Journal of Thoracic Oncology:
State of the Art: Concise Review
What to do with “Surprise” N2?: Intraoperative Management of Patients with Non-small Cell Lung Cancer
Detterbeck, Frank MD
Division of Thoracic Surgery, Department of Surgery, Yale University, New Haven, Connecticut.
Disclosure: The author declares no conflict of interest.
Address for correspondence: Frank C. Detterbeck, MD, Yale University, New Haven, CT. E-mail: firstname.lastname@example.org
There is debate about how patients should be managed when malignant involvement of mediastinal lymph nodes is encountered at the time of lung resection. A comprehensive review of the literature demonstrates that differences in which outcomes are reported and how extensively patients were staged preoperatively explain much of the conflicting data. Certain negative and positive prognostic factors can be defined, but in general the outcomes justify proceeding with resection unless it is clear that disease will be left behind. Reasonable arguments can be made that the approach should include a mediastinal lymph node dissection and adjuvant therapy.
The subject of intraoperative assessment and management of unanticipated N2 involvement remains a confusing area. The term “surprise N2” in this article refers to any patient who is discovered to have N2 lymph node involvement that was not suspected or documented preoperatively. The data often seems to be conflicting, in part because the patient populations vary (e.g., with respect to selection or the extent of preoperative staging investigations). Because of confusion about the data, approaches are often driven more by underlying attitudes or assumptions. For example, some take a simple, existentialistic approach that staging is relatively unimportant because outcomes are determined by fate, or at least factors about biologic behavior that we are not able to predict. The implication of this attitude is that treatments other than surgery are not useful. Others believe that dissemination of lung cancer is primarily though lymphatic drainage in a progressive manner, and therefore that resection of all potentially involved nodes is crucial (and that the highest node is negative). Others believe that nodal involvement is only useful as a prognostic marker, representing a surrogate measure of whether a tumor has developed the ability to grow significantly at other sites. Proponents of this theory cite the fact that tumor cells circulating in the bloodstream are quite frequent, even in node-negative cancers, but do not always lead to disseminated metastases. The data are not currently available to clearly prove or refute such different underlying beliefs.
This article takes a purely pragmatic approach, and discusses data that pertains to a number of practical clinical questions that surgeons face. These include whether intraoperative nodal assessments should affect if resection is carried out, whether it affects the extent of pulmonary resection, including if there are special situations in which these questions should be answered differently. Finally, this article considers the question whether there is a therapeutic benefit to complete removal of all lymph nodes by means of a mediastinal lymph node dissection (MLND), or whether the extent of intraoperative node assessment merely contributes to the accuracy of pathologic staging.
DOES MEDIASTINAL NODAL STATUS AFFECT THE DECISION TO RESECT?
Mortality and Quality of Life (QOL)
Should the status of mediastinal nodes as assessed at the time of thoracotomy affect the decision to proceed with a resection? This question really comes down to an assessment of the long-term survival versus the short-term mortality and the effect on QOL. Answering the question is complex, because the long-term survival, in particular, depends on many factors and must be carefully considered.
There seems to be little difference in the perioperative mortality of an exploratory thoracotomy versus a resection. The average reported operative mortality after an exploratory thoracotomy is 4% (0–7%).1–7 The average operative mortality for pulmonary resection is approximately 4%,1 although more recent series suggest it has decreased to about 2%.8–10
The data for QOL generally suggests that both short-term and long-term QOL considerations have little impact on intraoperative decision making. Most studies of perioperative QOL have suggested that although short-term QOL is decreased by surgical resection, QOL returns to baseline by 6 months.1,11,12 There is no formal data concerning the short-term morbidity of recovering from an exploratory thoracotomy versus a resection, but there is little reason to expect there to be a difference. Not undergoing a resection carries a psychologic burden of loss of hope, whereas resection is associated with loss of lung function, However, the majority of studies11,13–16 demonstrate good long-term functional capacity even in patients with limited pulmonary reserve (with only a few exceptions).17,18
Long-term survival of patients with pN2 disease (i.e., postresection N2 disease) varies markedly according to preoperative factors and the extent of preoperative staging investigations. It must be noted that pathologic staging, as officially defined, is staging done after a surgical resection. Clinical staging involves any and all information available before resection, and may be very extensive (e.g., including mediastinoscopy) or fairly limited. On one end of the spectrum are patients who were thought to have stage I or II disease after extensive preoperative staging involving imaging and invasive procedures, but are found postoperatively to have pN2 disease. The term incidental N2 has been used for such patients when the nodal involvement is discovered postoperatively, and perhaps “unsuspected N2” would be appropriate when it is found intraoperatively in such well-staged patients. On the other end of the spectrum are patients with suspicious mediastinal nodes (by computed tomography [CT] or positron emission tomography) who nevertheless undergo a resection (without further staging investigations), which then demonstrates pN2 involvement. These patients should perhaps be more appropriately called “ignored N2.” In between these groups are patients with more subtle suspicion of N2,3 involvement such as those with a central tumor or with N1 node enlargement, who do not undergo an invasive staging procedure (even though there is a well-documented 20% chance of N2 involvement despite a normal CT or positron emission tomography of the mediastinum).19,20 Such patients who are found to have pN2 disease at the time of resection should perhaps be called “underappreciated N2.” These distinctions are important, because pN2 patients with minimal preoperative investigations cannot necessarily be expected to have the same survival as those undergoing extensive preoperative staging. Omitting pursuit of a biopsy is not the same as a negative preoperative biopsy result.
