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Eur J Cardiothorac Surg 1998;13:1-12
© 1998 Elsevier Science NL

Review article

Present status of induction treatment in stage IIIA-N2 non-small cell lung cancer: a review

Johan Vansteenkistea, Paul De Leynb, Georges Deneffeb, Johan Mentenc, Tony Lerutb, Maurits Demedtsa The Leuven Lung Cancer Group

a Department of Pulmonology (Respiratory Tumor Unit), University Hospital Gasthuisberg, Catholic University, Herestraat 49, B-3000 Leuven, Belgium
b Department of Thoracic Surgery, University Hospital Gasthuisberg, Catholic University, Herestraat 49, B-3000 Leuven, Belgium
c Department of Radiotherapy, University Hospital Gasthuisberg, Catholic University, Herestraat 49, B-3000 Leuven, Belgium

Received 20 May 1997; received in revised form 25 August 1997; accepted 23 September 1997.

Corresponding author. Tel.: +32 16 346802; fax: +32 16 346803; e-mail: Johan.Vansteenkiste@uz.kuleuven.ac.be


   Abstract
Top
 Abstract
Introduction
Method
Results
Discussion
References
 
Background: Surgical exploration in mediastinoscopy proven N2 non-small cell lung cancer (NSCLC) is unrewarding. Theoretical concepts suggest a beneficial role for preoperative induction treatment. The solidity of the therapeutic results with this approach in the currently available data is examined. Methods: Literature on induction therapy followed by surgical exploration, consisting of randomized reports and phase II reports meeting some essential criteria, are reviewed. Results: Of the twenty-four analyzed phase II studies, thirteen lack adequate surgical staging. Stratification for various important prognostic factors in N2 disease is missing in many instances. Results with induction with a cisplatinum dose of less than 80 mg/m2 seem to be inferior. The use of mitomycin-C in patients scheduled for lung resection or irradiation deserves caution. No evident difference in efficacy between induction chemotherapy or chemo-radiotherapy is suggested, but toxicity and mortality appear to be somewhat higher with chemo-radiotherapy. Pathological complete response is mainly found after an at least partial clinical response. Effect on survival in non-controlled phase II studies and small randomized reports is encouraging. Conclusions: the role of chemotherapy induction in improving the long-term survival of N2 NSCLC is promising, but needs to be confirmed by large multi-center randomized data. Adequate surgical staging and attention to important prognostic factors in N2 disease should minimize the numerous institution based differences interfering in the currently available non-controlled studies.

Key Words: Non-small cell lung carcinoma • Combined modality treatment • Induction chemotherapy • Lung surgery • N2 disease


   Introduction
Top
 Abstract
 Introduction
Method
Results
Discussion
References
 
The involvement of mediastinal lymph nodes (MLN) is a very important prognostic factor in patients with potentially resectable non-small cell lung cancer (NSCLC). N2 disease is defined as involvement of the ipsilateral mediastinal or subcarinal lymph nodes. A 5-year survival of 20% after resection can only be expected in patients with so-called `unforeseen N2' (i.e. found during thoracotomy after a negative preoperative mediastinoscopy) [1] [2] [3] [4] [5] [6] or those with `minimal N2' at mediastinoscopy (i.e. one positive lower mediastinal nodal station excluding subcarinal adenopathy [7]). In patients with `non-minimal N2' at mediastinoscopy, the results of direct surgical exploration are marginal [5] [8] [9] [10]. The poor prognosis after surgical exploration is mainly due to systemic relapses [11]. It is hoped that the prognosis of these patients can be improved by better systemic therapy (preoperative induction chemotherapy), either alone, or combined with thoracic irradiation to improve local control [12].

Many phase II trials on induction therapy in stage IIIA-N2 NSCLC have been reported. They show a large variation in objective response to induction treatment, in surgical findings after induction treatment, and in toxicity and survival. Furthermore, at the time of writing, three small randomized series have been published. This contribution is a comprehensive overview of these data, looking for factors that could possibly explain their large variability, and reflecting on the solidity of the current facts in favor of induction treatment.


