,9]. Recently, concurrent chemoradiotherapy protocols represent the most active approach with 5-year survival rates in stage IIIA disease that range from 12% to 25%, based on the patients selected in the treated population [5,9]. Although chemoradiotherapy has its own typical toxicity profile (esophagitis, radiation pneumonitis), treatment-related deaths rarely are observed following this therapy and do not exceed 1% to 2%. Newer strategies to give postoperative consolidation chemotherapy (taxane-based) can add to the postoperative morbidity and mortality in this treatment schema, however. From
Table 2 Selected phase II–III studies of induction chemotherapy followed by surgery Stages
Patients
Regimen
ORR
R0
TRD
OMS
1-y OS
5-y OS
Depierre et al [14]
I-IIIA
179 176
2 P/I/MMC + S F P/I/MMC S
64% —
86% 85%
9% 5%
— —
77% 73%
44%a 35%a
Van Kooten et al [22] Mattson et al [23]
IIIAB IIIAB
JCOG 9209 [24]
IIIA
Betticher et al [25] Cigolari et al [26] EORTC 08958 [27]
IIIA IIIB IIIA
29 134 140 31 31 90 30 52
62% 28% — 28% — 66% 60% 64%
— — — 10% 22% — — —
129 42 131
3% 2% 0% 0% 0% 3% 0% 0% 0% 0% 0% b1%
61% 59% 51% 68% 65% 65% — 68.5%
IIIAB IIIAB IIIA
48% 13% 16% 65% 77% 48% 37% 13% — 29% 38% 47%
17 14.8 12.6 16 17 28 23 20.5
Cappuzzo et al [28] Cappuzzo et al [29] Lorent et al [30]
2 P/Gem + S or RT Doc 3 + S or RT S or RT 2 P/V + S versus S alone 3 P/Doc + S F RT (33 patients) 3 P/V + S 3 Tax/CP + S (15 patients) versus 3 Tac/CP + RT 4 P/Gem + S F postoperative RT 3 P/Gem/Tax + S or RT 3 P/I/V + S
19.4 21.7 24
74% 92% —
— — 21%
62% 71% 54%
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Study [reference]
Abbreviations: Doc, docetaxel; Gem, gemcitabine; I, ifosfamide; MMC, mitomicin C; OMS, overall median survival; ORR, overall response rate; R0, microscopically complete resection rate; RT, radiotherapy; S, surgery; TRD, treatment-related death rate. a 4-y survival.
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analysis of competing risks for this patient group it is clear that adequate systemic treatment with platinum-based chemotherapy is necessary to reduce the risk of systemic relapse outside the brain (Fig. 1). Therefore, alternative ways to add this systemic therapy include induction chemotherapy before chemoradiation or consolidation chemotherapy following concurrent chemoradiotherapy.
Induction chemoradiotherapy followed by surgery in stage IIIA disease To optimize preoperative downsizing and downstaging, different groups used chemoradiotherapy protocols before definitive surgery in stage IIIA NSCLC. The largest experience comes from the Southwest Oncology Group (SWOG); cisplatin and etoposide were given concurrently with 45 Gy conventionally fractionated radiotherapy before definitive surgery (Table 3) [32–44]. In this experience, 75 patients who had stage IIIA disease were treated with concurrent chemotherapy and radiotherapy. Overall, 85% of these patients’ disease could be resected. Long-term survival rates were promising although the treatment-related death rate seemed to be high (10%). Since then, many prospective phase II trials have been performed with different patient selection criteria (including IIIA and selected IIIB subsets) and different chemotherapy protocols (second-generation versus third-generation protocols) [32–44]. Most investigations showed a clear learning curve in the morbidity and mortality analysis; fewer adverse events usually appeared in the second half of the trial. The treatment-related death rate ranged from 2% to 10%, with the newer studies showing a reduced rate of approximately 4% to 6%. Different ways to combine chemotherapy and radiotherapy were used in the different investigations. Hyperfractionated accelerated radiotherapy was used in some of the trials [33,34,39,40,42,43], whereas conventionally fractionated radiation was used in others [32,35–38,41]. Generally, clinical response rates and complete resection rates (R0) were approximately 55% to 85% or 50% to 75%; these were increased treatment related events local relapse loco-regional relapse
competing risks
systemic relapse outside the brain brain relapse events due to co-morbidities natural death hazard
Fig. 1. Competing risks in patients who have stage IIIA disease.