In assessing long-term outcomes one must be careful to avoid being misled by studies that report only the survival of the best subgroup, selected after the fact (i.e., excluding incompletely resected patients or perioperative deaths). It is best to consider the outcome for all patients who were subjected to surgery, because only these data are clinically applicable to new patients who are being considered for surgery or are undergoing surgery and are found to have “surprise” N2 disease. Whether a microscopically complete resection will be achieved cannot really be determined until after the resection has been completed. Among patients with cN2 disease by CT (and pN2 involvement), approximately one-third will undergo incomplete resection, whereas among those with cN0,1 disease (and pN2 involvement), approximately one-fourth are incompletely resected. The vast majority of studies have found extremely poor 5-year survival in incompletely resected studies (average 4%).21–36
Long-term survival according to how preoperative staging was done is summarized in Table 1. Only a few studies have reported outcomes in patients in whom N2 involvement was proven preoperatively. Although these studies involved very highly selected patients (generally thought to have only microscopic disease in a single-node station), 5-year survival for all patients is only 10 to 15%. This demonstrates that we have poor ability to select a favorable cohort among patients with preoperatively proven N2 disease. In other words, if N2 disease is documented preoperatively, resection does not seem to be justified because the long-term outcomes are so poor (even among highly selected patients). The results of alternative treatment approaches (i.e., neoadjuvant therapy and resection or definitive chemoradiotherapy) for patients with stage III non-small cell lung cancer (NSCLC) is generally >15%, even though these approaches have usually involved a broader group of patients with a larger disease burden in the mediastinum (see Alternative Treatments section).
In patients with cN2 disease by CT in whom minimal surgical staging was done, survival after resection is similarly poor (∼15%) when pN2 involvement is found. Although the outcomes seem to be a few percentage points higher than for preoperatively proven N2 disease, this is likely because of the inclusion of many studies from Asia (Asian studies generally seem to have better outcomes, see below). The argument to forego invasive staging in cN2 patients because of good long-term outcomes after resection does not seem justified. The outcomes show that our ability to select favorable patients among those with suspected N2 disease is disappointingly poor, and suggests that it is not justified to subject patients with cN2 disease (“ignored N2”) to thoracotomy (except perhaps after preoperative chemotherapy in a multimodality treatment plan). One could draw the conclusion that such cN2 patients should be closed and receive chemotherapy and radiation (with or without subsequent reoperation and resection). However, the real conclusion has to be that the N2 involvement in these patients should be identified by other means instead of a thoracotomy.