   Method
Top
 Abstract
 Introduction
Method
Results
Discussion
References
 
Literature data on induction therapy followed by surgical exploration in patients with stage IIIA-N2 NSCLC were reviewed. All randomized reports, and phase II reports meeting all of the following criteria were selected: English language (or at least extended English summary) and listed in Index Medicus; published as a full paper in a peer reviewed journal; information on at least 25 patients; data mainly on patients with stage IIIA-N2 disease (some series also studied some stage IIIB patients). We consider that these criteria help to focus on studies with the most reliable information. The following items were searched for in each of these series: stage of the patients under study; percentage of the patients undergoing surgical staging; proportion of N2 in the IIIA group; induction regimen used; clinical response with this regimen; percentage of the patients undergoing surgical exploration or complete resection; percentage of the patients with a pathological complete response in the resection specimen; previous clinical response in patients with pathological complete response; survival; factors associated with better survival; patterns of relapse; toxicity of the regimen; induction and surgery related mortality.


   Results
Top
 Abstract
 Introduction
Method
Results
Discussion
References
 
Twenty-four phase II [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] and three randomized series [37] [38] [39] were analyzed. The experience of one institute is sometimes reported in several journals, since the results may be important for thoracic surgeons, pulmonary and radiation oncologists. Furthermore, an early report is often followed by one with more mature data. Only the most adequate report for our study purpose, usually the most recent one, was used.

Studies on induction chemotherapy (Table 1)
Ten phase II studies are listed according to `solidity' of the staging and the homogeneity of the IIIA-N2 group (see discussion below).


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  		Table 1. Staging and characteristics of treatment in studies on induction chemotherapy

 
In only four studies [13] [14] [15] [16], (nearly) all patients underwent surgical staging of the mediastinum and had stage IIIA-N2 disease. In two of them [14] [15], the MVP schedule, as originally described by Martini et al. [15], was used: two cycles with mitomycin-C, vindesine and a high dose of cisplatinum (120 mg/m2) before and after the surgical exploration. Postoperative radiation therapy was used for pN2 patients by Martini et al. [15] and not by Burkes et al. [14].

A two-drug regimen with vinblastine and high-dose cisplatinum (VP) was used in the study by Sugarbaker et al. [13]. All patients had 54 to 60 Gy postoperative radiation therapy.

Elias et al. [16] used cyclophosphamide and adriamycin combined with low-dose cisplatinum (CAP). Thoracic irradiation was used depending on the response to induction chemotherapy: patients with at least partial (or minimal) response underwent surgical resection, followed by irradiation; while patients with stable or locally progressive disease had additive induction with irradiation, followed by surgery.

In four studies [17] [18] [19] [20], surgical staging was used in only a minority or none of the patients, while two others [21] [22] contained an undefined mixture of stage IIIA and IIIB disease.

Studies on induction chemo-radiotherapy (Table 2)
In thirteen of the fourteen reports, both induction treatments were given concomitantly, trying to take advantage of the radiosensitizing properties of platinum compounds [40]. The study by Skarin et al. [30] was the only exception.


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  		Table 2. Staging and characteristics of treatment in studies on induction chemo-radiotherapy

 
In seven of the fourteen studies [23] [24] [25] [26] [27] [28] [29], staging was surgical in (nearly) all patients.

In four of those [24] [27] [28] [29], (nearly) all patients had stage IIIA-N2. Chemotherapy, consisting of etoposide or vindesine, 5-fluorouracil and high-dose cisplatinum (VP5FU/EP5FU), together with radiation therapy was used by Mathisen et al. [24] and Strauss et al. [28]. These studies used the synergistic action of cisplatinum and 5-fluorouracil [41] [42] and the attractive combination with radiation therapy [40] [43]. Weitberg et al. [27] used two agents, etoposide combined with high-dose cisplatinum (EP), concurrently with radiation therapy. Cyclophosphamide, adriamycin and low-dose cisplatinum (CAP), with concurrent radiation therapy was given by Eagan et al. [29].