Table 3 Selected phase II–III studies of induction chemoradiotherapy followed by surgery Stages
Patients
Regimen
ORR
R0
TRD
OMS
1-y OS
5-y OS
SWOG 8805 [32] Choi et al [33] Eberhardt et al [34] RTOG 89-01 [35]
IIIAB IIIA IIIAB IIIA
126 42 94 73
59% 74% 64%
Pisch et al [36]
IIIAB
80
—
83% 81% 53% 73% — —
10% 7% 6% 8% 5% 0%
— 25 20 19.4 17.4 28
— — — 70% 66% 68%
26%a 37% 26% — — —
Kuten et al [37] De Candis et al [38] DeCamp et al [39] Trodella et al [40] Machtay et al [41] Gauler et al [42] Friedel et al [43]
IIIAB IIIAB IIIAB IIIAB IIIA IIIAB IIIAB
37 43 105 92 53 64 114
P/E/RT 45 Gy + S F boost P/Vbl/FU/HFRT 42 Gy + S F boost 3 P/E + P/E/HFRT 45 Gy + S P/V/MMC + S (26 patients) versus P/V/MMC + RT 64 Gy (19 patients) P/Tax/HFRT 45 Gy + S or (28 patients) P/Tax/HFRT 60 Gy (52 patients) Tax/CP/RT 50.4 Gy + S or RT boost 4 Tax/CP + S + RT or RT/P P/Tax/HFRT + S + boost P/Tax/HFRT CP/RT or P/FU/HFRT + S P/E or CP/Tax + RT 45–54 Gy + S 3 P/Tax/HFRT 45 Gy + S 2 CP/Tax + CP/Tax/HFRT 45 Gy + S
52% 45% 62% 69% — 84% 60%
49% 29% 79% 61% 72% 52% 52%
3% 2% 9% 8% 9% 5%
22 15 27 17.2 21 25 22
— 51% 67% 59% — —
— — 30% 15% 31% 28%a 37%a
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Study [reference]
Abbreviations: FU, 5-Fluorouracil; HFRT, hyperfractionated RT; IIIAB, stages IIIA and IIIB. a 3-y survival.
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in comparison with induction chemotherapy–only trials. The optimal schedule for chemotherapy and radiotherapy is not known in this preoperative setting.
Trimodality including surgery versus bimodality: implications of Intergroup Trial 0139 Based on two major phase II pilots within SWOG, the phase III trial was aimed at testing trimodality versus bimodality strategies in stage IIIA(N2) disease [44]. The SWOG pilot had tested surgery following chemoradiation in 125 patients who had stage IIIA(N2) and IIIB disease [32]. Seventy-five patients of this subset were classified and pathologically proven as having stage IIIA(N2) disease. Surgery turned out to be feasible following chemoradiation and could be performed in this setting with acceptable morbidity and mortality. A follow-up phase II study piloted a definitive chemoradiation protocol with radiation doses of 61 Gy followed by consolidation chemotherapy; the 5-year survival rate was approximately 20% in a patient population of comparable (pathologically proven) patients who had IIIB disease [45]. The results of both consecutive trials led to the development of the randomized phase III Intergroup 0139 study design (Table 4) [44]. This trial randomized 429 patients to test chemoradiation followed by surgery (trimodality) versus a definitive chemoradiation protocol. Three-hundred and ninety-two patients were evaluable for the final analysis. The results of this trial were presented at ASCO 2003 and updated at the International Association for the Study of Lung Cancer World Conference on Lung Cancer in Vancouver in the fall of 2003 [44,46]. Although a significant improvement was observed in the progression-free survival results for the arm that included surgery, this did not translate into a significant overall survival benefit. Longer follow-up of this study will give more detailed information, including whether there also is a small survival benefit for selected patient subgroups following the inclusion of surgery in such a multimodality approach. One of the major findings of this prospective randomized trial was that surgery turned out to be safe and feasible, even after an intensive chemoradiation protocol in the multicenter setting. Learning effects showed reduced treatment-related mortality in the progress of the trial. This is a typical and constant finding within multicenter randomized trials, including surgical arms in the setting of stage III disease. After the logistics of such an approach have been set up and the multimodality groups have become more experienced with these protocols, the treatment-related death rate decreases to comparable rates as in settings with surgical treatment up-front, without any preoperative induction therapy.