Careful preoperative staging therefore seems to be important, because outcomes of patients with cN2 disease (either biopsy proven or radiographically suspected) are poor. It is disturbing, however, that the 5-year survival was very poor (5–10%) in reported series of patients with cN2 disease (by CT) in whom the majority underwent a negative mediastinoscopy (but were nevertheless pN2 after resection).29,37 Therefore a false-negative mediastinoscopy does not predict a better outcome. Perhaps these are patients in whom resection should be aborted in favor of an alternative approach (chemoradiotherapy or neoadjuvant therapy and later resection). The quality of how well mediastinoscopy is performed is probably important. A large series from United States found that not even a single lymph node was biopsied in approximately half of all mediastinoscopies for staging of lung cancer.38 At the other end of the spectrum is a complete bilateral transcervical extended lymphadenectomy for staging (average of 39 nodes removed, missed mediastinal nodes in only 13%, and a negative predictive value for N2 disease of 96%).39
Survival is more acceptable in patients with pN2 disease that are cN0,1 by CT. In series where limited confirmation of the mediastinal nodes was done, the 5-year survival for all patients is approximately 27%. Similarly, in series in which all patients had a negative mediastinoscopy (and cN0-2 disease by CT) the 5-year survival is 26%. Series involving less rigorously selected patients (cN0-2 by CT and “selective” [negative] mediastinoscopy) have reported somewhat inferior survival (22% for all patients, 19% for R0 patients).26,28,30,40–42 These outcomes suggest that resection of fairly rigorously staged patients with cN0,1 disease is justified even if pN2 involvement is found (“incidental N2”). The survival of patients who have more selective staging and are found to be pN2 is slightly inferior. Patients with “underappreciated N2” disease probably fall within this group. The survival of this group indicates that resection is reasonable, although it also suggests that more diligent preoperative staging may be worthwhile.
Across all studies the 5-year survival in series from North America seems to be approximately half that of European of Asian series (7 versus 18 versus 17% for cN2; 14 versus 28 versus 30% for cN0,1 with limited preoperative invasive staging, respectively). This is important to keep in mind, as there are regional differences in lung cancer on different continents (high proportion of squamous cancers in Europe, higher proportion of adenocarcinoma, bronchioloalveolar carcinoma, and endothelial growth factor receptor abnormalities in Asia). There also seem to be cultural differences in how specific lymph nodes are classified, and a node near the pleural reflection is more likely to be classified as N2 by Japanese surgeons and N1 by European surgeons.43 It is unclear how this compares with classification practices in North America. A revised node map that seeks to reconcile continental differences is being developed.44
It is difficult to define how a specific factor should influence the intraoperative decision of whether to proceed with resection, because one factor can really not be viewed in isolation from others. The importance of the extent of preoperative staging has already been discussed. Furthermore, there are geographic variations in outcomes. Finally, it is unclear how well postoperative criteria that define subgroups with good or poor survival can be extrapolated to factors that can de determined intraoperatively. Each of these issues confounds the ability to define prognosis relative to a single factor accurately enough to dictate how such a patient should be managed when surprise N2 is found.
Several studies have performed multivariate analyses of multiple factors, which is the necessary approach when there are multiple interrelated factors (Table 2). These studies indicate that an incomplete resection, multilevel N2 involvement, clinical N2 stage (by CT), and subcarinal node involvement are independent markers of poor prognosis in more than half of the studies. The presence of T3,4 tumors, pN1 disease, and increasing age are less consistent negative prognostic markers of a worse prognosis. The histologic type of NSCLC, or whether the tumor involves a lower or upper lobe does not seem to be important. Similarly whether a pneumonectomy or lobectomy is needed has little independent prognostic significance.
The clinically relevant issue is whether any intraoperative findings preclude proceeding with a resection because the outcome is likely to be very poor. An analysis of all larger series reporting survival data on particular patient subgroups is shown in Tables 3 and 4. The inclusion criterion for this review was chosen so that there would be sufficient numbers of patients in each group to have reasonably reliable survival estimates. Furthermore, it was chosen to focus on studies reporting on a variety of factors (as opposed to smaller studies that focused on a specific factor) in an effort to reduce publication bias. However, this review is compared with another systematic review involving any study reporting on ≥20 patients in a particular subgroup.40
The available data suggests that resection is not justified if it is incomplete. The long-term survival is consistently poor (average 5%, range 0–10%). This is true in this review and in others (involving different inclusion criteria).40 The definition of an incomplete resection varies, being defined by some as a microscopically positive margin,27–31,35,41,45,46 whereas others also include patients with extracapsular involvement of a mediastinal node,47 and others include patients in whom the most distant (highest) node was positive.24,33,34,48 However, the survival of incompletely resected patients seems to be consistently poor, regardless of the definition. Extracapsular extension was not of prognostic significance in multivariate analyses,27,31 and neither was involvement of the highest lymph node (Table 2). The only study to investigate some aspects of the definition of incomplete resection concluded that only a mere lack of a complete lymph node dissection did not confer a poor outcome and should not be used as a definition of incomplete resection (as opposed to a positive margin or the most distant node being positive).7 Therefore, it seems reasonable to conclude that there is little justification for proceeding with a resection if it can be determined that it will be incomplete, with the most robust definition being a positive margin.