In three studies [23] [25] [26], the results from a well defined number of stage IIIA-N2 or IIIB patients were reported. Albain et al. [23] used two cycles of etoposide, high-dose cisplatinum (EP) and 45 Gy radiotherapy preoperatively, completed by two identical cycles after the surgical exploration. The induction regimen described by Rice et al. [25] was a very accelerated one: one cycle of etoposide, cisplatinum and 5-fluorouracil (EP5FU) plus a concurrent 27 Gy hyperfractionated radiation therapy in 11 days. Wagner et al. [26] gave three preoperative cycles of etoposide, ifosfamide and (carbo)platinum (EIP) concurrently with 45 Gy radiation therapy.

In the seven other studies [30] [31] [32] [33] [34] [35] [36], surgical staging was used in only some or none of the patients.

Clinical response (Table 3)
The standard oncological guidelines for clinical response evaluation [44] were followed by most authors. In some studies the term `minimal regression' was used, though this is not a U.I.C.C. accepted response criterion. In our analysis, we classified these cases as stable disease, in accordance with international definitions [44].


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  		Table 3. Results of induction treatment in studies with surgical staging of the mediastinum

 
Reported response rates with induction chemotherapy varied from 64 [14] to 77% [15], with 8 to 10% complete responses. In the study with low-dose cisplatinum [16], this was only 39% with a 4% complete response rate. In the paper by Sugarbaker et al. [13], 88% of the patients had either a response or stable disease, but the proportion of these two was not mentioned. In the studies with induction chemo-radiotherapy, the response rates were between 46 [28] and 89% [27], with a very varying complete response rate from 0 [25] [28] to 17% [27].

Surgical findings and survival (Table 3)
Surgical exploration was intended in case of a complete or partial response. Some surgical teams [15] [24] [25] [28], however, explored all patients (of course with the exception of those developing distant metastases), while others [13] [16] [23] [26] [29] operated on patients having an objective response or stable disease (including `minimal response'). The percentage of patients undergoing surgical exploration was 56 [14] and 62% [27] in teams operating only on responders, and varied between 51 [29] and 88% [24] in the others. The complete resection rate (defined as the number of complete resections over the number of surgical explorations) varied between 65 [29] and 94% [25], except for the study of Sugarbaker et al. [13] where it was 37%.

Pathological complete response after induction therapy means the disappearance of all viable tumor cells in the resection specimen; the pathological complete response rate (pCR) (defined as the number of pathological complete responses over the total number of patients at the start) was either not reported [26] [29], absent [13], varying between 5 and 15%, or very high (23%) in one study [27]. Data on the previous clinical responses in patients with a pathological complete response in the resection specimen were available for 38 patients from 4 series [14] [15] [27] [28]: ten of them had a clinical complete response, 27 a partial one, while only one patient had stable disease.

Reported survival results are given in the last column in Table 3. Median survival time varied between 13 [23] and 28 months [24], and 2-year survival between 34 [13] and 54% [25], except for the disappointingly low figures in the study of Eagan et al. [29]. Factors reported to be associated with a more favorable survival were a lower T-stage [14] [15] [16] [23], the clinical response [15] [16], the possibility of a complete resection [14] [15] [16] [24] [29], the achievement of a pathological complete response [15] [23] [25] [27] [28], and a squamous histology [14]. Information on the relapse patterns is available in 6 series. After induction chemotherapy [13] [15] [16], recurrence in a total of 103 patients is described: 61 distant, 22 locoregional and 20 in both sites. After induction chemo-radiotherapy [23] [25] [28], relapse of 109 patients is described: 26 distant, 63 locoregional and 20 in both sites.