Other randomized trials in stage IIIA disease including surgery The survival analysis is awaited for the large, randomized phase III trial that is being performed by the EORTC Lung Cancer Cooperative Group. Following
Table 4 Randomized trials including surgery in stage IIIA disease Stage
Patients
Regimen
R0
PnR
TRD
PFS (mo)
3-y survival
P
Albain et al [44]
IIIA (N2)
429a 558b
Eberhardt et al [50]
IIIA IIIB IIIA (min)
EORTC 08941 [31]
IIIA
167e NA
R0333/SS0332 [48]f
IIIA
84% — 45% 45% 60% 71% 44% — —
— — 35% 33% 20% 43% 41% — —
7% — 6% 6% 5% 2% 4% — —
14 11.7 10 10 29 15 — — —
38% 33% 24% 23% 38% 35% — — —
NS
Thomas et al [47]
P/E 2 + 45 Gy + S + P/E 2 P/E 2 + 61 Gy + P/E 2 P/E 3 + 45 Gy/bid/CP/V + S + 24 Gyc P/E 3 + S + 54 Gy F 24 Gy P/E 3 + 45 Gy/bid/P/E + PCI + S S + 45 Gy 3 C/X or 3 CP/X + S F RT 3 C/X or 3 CP/X + RT 2 P/Doc/RT 45 Gy + S + 3 P/Doc 2 P/Doc + S + 3 P/Doc
112d
NS NS — — —
Abbreviations: bid, twice daily; C/X, cisplatin and partner regimen; CP/X, carboplatin and partner regimen; Min, minimal; NS, not significant; PCI, prophylactic cranial irradiation; PFS, progression-free survival; PnR, pneumonectomy rate. a Data on 392 patients. b Data on 526 patients. c Additional dose on patients with R1/R2 resection. d Data on 106 patients. e Only data on patients randomized to surgery. f Ongoing trial.
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three cycles of platinum-based induction chemotherapy, patients with objective response (complete response [CR], partial response, or minor response) were randomized to receive surgical resection or definitive radiotherapy [31]. Accrual to this study has been finished and the final survival analysis probably will be presented at one of the upcoming oncology meetings next year. A prospectively randomized phase III study by the German Lung Cancer Cooperative Group included patients who had inoperable stages IIIA and IIIB disease [47]. Patients were randomized to: (1) induction chemotherapy with cisplatinum and etoposide followed by chemoradiation with weekly carboplatin and vindesine and hyperfractionated accelerated radiotherapy of 45 Gy leading to definitive surgery, if possible, or (2) the same induction chemotherapy protocol with cisplatin and etoposide followed by surgery, if possible, and postoperative radiotherapy up to 68 Gy. The analysis of this study was presented at ASCO 2004; there were no differences in complete resection rate, overall survival, and progression-free survival between the two randomization arms [47]. There is major criticism of the design of this trial because there is no evidence for the efficacy of weekly carboplatin and vindesine in concurrent chemoradiotherapy protocols. Also, both study arms were given radiotherapy in this setting—one arm before surgery, the other postoperatively. Furthermore, more than two thirds of patients had more advanced stage IIIB disease. It also may be that the patient selection included a heterogeneous population. As a consequence of the North American Intergroup Trial 0139, the follow-up phase III trial recently started accrual. The purpose of that trial is to compare induction chemoradiotherapy followed by surgery and consolidation chemotherapy with induction chemotherapy followed by surgery and consolidation chemotherapy (see Table 4) [48]. This study is a high priority North American Intergroup Trial that is led by SWOG and the Radiation Therapy Oncology Group (RTOG). This trial most likely will include more patients who have early and operable stage IIIA disease, not the bulky and multilevel N2 disease that also had been included in the earlier 0139 study.
Toxicity considerations of surgery in stage IIIA disease Although the early trials that included surgery in the setting of multimodality protocols for stage IIIA disease showed considerable morbidity and mortality, recent investigations proved that surgery can be performed safely by experienced multimodality treatment teams. Perioperative mortality has been reduced to approximately 1% to 2% for lobectomies and less than 4% for pneumonectomies with this strategy [49]. Therefore, surgery has become a safe means to achieve definitive local control at the location of the primary tumor. These mortalities no longer are significantly different from up-front surgery in the same setting. Moreover, it can be speculated that in selected patients, induction protocols of combination chemotherapy or concurrent chemoradiation can induce downsizing and downstaging, and thus, lead to increased complete resection rates and organ-
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sparing surgical approaches [50]. A randomized German Krebshilfe Trial that was performed by the West German Cancer Center Consortium was the first to demonstrate an organ-sparing effect of induction chemoradiotherapy (bimodality) before surgery when compared with local treatment alone (surgery followed by radiation) in a prospectively randomized trial [50]. More data on a reduction of the rate of pneumonectomies following induction therapy have not been reported. Therefore, the dogma of ‘‘oncologic resection within the boundaries of the initial tumor volume’’ still remains to be challenged. Experience from several other solid tumors, including breast cancer, cervical cancer, and esophageal cancer, however, has taught us that downstaging can be effective, especially when concurrent radiation therapy is added. With a further reduction of morbidity and mortality being realistic by taking into account the comorbidity profiles of the patients, and with a positive selection strategy of patients for the performance of surgery, organ-sparing surgery based on the postinduction disease may become even more attractive as a routine treatment in this patient group.