Several factors listed in Table 3 can be grouped as relatively negative prognostic factors, namely clinical N2 by CT, multilevel N2, T3 tumors, or subcarinal node involvement (5-year survival of 14, 13, 11, and 17% respectively, as shown graphically in Figure 1A). These data are in close agreement with a previous systematic review (5-year survival rates of 15, 13, and 15% for multilevel N2, T3 tumors, or subcarinal node involvement, respectively).40 However, the range of reported results varies quite widely from values that would quite clearly argue against proceeding with resection (<5% 5-year survival), to values that would argue for resection (>20% 5-year survival). This is likely because of the confounding factors. For example, the subcarinal node results are likely confounded by inclusion of patients with multilevel or nonregional node involvement, because more lung cancers originate in the upper lobes, which predominately spread to paratracheal nodes. The large International Association for the Study of Lung Cancer (IASLC) staging revision database confirmed worse survival for multilevel pN2 involvement with a 5-year survival of 20% (other factors such as T stage were not able to be analyzed).49
Several factors stand out as relatively consistent positive prognostic factors (Figure 1B). These include a R0 resection, a T1,2 tumor, single-level N2 involvement, and patients staged as clinical N0,1. Although the reported survival ranges are broad (Table 4), they do quite consistently support resection for surprise N2 discovered at thoracotomy. These results are consistent with that of other reviews.40,49,50
Factors that seem to have limited value in differentiating patients with good or poor prognosis include the histology, extent of resection, and in more limited data the location of the tumor (upper versus lower lobe), and the presence of involved N1 nodes (5-year survivals of 20% for adenocarcinoma, 26% for squamous cancer, 19% for pneumonectomy, 24% for lobectomy, 20% for lower lobe, 24% for upper lobe [among operated patients], and 23 versus 40% for nonskip and skip N2 [among completely resected patients]). These results are all consistent with another systematic review,40 and the IASLC staging project did not define a consistent difference with respect to skip N2 involvement.49 A limited amount of data in the analysis presented here suggests that survival is poor (6%) if there is involvement of the highest mediastinal nodes (stations 1 and 2). However, another systematic review found an average 5-year survival of 18% in such patients (involving three studies of >20 such patients, primarily completely resected).40 Finally, multivariate analyses have not found this factor to be important.
Tumors in the left upper lobe (LUL) with involvement of aortopulmonary window (APW) lymph nodes deserve specific mention. A number of authors have reported particularly good results (>40% 5-year survival) in these patients, but have done so by reporting on only selected patients (only completely resected, often with other node stations negative).51–53 Results applicable prospectively to patients as they are encountered in the clinic or operating room demonstrate approximately 20 to 30% 5-year survival for patients with station 5 nodal involvement.40 These results are not clearly different than those of tumors in other lobes involving only a single mediastinal node station. Furthermore, multivariate analysis has not demonstrated that APW nodes carry any particular significance. A previous review of studies involving ≥20 patients found similar survival among pN2 patients with or without APW node involvement, with conflicting trends and no statistically significant difference in any of the studies analyzing this.40 The IASLC staging revision project found no difference in survival for single-level pN2 involvement of subcarinal versus APW nodes for left-sided lung cancers.49 Therefore, although the data suggests that LUL resection should proceed if APW node involvement is found, the preponderance of data does not support that the LUL and the APW represent a biologically different situation than other lobes and regional nodal areas.
A few studies have investigated the prognostic value of involvement of only “regional” N2 nodes,24,27,32,53 with conflicting and unclear results. Okada et al. suggested that survival is dramatically better for patients with upper lobe tumors involving only stations 1 to 6 versus 7 to 9, for lower lobe tumors involving stations 7 to 9 versus 1 to 4, and to a lesser extent left upper lobe tumors involving stations 5 and 6 versus any others.53 Another study has qualitatively reported very poor outcomes with involvement of nonregional nodes.27 However, a third study found no survival difference in patients with upper lobe tumors involving stations 1 to 4 versus 7 to 9, and found significantly worse survival with lower lobe tumors involving stations 7 to 9 versus 1 to 4.24 Finally, Watanabe et al. found no difference in 144 completely resected patients.32
What conclusions can be drawn? First, application of the data regarding a specific factor should be done with caution, because of confounding variables such as the extent of preoperative staging, clinical node status, geographic variation, and other factors. Second, it seems fairly clear that there is little point in proceeding with a resection that is expected to be incomplete. Third, if it seems likely that a complete resection can be accomplished it is generally appropriate to proceed, given that the morbidity and mortality of the thoracotomy and its effect on the feasibility of delivering chemoradiotherapy in a timely fashion has already been incurred. This is fairly clearly true in the case of a T1,2 tumor, single-level node involvement, and patients with a cN0,1 tumor based on careful preoperative staging. This is probably also true for patients with upper lobe tumors involving only regional nodes (LUL and station 5 or right upper lobe and R4). One should not hesitate to carry out a pneumonectomy if necessary (provided the patient is able to tolerate this), and should not change the approach based on the histologic subtype. The situation is less clear in patients with multilevel N2, clinical N2 by CT, T3 tumors, or subcarinal node involvement. However, although these patients seem to have worse survival (around 15%), in general resection is justified unless there are significant comorbidities or multiple poor prognostic factors.