Toxicity and mortality (Table 4)
In the induction studies listed in this analysis, toxicity scores were apparently reported with varying degrees of diligence and, therefore, with varying percentages, thus making it impossible to obtain a systematic comparison of the different series. The most obvious toxicity's are shown in Table 4. In the induction chemotherapy studies induction related mortality ranged from 1 [15] to 3% [13] except for the study of Burkes et al. [14] where it was 10%. In the induction chemo-radiotherapy studies 2 [25] to 7% [28] was reported. Surgery related mortality ranged from 0 [16] to 4% [15] in the reports on induction chemotherapy, except again for the high number in the series of Burkes et al. [14]. In the induction chemo-radiotherapy series, 6 [24] [27] to 11% [25] was reported, except for the 0% of Eagan et al. [29].


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  		Table 4. Toxicity of induction treatment in studies with surgical staging of the mediastinum

 
Randomized data (Table 5)
Three small randomized studies have been published at the time of writing. The first one by Rosell et al. [37] compared a multimodality treatment either without (30 patients) or with (30 patients) mitomycin-C, ifosfamide and low-dose cisplatinum (MIP), followed by surgery and postoperative radiotherapy. N2 disease was confirmed by mediastinoscopy in 73% of the patients. The clinical response rate was 60%. Median survival time (8 versus 26 months) and 2-year survival (0 versus 30%) were significantly (P<0.001) in favor of chemotherapy. Roth et al. [38] randomized 32 patients to immediate surgery (complete resection in 21), followed by thoracic radiotherapy in case of incomplete resection, versus 28 patients to three preoperative cycles of etoposide, cyclophosphamide and high-dose cisplatinum, followed by surgical exploration in 20 (complete resection in 11) and also followed by thoracic radiotherapy in case of incomplete resection. Three postoperative chemotherapy cycles were added for responders to chemotherapy. Surgical staging of the mediastinum was performed in `most' patients. The clinical response rate to chemotherapy was rather low (35%). Patients treated with chemotherapy had a significantly (P<0.008) better survival: median survival time 11 versus 60 months, 2-year survival 25 versus 60%. Pass et al. [39] reported on 14 patients randomized to surgery (complete resection in 12) followed by thoracic radiotherapy versus 13 patients randomized to 2 preoperative cycles of etoposide and high-dose cisplatinum followed by surgery (complete resection in 11) followed by 4 postoperative chemotherapy cycles. All patients had surgically staged stage IIIA-N2 disease. The clinical response rate was 62%. Median survival time was better in the chemotherapy arm (P=0.095).


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  		Table 5. Randomized studies on induction treatment

 

   Discussion
Top
 Abstract
 Introduction
Method
Results
Discussion
References
 
There is a twofold rationale for using induction treatment in stage IIIA-N2 NSCLC. The most important objective is to inhibit the mainly systemic relapse pattern after surgical exploration [11] by eradicating subclinical microscopic metastatic disease, usually associated with locally advanced tumors. Another possible objective is to reduce the local extension of the tumor, so that a complete resection becomes feasible.

The theoretical advantages of using chemotherapy as a preoperative (induction) treatment, rather than in an adjuvant setting, have been described by Goldie [45]. Earlier administered chemotherapy can be more effective, resulting in higher chances of eradication of still very small microscopic metastases (less than 106 cells). Preoperatively used chemotherapeutic agents are more equally distributed in the tumor and lymph nodes, since the vascularisation remains intact before surgery. The effectiveness of the chemotherapy can be evaluated in detail on imaging studies and pathologically confirmed by examination of the resection specimens. Based on these findings, the decision on further postoperative chemotherapy can be taken.

The 24 non-controlled phase II induction studies in stage IIIA-N2 NSCLC deal with a total of 1260 patients, 977 with stage IIIA (at least 880 with IIIA-N2), 224 with stage IIIB and 59 in which the stage is not well defined. There is a large variability in the results. We think this can be explained by several factors.

First, the numerous institution based differences, which are always operative in non-controlled trials: selection and inclusion of patients, unknown institution related habits, opinions on resectability, interpretation of CT-scans and histopathology.

Second, the problem of diminishing denominators in the calculation of the survival rate in many of these studies.