Surgery as a tool to evaluate pathologic response to new treatment principles New treatment principles may be added to induction protocols; their overall activity on the biology of the tumors may be monitored by pathologic examination of the resected specimen. Epithelial growth factor receptor targeting agents and vessel endothelial growth factor receptor (VEGF-R) acting drugs could be of interest for induction chemotherapy and concurrent chemoradiation protocols. The rate of pathologic CR at the time of surgery may be a good surrogate of biologic activity of such an innovative combination strategy. Therefore, surgery may be a good and valuable diagnostic tool in this clinical model of locally-advanced stage IIIA NSCLC when testing new induction therapies (eg. thyrosine kinase inhibitors, monoclonal antibodies, VEGF-R inhibitors).
Competing risks of patients who have stage IIIA disease When discussing possible treatment options for the management of stage IIIA NSCLC, the different competing risks of these patients must be taken into account. Surgery can only aim at the local disease at the location of the primary tumor (T1,T2) and some parts of the regional disease in the loco-regional structures (T3) or the mediastinal nodes (N2). The systemic disease outside the brain and the risk to develop disease within the brain are not controlled readily by surgery. Systemic chemotherapy can reduce that rate of relapse outside the brain significantly, but may not be active prophylactically on the risk of brain relapse. The risk of brain relapse may be reduced significantly by the introduction of prophylactic cranial irradiation (PCI) into this setting; however, its overall value
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has not been determined within this context [51]. Ongoing randomized trials on the role of PCI continue, including RTOG 0214 in locally advanced NSCLC. New molecular-targeted agents also may be active on the systemic disease outside the brain, but their ability to reduce brain relapse is not probable. It may be projected that the importance of surgery for definitive local control may become more important if and when systemic risk outside the brain and within the brain can be reduced significantly by inclusion of chemotherapy, molecular-targeted agents, and PCI. In this respect, careful selection of patients in whom the inclusion of surgery for definitive local control might lead to a real survival benefit must be guided by scientific and clinical evidence. These principles have to be developed within carefully planned prospectively randomized phase III trials. Also, the development of clinical and molecular prognostic or predictive factors has to be a major focus of research. This may lead eventually to a more adequate treatment individualization. The prognostic and clinical heterogeneity of stage IIIA disease has been pointed out and needs to be addressed properly to achieve this ultimate goal.
Summary Surgery has a definitive role in the subset of patients that has microscopic N2-disease—single level involvement without bulky or multilevel mediastinal infiltration shown at mediastinoscopy. This small group of patients that has ‘‘operable IIIA(N2)’’ or ‘‘minimal N2-disease’’ represents less than 15% of all patients who have stage IIIA disease. Following the IALT results, surgery followed by adjuvant chemotherapy with or without sequential radiotherapy represents a valid treatment strategy for this small and selected group of patients. All other subsets of stage IIIA disease are treated at most thoracic centers within concurrent chemoradiation protocols. Surgery following a bimodality induction is feasible and has an overall comparable toxicity profile to definitive bimodality (dose-escalated chemoradiation) or to surgery following induction chemotherapy alone. Recent results from single center or multicenter experiences demonstrated that the overall morbidity and mortality following surgery have decreased remarkably, probably as a result of improved supportive measures and learning effects. Long-term follow-up reports of bimodality protocols without surgery versus bimodality followed by surgical resection are awaited, including the North American Intergroup Trial (0139). These results will help to define the standards of care for the group of patients that has stage IIIA(N2) disease. The preliminary follow-up of this trial could demonstrate significantly increased rates of progression-free survival at 4 years; however, these data have not translated yet into a significant improvement of overall survival rates at 4 and 5 years. Further follow-up is awaited to give final conclusions on this issue. Induction chemotherapy that is followed by surgery represents another strategy in stage IIIA disease that was investigated by other cooperative groups. Future decision-making will have to take into account treatment morbidity and mortality and parameters of
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organ-sparing surgery following induction, probably best represented by rates of pneumonectomy or rates of lobectomy in the different patient groups.
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