HOW MUCH RESECTION IS NEEDED?
Lobectomy versus Pneumonectomy
Controversy exists about whether a lobectomy or pneumonectomy should be performed if N2 disease is encountered. Some surgeons believe that a pneumonectomy should always be performed if N2 disease is encountered, to more completely remove tumor-bearing lymphatics. Unfortunately, this issue has not clearly been addressed by any study. Most studies have shown worse survival after pneumonectomy than lobectomy,26,28,37,54,55 although some found the opposite.27,41 This is almost certainly confounded by more extensive tumors (higher T stage) in patients requiring pneumonectomy.37,54 Nevertheless, these data undermine the argument that there is something to be gained from a pneumonectomy, and the data in Table 3 suggest that survival is reasonable even if pneumonectomy is required. Furthermore, the meta-analyses in Table 2 do not demonstrate the extent of resection to be of prognostic significance. Finally, although the lymph nodes in stations R4, 7, and 5 are adjacent to the mainstem bronchi, it is not clear how pneumonectomy and MLND actually result in a more complete resection of involved N2 nodes compared with a lobectomy and MLND.
Occasionally, a central tumor is amenable to a sleeve resection (involving the bronchus, pulmonary artery, or both) as an alternative to a pneumonectomy. An average 5-year survival of 27% has been found among studies reporting specifically on patients with pN2 disease undergoing sleeve resection.56–62 This does not seem to be noticeably different than the survival of pN2 patients undergoing a standard lobectomy, and is not worse than the survival of pN2 patients undergoing pneumonectomy (Tables 3 and 4). Therefore, the data support sleeve resection as a reasonable alternative to pneumonectomy even in the face of N2 disease.
THE VALUE OF MLND
Role of MLND in Staging
Intraoperative handling of the mediastinum can involve a complete MLND, a systematic node sampling, or a selective sampling. A formal MLND involves removal of all of the node-bearing tissues, leaving only the skeletonized trachea, phrenic nerves, aorta, and superior vena cava behind.35 A systematic mediastinal node sampling means that the pleura overlying each ipsilateral node station is opened, explored, and representative biopsies of nodes are obtained. A selective sampling, on the other hand, involves biopsy of only selected mediastinal nodes that are felt to be abnormal. Some authors advocate a lobe-specific systematic node dissection, which consists of a complete dissection of those nodal regions most often involved by tumors in a particular lobe.63
It is well established that a complete MLND can be carried out safely with only a minor impact on operative times or morbidity (Table 5).10,64–68 The standard of care for surgical management of lung cancer in general is to perform either a systematic lymph node sampling, a complete MLND, or a lobe-specific MLND.63,69,70 The issue to be considered here is whether a particular approach can be recommended when surprise N2 disease is encountered.
The accuracy of staging seems to be improved by diligent intraoperative attention to mediastinal staging. Several controlled and randomized studies have shown that systematic sampling approximately doubles the rate of discovery of N2 node involvement relative to a selective mediastinal node sampling.10,64,68 However, a systematic node sampling detects essentially the same number of patients with pN2 node involvement as a complete MLND.65,67,71 A MLND may detect more patients with multilevel N2 involvement than systematic sampling,65,71 even though the stage classification is the same (59% versus 17%, p < 0.01 in one study of cI–IIIa patients,71 but no difference in another involving cIa patients67). This staging data suggest that less extensive node removal at thoracotomy might leave tumor behind in some instances.