Third, the lack of stratification for the various prognostic factors in N2 disease. In previous study [46] we showed that performance status, local extent (T-factor) and pathology of the tumor, number of metastatic levels and nodal capsule rupture were important factors.

Finally, the very important issue of exact patient definition and clinical node staging. It is well known that a CT-scan is only a very rough tool to stage the mediastinum in NSCLC, with an accuracy of only 60%, and a large risk of both under- and overstaging [47] [48] [49]. One of the most striking points in the reviewed literature is that staging is non-surgical in 13 of the 24 studies, and that patients are considered to have stage IIIA-N2 based on the CT-scan findings only! Too often, this point is not mentioned in non-surgical discussions on this issue. The problem in the interpretation of the results is that patients with contralateral normal sized MLN on the CT-scan, can nonetheless harbor metastases in these nodes, and in fact have stage IIIB-N3 disease, where both response and survival rates are expected to be worse [50] [51]. On the other hand, patients with enlarged ipsilateral MLN on the CT-scan, can have inflammatory nodes, and in fact N0 disease, which has a much better prognosis [51]. Another important point is the heterogeneity of stage IIIA-N2. Patients with a T3N0 or T3N1 tumor have a far better prognosis than those with N2 disease, especially if the T3-factor is caused by resectable chest wall invasion [52] [53]. So, the number of N2 patients in the stage IIIA group is of crucial importance. It's difficult to reflect on the therapeutic chances of a patient with N2 disease based on data of vaguely defined `stage III' patients.

Consequently, we concentrate our further comment to series with well-defined stage IIIA-N2 groups. The clinical response rates of the various induction regimens (Table 3) are between 39 and 89%. The lowest figure comes from a study with low-dose (60 mg/m2) cisplatinum induction chemotherapy [16]. Apart from this study, there seems to be no clear difference in clinical response rate between induction chemotherapy or chemo-radiotherapy. Complete clinical response rates are very variable, especially those after chemo-radiotherapy, and it is remarkable that two groups using chemo-radiotherapy [25] [28] did not report complete responses. The effect of response review by a panel, the difficulty in the interpretation of the CT-scan after chemo-radiotherapy, or the fact that these two groups gave only half of the treatment preoperatively are hypotheses to explain this finding. Only one abstract [54], presented in 1993, made a randomized comparison between induction chemo-radiotherapy (high-dose cisplatinum, etoposide and radiotherapy) or chemotherapy (mitomycin-C, vinblastine and high-dose cisplatinum). The response rate was higher in the chemoradiation therapy arm, and more patients remained free from progression at the time of reporting. Until now, no update or full report of these results has appeared.

The percentage of patients undergoing surgical exploration varied between 56 and 88%. This broad range can be attributed to the decision whether or not to operate on patients with stable disease, and to varying attitudes towards the feasibility of surgical exploration in different centers. Surgical exploration may be feasible in many patients, long-term survival, however, can only be obtained after a complete resection. Some reports did not give a precise definition of this important issue [16] [26], in others complete resection was the removal of the primary tumor with mediastinal sampling [28] [29] or dissection [14] [15] [25] [27]. Free resection margins on microscopic examination as an additional criterion for complete resection were mentioned in three studies [13] [23] [24]. Bearing in mind the limitation of a varying definition of complete resection, the complete resection rate is, nonetheless, very similar in all reports, except for the one by Sugarbaker et al. [13]. We could not find a clear reason for this. The report comes from a very experienced center; maybe the very strict definition of complete resection or the inclusion of many patients with bulky N2 played a role. It remains unclear if induction therapy improves resectability. The complete resectability rate in clinical N2 patients in earlier studies with surgical treatment only varied from 18 [9], over 24 [55], 28 [56] to 65% [5]. Uniform resectability criteria and randomized data are clearly needed to clarify this point.

A pathological complete response in the resection specimen was either not reported or reported in 5 to 15% of the patients. The study by Weitberg et al. [27] is a notable exception with 23%. The very high dose of preoperative radiotherapy (54 Gy) may explain this. Achievement of a pathological complete response is a crucial point in induction treatment, as mentioned by several groups [15] [23] [25] [27] [28]. This was further emphasized by Pisters et al. [57] in the large Memorial–Sloan–Kettering data on chemotherapy induction. The 5 year survival of patients with a pathological complete response, in their experience, was estimated to be 54%, while the 5 year survival of those without it was only 15%. Most of these pathological complete responses occurred in patients achieving a previous clinical response that was either complete or partial. Consequently, there is general agreement on surgical exploration in patients with at least a partial clinical response. In an attempt to salvage as many patients as possible, some authors also suggest it in patients with stable disease during induction treatment [13] [15] [23] [24] [25] [26] [28]. Looking at the correlation between clinical response and pathological complete response in the data, we see that all but one patient with a pathological complete response after induction had an at least partial clinical response. Pathological complete response, essential for a good prognosis, was thus exceptional in clinically non-responding patients. As a whole, surgical exploration in patients with stable disease will only have a marginal effect in improving long-term survival results in these patients.

Survival is always difficult to interpret in phase II studies, due to the problems already mentioned above. The importance of unknown prognostic factors is illustrated when one compares the survival results in the two very well defined studies of Strauss et al. [28] and Mathisen et al. [24]. Although they both used an apparently very similar treatment (Table 2), the respective median survival times and 3-year survival rates were 16 versus 28 months and 27 versus 43%. This difference can probably be explained in part by the presence of 27 on 40 patients with only one single metastatic MLN level at mediastinoscopy in the second series. The number of involved lymph nodes is, indeed, a well known prognostic factor in N2 disease [46]. Nonetheless, the survival data with median survival times between 11 and 28 months and 3-year survival rates between 23 and 43% are hopeful, compared to data in mediastinoscopy proven N2 disease [5] [9] [46]. Large-scale randomized phase III studies, currently underway, will probably solve the key question if induction therapy improves long-term survival in mediastinoscopy proven N2 disease.

The factors reported to be associated with better survival are logical. The importance of the clinical and pathological response have already been mentioned above; the relevance of a squamous histology, a complete resection and a lower T-stage are known from data on surgically treated N2 disease [46].

The reported relapse patterns show more locoregional relapses in patients treated with induction chemo-radiotherapy (63/109) compared with those receiving chemotherapy alone (22/103). Intuitively, one would expect the opposite, and an explaination of this finding is speculative at the moment. One hypothesis could be the higher occurrence of dose reduction of either the chemo- or radiotherapy, when both modalities are given in a simultaneous way preoperatively. Another reason could be the differences in assiduousness of the follow-up examinations after treatment.

Leukopenia and severe infections emerge as an important cause of induction related toxicity with an occurrence that tends to be higher in the series with induction chemo-radiotherapy. Furthermore, radiation pneumonitis, sometimes pericarditis, and severe radiation oesophagitis are a matter of concern in simultaneous chemo-radiotherapy. The pulmonary toxicity associated with the use of mitomycin-C deserves attention. Mitomycin-C can be responsible for acute interstitial pneumonitis [58] [59], slowly developing interstitial fibrosis [60] [61], diffuse alveolar damage [58] and pulmonary hypertension [62]. The reaction is dose-dependent, occurring at a cumulative dose greater than 10 mg/m2. A substantial regression of this pulmonary toxicity can be achieved by high-dose glucocorticosteroids [60] [63]. The mitomycin-C containing MVP regimen is a well known and effective regimen in metastatic NSCLC [64]. In a context of induction chemotherapy, however, where patients also have to undergo lung resection or lung irradiation, mitomycin-C needs to be administered with caution or perhaps be avoided, since other equally effective regimens exist [65]. Interesting data on this issue are found in the large series of Martini et al. [15]: 15 of 18 cases of pulmonary toxicity were attributed to mitomycin-C. In 10 patients this problem developed preoperatively: surgery was cancelled in four, and there was one severe and one fatal complication in the six others. Five patients had postoperative pulmonary problems, a second patient died of this complication after having a pneumonectomy.