THERAPEUTIC ROLE OF MLND
The therapeutic role of MLND is unclear at this time. Four randomized trials have been conducted (Table 6),10,66–68 but survival data are not available yet from the largest one (American College of Surgeons Oncology Group Z0030).10 A smaller study of stage cIa patients found no survival difference, but is probably less applicable to the topic of this review.67 The other two trials are somewhat suggestive of a benefit either in overall survival or in local control.66,68 A systematic review of these trials carried out by the Cochrane collaboration found better 4-year survival with MLND versus node sampling (hazard ratio 0.78, p = 0.005).72 A retrospective review of data from a large trial of adjuvant therapy (355 patients, pII–IIIa) suggested a survival benefit with MLND,73 but another retrospective study (125 patients, pIa) suggested worse survival.74
An extended mediastinal node dissection involving bilateral mediastinal node dissection by means of a sternotomy has been advocated by some to more completely remove all nodal disease.52 In a study of 44 patients with cI–IIIa LUL tumors, 32% were found to be pN2, of which half had involvement of stations 1, 2R, 4R, 2L. However, although survival was good for those patients with pN2 limited to the usual nodal regions assessed during LUL resection (stations 4L. 5–7), none of the patients with involvement of nodes in the extended field of resection survived 5 years. The patients in this study were treated with surgery alone in the vast majority (no neoadjuvant or adjuvant chemo- or radiotherapy).52 Thus there seems to be little benefit to such extended node dissection, at least in the absence of additional treatment modalities.
Therefore the available data does not clearly define whether there is a therapeutic benefit to MLND. However, it seems reasonable to recommend that in general a MLND be done if intraoperative N2 disease is found. This recommendation is based on the trend to better survival and decreased local recurrence in the randomized studies. Furthermore, the randomized studies involved a broader group of patients of which only a minority had pN2 disease. If intraoperative N2 disease is found, it seems prudent to try to remove the ipsilateral nodal areas as completely as possible.
POSTOPERATIVE (ADJUVANT) THERAPY
A full discussion of the role of adjuvant therapy for pN2 patients is beyond the scope of this article. In general, adjuvant chemotherapy has become standard for resected stage II–IIIa NSCLC patients. Specific evidence-based recommendations for resected stage pIIIa patients are addressed by the recently revised ACCP guidelines.69 These guidelines recommend postoperative chemotherapy, and suggest that consideration be given to subsequent postoperative radiotherapy (RT) as well. Concurrent adjuvant chemoradiotherapy is not recommended.69
A stage-specific meta-analysis of adjuvant chemotherapy for patients with stage IIIa disease published in 2005 found a hazard ratio strongly in favor of chemotherapy of 0.85 (95% confidence interval 0.69–1.04).75 This did not quite meet criteria for statistical significance. It is probably significant that this meta-analysis did not include the more recently reported results of the Adjuvant Navelbine International Trialist Association trial, which were strongly positive in favor of adjuvant chemotherapy.76 Taken in the broader context of adjuvant therapy studies including such more recent results there is little doubt that adjuvant chemotherapy is beneficial. This is reflected in the guideline statements mentioned above.
The role of adjuvant RT for patients with stage IIIa disease is not clear. Systematic reviews of adjuvant RT for completely resected (R0) stage pI–IIIa NSCLC have generally found that there is a detriment to survival, although local control seems to be improved.77–79 The survival detriment was manifest primarily in patients with stages I and II NSCLC. The available data did not allow a specific recommendation for patients with stage IIIa tumors in these reviews. A retrospective review in 2006 of Surveillance, Epidemiology and End Results (SEER) data in 7465 patients suggested that patients with pN2 disease have a survival benefit with adjuvant RT.80 It was suggested that modern RT techniques may have decreased the toxicity of treatment to the point where a survival benefit in stage III was realized. This leaves it unclear whether RT should be used in completely resected patients with pIIIa tumors.
Adjuvant RT is generally given to incompletely resected (R1) patients. The argument for this is that the trend to better local control with adjuvant RT justifies its use in patients suspected to be at high risk for local failure such as those with an incomplete resection. However, there is little data to substantiate (or refute) this argument.78 Nevertheless, this seems to be a rational approach, and should probably be followed sequentially by chemotherapy. In the case of gross residual disease (R2), it seems best to treat the patient as if they had undergone a large biopsy rather than a resection. These patients should be managed with concurrent chemoradiotherapy once they have sufficiently recovered from surgery (although direct data to substantiate this strategy is not available).
Does the delivery of adjuvant therapy affect the intraoperative management when N2 disease is discovered? There is no data that directly examines this. One must keep in mind that the ability to deliver adjuvant therapy postoperatively has consistently been relatively poor (approximately 65%).69,78,88 Nevertheless, the data reviewed in this article comes from studies in which many patients did receive adjuvant therapy (Table 1). Therefore, it would seem that the data presented and conclusions reached in this review apply to patients in the current setting, in which adjuvant therapy is generally recommended for pN2 patients.
ALTERNATIVE TREATMENT APPROACHES
Primary Alternative Treatment Approaches
A full discussion of alternative treatment approaches other than primary surgery for patients with pN2 disease is beyond the scope of this article. Nevertheless, a brief summary is necessary to place the results with primary surgery in the proper perspective.
The standard of care for stage IIIa NSCLC is concurrent chemoradiotherapy.69 The 5-year survival rates in these studies has been approximately 15 to 20%.81,82 It is important to note that these trials have included patients with much more extensive stages IIIa and IIIb disease than the patients that are the focus of this article. Induction therapy followed by surgical resection is a reasonable alternative, although at the present time it should ideally be done in the context of a clinical trial.69 This has been compared with chemoradiotherapy alone in a randomized trial, with no statistical difference in overall survival.83,84 Significantly better progression-free survival in the surgical arm was offset by an increase in initial (perioperative) mortality. The 5-year survival seems to be approximately 25% for such trimodality approaches in preoperatively proven cN2 involvement.69,84,85 More aggressive chemoradiotherapy approaches are also being explored, with survival rates of 25 to 30% in phase II studies (in a broad group of stages IIIa and IIIb patients).13,86,87 Although direct comparisons are not possible because of differences between the patients included in these studies and patients with “surprise” pN2 disease, these results must be kept in mind when considering the role of primary resection.
Effect of Exploration on Alternative Approaches
Should an alternative treatment strategy be considered when surprise N2 disease is encountered at thoracotomy? The outcomes of alternative treatment approaches just discussed pertain to patients that have not been subjected to an exploratory thoracotomy. No data are available that specifically defines the ability to carry out such an alternative approach after a thoracotomy. However, there are extensive data that adjuvant chemotherapy can be administered as planned in only about 65% of patients after a resection.69,78,88 It is possible that a higher percentage of patients can tolerate and complete chemotherapy after an exploratory thoracotomy compared with after a resection, but this is speculative and not supported by the similar perioperative mortality of exploration and resection. Furthermore, definitive chemoradiotherapy treatment approaches for stage III NSCLC have involved more intense treatment than those of adjuvant therapy. This makes it likely that any better tolerance of alternative treatment that might be realized after an exploratory thoracotomy compared with resection would probably be offset by worse tolerance of more intensive therapy than the 65% reported in adjuvant chemotherapy studies. In summary, speculative extrapolation of existing data suggests that only about two-thirds of patients are likely to complete definitive chemoradiotherapy after an exploratory thoracotomy.
The likelihood of completing the planned treatment seems likely to be worse if the alternative therapy under consideration is neoadjuvant chemotherapy followed by a second thoracotomy, this time with resection. The same concerns about the ability to complete the neoadjuvant treatment in a postoperative patient apply as was discussed in the preceding paragraph. In addition, studies of neoadjuvant treatment followed by resection have consistently found that only about 65% of patients are well enough to undergo resection after the induction therapy.81 Thus, only about 50% of patients who are closed after finding surprise N2 disease at thoracotomy can be expected to complete neoadjuvant therapy and subsequent surgical resection. It is highly likely that those patients not completing the planned alternative therapy will experience very poor survival. Unfortunately, no direct data to confirm or refute these extrapolative estimates are available.
SUMMARY: APPROACH TO PATIENTS
What conclusions can be drawn? First, any suspicion of N2 disease warrants careful and thorough invasive staging, and documentation of N2 involvement should preclude initial thoracotomy and resection. Such patients with pN2 disease who are cN2 by imaging studies have a 10 to 15% survival rate (despite adjuvant RT). Given the morbidity of surgery, and the fact that other curative-intent treatment options are available, surgical resection as the initial treatment does not seem justified. The nodal involvement should be identified using a less invasive method than a thoracotomy. It is not entirely clear whether these patients should be managed by chemoradiotherapy alone or in some instances by neoadjuvant treatment followed by resection, although the most recent guideline recommendation is for chemoradiotherapy alone outside of a clinical trial.69
Some patients will be found to have N2 involvement at the time of resection, even if appropriate preoperative staging has been done (“unsuspected N2”). The only clear reason to abort the planned operation is if it is apparent that a complete resection is not possible. Aside from this, it seems in general to be appropriate to proceed with resection (especially if careful preoperative staging demonstrated cN0,1 disease). Survival of some subgroups may be slightly better and of others slightly worse, but the outcomes are nevertheless good enough to proceed with resection. This argument is based on data that a 5-year survival of 10 to 50% can be anticipated and on data that there is little difference in the operative mortality or QOL whether the procedure is aborted or carried out. Furthermore, the ability to give an alternative treatment (definitive chemoradiotherapy or neoadjuvant therapy followed by resection) is somewhat questionable in a postoperative patient.