The total (induction and surgery related) mortality appears to be a little lower in the chemotherapy series than in chemo-radiotherapy ones: 2–5% versus 6–15%. The only exception is the study by Burkes et al. [14], where the unexpectedly high mortality could be attributed to four septic deaths in patients with obstructive pneumonitis. Respiratory insufficiency and the development of a bronchopleural fistula are the main causes of the higher postoperative mortality than expected in modern thoracic surgery [66]. The higher risk of a bronchopleural fistula in patients with previous irradiation was already documented long ago [67] and in the early 1980s by Pearson et al. [5].

The actually available randomized data on induction chemotherapy are encouraging, but small, and need to be interpreted with caution. In the study of Rosell et al. [37] 60 patients with potentially resectable stage IIIA (mostly N2) were randomized. A significant difference in survival emerged at an interim analysis. A real problem with this study is the unexpectedly poor survival in the arm treated without chemotherapy. Better survival is known in surgically treated patients with potentially resectable tumors, with median survival times in the range of at least 12 months and 5-year survival rates of 13.9 [68], 6 [69], 10.6 [70], 9 [5], 14.3 [55] and 6% [56]. Here again, prognostic factors, not taken into account with stratification, probably disturb the analysis. One of them was emphasized by the authors: the biologically important prognostic factor K-ras expression [71] was present in 10/24 specimens (42%) in the surgery-only arm (9 of these 10 patients died early due to distant metastasis), while it was found in only 3/20 (15%) in the chemotherapy arm. The study of Roth et al. [38] is remarkable in the opposite direction. The median survival time (11 months) and 3-year survival (15%) are what we can expect from surgical treatment in this cohort of patients. In the chemotherapy group median survival time (64 months) and 3-year survival (56%) are very high and, thus, we suppose that in spite of the randomized design again some imbalance in prognostic factors still influences the results. The importance of this is further illustrated by the striking similarity of the survival at 2 years of the `surgery-only' patients of Roth et al. (25%) with the `chemotherapy-plus-surgery' patients of Rosell et al. (30%).

It is quite obvious that it is difficult to draw an overall conclusion from the available data, but some interesting points emerge from this analysis.

A striking finding in the 24 analyzed phase II studies is the lack of adequate surgical staging in 13 of them. This fact, together with the lack of stratification for various important prognostic factors in N2 disease, and the numerous institution based differences operative in non-controlled studies, probably explain a large part of the varying therapeutic results.

As for the induction regimen, a cisplatinum dose of at least 80 mg/m2 is to be preferred. The pulmonary toxicity associated with the use of mitomycin-C deserves attention. No evident difference in efficacy between induction chemotherapy or chemo-radiotherapy is suggested from the current data. Furthermore, some toxicity and mortality appear to be a little higher with chemo-radiotherapy than with chemotherapy.

Whether there is an improvement in resectability is unclear, uniform resectability criteria and randomized data are clearly needed to clarify this point in the future.

Pathological complete response, essential for a good prognosis, is mainly found after an at least partial clinical response, and it is to be expected that surgical exploration in patients with stable disease will only have a marginal effect in improving long-term survival results of these patients.

The role of induction chemotherapy in improving the long-term survival of patients with stage IIIA-N2 NSCLC is far from clear, but there are encouraging findings in non-controlled phase II studies and small randomized reports. Much larger numbers of patients will be needed to prove that this therapeutic approach actually works, especially since a recent meta-analysis on the role of chemotherapy in NSCLC [72] suggested that the benefits are real but small. So this approach can not yet be considered as a clinical standard, but there is an urgent place for it in large-scale randomized trials.


   Acknowledgments
 
This study was supported in part by a private grant (8 E01 2010 27 1612) from Baron Georges Stalpaert, Emeritus Professor of Thoracic Surgery.


   References
Top
 Abstract
 Introduction
Method
Results
Discussion
References
 

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