Defining particular factors that might influence the intraoperative decision to resect should be done very cautiously, because the reported results vary and are likely confounded by multiple undefined additional factors. Proceeding with resection is clearly justified in the case of a T1,2 tumor, single-level node involvement, and patients with a cN0,1 tumor based on careful preoperative staging. This is probably also true for patients with upper lobe tumors involving only regional nodes (LUL and station 5, or RUL and R4). One should not hesitate to carry out a pneumonectomy if necessary (provided the patient is able to tolerate this), and should not change the approach based on the histologic subtype. Worse outcomes (around 15% 5-year survival) are seen in patients with multilevel N2, clinical N2 by CT, T3,4 tumors, or subcarinal node involvement, but in general resection is still justified unless there are significant comorbidities or perhaps multiple poor prognostic factors.
It seems appropriate to proceed with resection even when faced at the time of thoracotomy with N2 involvement and an expected 15% 5-year survival (with negative prognostic factors), whereas at the same time it seems appropriate to avoid surgery altogether for patients with cN2 as defined preoperatively (because of 10–15% expected survival). This is because there is much more to be gained from avoidance of the morbidity of a thoracotomy than from aborting a resection once the thoracotomy has been done. Furthermore, alternative treatment is easily available if thoracotomy is avoided, but is more difficult once it has been done.
This conclusion is in conflict with an earlier study using mathematical modeling, which concluded that it was always better to close on finding surprise N2 and to administer neoadjuvant therapy and then resection.89 However, this model was based on several assumptions that are not borne out by current literature: a 2.6-fold improvement in survival after neoadjuvant therapy and resection versus chemoradiotherapy alone, a 100% ability to deliver neoadjuvant therapy after exploratory thoracotomy, no benefit to adjuvant therapy after resection, and an operative mortality for exploratory thoracotomy of 0.5%. Countering these assumptions is the data from the only randomized study, which found no difference between neoadjuvant therapy and resection versus chemoradiotherapy alone.83,84 Meta-analyses have demonstrated a benefit to adjuvant chemotherapy for resected IIIa patients.69 The ability to deliver chemoradiotherapy seems to be poor, as discussed in the Effect of Exploration on Alternative Approaches section. The preponderance of data documents a much higher operative mortality than was assumed in the mathematical model.1–7 In addition, the actual data for outcomes are dependent on details of the patient cohort, as is discussed in this review. An admitted limitation of the mathematical modeling was that estimates for the various treatment approaches were derived using different patient cohorts.89 Finally, the mathematical model lumps all surprise N2 patients together, whereas the data reviewed here leads to the conclusion that poorly staged patients (“ignored N2”) should not be subjected to an exploratory thoracotomy in the first place, whereas well-staged patients should be resected even if “unsuspected N2” involvement is found.
There seems to be little benefit to frozen section analysis of lymph nodes at the time of thoracotomy in patients who are well-staged preoperatively. This follows from the conclusion that no specific characteristics of N2 involvement preclude proceeding with resection. The role of frozen section is primarily to demonstrate tumor that cannot be resected. An argument can be made that a surprise N2 node by frozen section indicates that a MLND should be done if this was not already planned.
In summary, careful preoperative staging is important, and resection as the first step for patients with cN2 disease does not seem justified. If unanticipated N2 involvement is encountered in a well-staged patient, resection is justified unless it is apparent that disease will be left behind. This seems to be reasonable even in the face of negative prognostic factors. Resection of patients with pN2 disease should probably include a formal MLND, although conclusive data to prove this are not available. Adjuvant therapy should be given, with the data being most clear for adjuvant chemotherapy.
I acknowledge the helpful suggestions and critique offered by Tomasz Grodzki, MD, Robert Cerfolio, MD, and Mark K. Ferguson, MD.
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