Table of Contents  

Watzka, Krajc, and Rolf Mueller: Surgical treatment of non-small-cell lung cancer

Treatment of non-small-cell lung cancer according to stages

The treatment of choice in the early stages of non-small-cell lung cancer (NSCLC) is complete surgical resection of the tumour and of the regional and mediastinal lymph node stations, usually without neoadjuvant or adjuvant chemotherapy. A recent large retrospective trial comparing five different treatment strategies (lobectomy, sublobar resection, conventional radiation, stereotactic ablative radiotherapy and observation) in 10 923 patients older than 66 years confirmed that lobectomy results in the best overall and disease-specific survival.1

In patients with clinical stage II or III disease, a combination of local and systemic therapy has been established as the currently recommended strategy. Clinical stage III, in particular, encompasses a heterogeneous group of diseases, including primarily resectable tumours and mediastinal lymph node involvement, but also locally advanced tumours without lymphatic involvement. Thus, the best course of action should be decided individually by an interdisciplinary board.

Of practical relevance, the Robinson criteria, published in 2007, describe the extent of mediastinal lymph node involvement in stage IIIa more precisely. Lymph node involvement can take the form of nodal micrometastases as well as bulky lymph node disease. In any event, some type of multimodality therapy is the preferred therapeutic approach in most situations.2 In order to choose the right multimodality approach, accurate preoperative staging of mediastinal lymph nodes, either by mediastinoscopy or by endobronchial ultrasound, is of vital importance.3

Depending on preoperative stage, the available therapeutic strategies are primary resection, multimodal treatment comprising neoadjuvant chemoradiotherapy with subsequent surgical resection, and definitive chemoradiotherapy. The evidence indicates that neoadjuvant chemoradiotherapy followed by resection is overall superior to other therapeutic strategies in terms of disease-free and long-term survival.4 Other authors, however, have been unable to confirm a significant survival benefit of induction therapy5 or the superiority of neoadjuvant chemoradiotherapy to chemotherapy.6 Moreover, results of a randomized trial performed by the German Lung Cancer Cooperative Group suggest no benefit of adding preoperative chemoradiotherapy to chemotherapy.7

In clinical stage IV – the presence of distant metastases – treatment in most cases consists of only systemic therapy, combined with optional radiotherapy as a local measure.8 In exceptional cases, surgical resection of the primary tumour in the presence of metastasis to a single organ (oligometastatic stage with isolated brain or adrenal metastasis) can be offered after induction chemotherapy and successful treatment of distant metastasis, since the oligometastatic stage is a subgroup with a better prognosis,9,10 and since it has been shown in several studies that patients with solitary metastases (e.g. of the brain, liver, adrenal glands) experience improved long-term survival.1117

In 1995, Hellman and Weichselbaum18 proposed the concept of oligometastases, later refined to synchronous and metachronous oligometastases by Niibe et al.19 Synchronous oligometastases appear together with the primary lesion, and can be controlled by local therapy. Metachronous oligometastases, however, appear after the removal of the primary lesion, and are then called oligo-recurrence.20 Regardless, a prerequisite for the aggressive treatment of oligometastatic disease is that the number of oligometastases does not exceed five and that the primary lesion is controlled or controllable.

As for the management of contralateral lung lesions in the presence of NSCLC, it is important to differentiate true metastatic lesions from synchronous primary lung cancers, since treatment and prognosis are very different in the two cases.8 Regarding multiple primary lung cancers, it has been shown in several studies that bilateral lesions may be resected successfully, and that survival is improved after bilateral resection.2123

In small-cell lung cancer (SCLC) surgical treatment plays a subordinate role, and only patients with clinical stage I disease who show a good response to chemotherapy can benefit from surgical resection. In fact, in recent studies it has been shown that the prognosis of patients with very early SCLC is comparable to that of patients with NSCLC, and that the outcome of surgically resected very early SCLC (after chemotherapy) is better than that of SCLC treated by solely chemotherapy.24

Technical aspects

The aim of surgery is radical removal of the primary tumour within clearly defined anatomical limits and systematic mediastinal lymph node dissection. However, views differ regarding the optimum route of surgical access as well as the technique used to achieve anatomical resection and lymphadenectomy. For this reason, the International Association for the Study of Lung Cancer (IASLC) – but also other societies – has developed and published guidelines for the standardization of surgical treatment of lung cancer. The IASLC guidelines define complete resection as follows: anatomical lung resection with microscopically proven tumour-free resection margins; complete mediastinal lymphadenectomy or lobe-specific lymphadenectomy, with the most distant mediastinal lymph node tumour negative; and the absence of extracapsular nodal extension of the tumour.25 In a recent comparison of the survival relevance of surgical treatment according to IASLC guidelines – compared with treatment not following guidelines or treatment following other guidelines [American College of Surgeons Oncology Group (ACOSOG), National Comprehensive Cancer Network (NCCN) and the OSI Pharmaceutical RADIANT trial] – compliance with IASLC guidelines was associated with a significantly increased overall survival.26

Lobectomy is still considered the oncological gold standard based on a prospective randomized multicentre trial carried out in 1995, in which lobectomy was shown to carry a significantly lower local recurrence risk than a, so-called, sublobar resection.27 This concept is implementable in earlier tumour stages, but in the presence of central tumour with infiltration of the hilar vessels or bronchi, or in the case of lobe exceedance and infiltration of adjacent structures, it may be necessary to perform extended resections to ensure complete tumour removal.

In this regard, the indication for performing a pneumonectomy was initially much more liberal, on the assumption that it would result in improved local tumour control. However, because of convincing evidence of significantly higher morbidity and mortality and a decreased overall survival after pneumonectomy,28 lung-saving bronchoplastic and angioplastic procedures (Figure 1) replaced pneumonectomy in most thoracic surgical centres.29

FIGURE 1

Broncho-angioplastic pulmonary resection of the left upper lobe (so-called double sleeve). The lumen in the lower half corresponds to the left main bronchus, vis-à-vis the segmental ostia of the lower lobe. The open stumps of the left pulmonary artery are clamped. The bronchus is anastomosed first, then the artery.

9-1-7-fig1.jpg

Today, in specialized centres, there are virtually no technical limitations to the resection of locally advanced nodal negative tumours (T3N0, T4N0). Thus, in carefully selected patients30 infiltration of the tracheal bifurcation, the atria, the chest wall and spine (Figure 2), the great vessels and the oesophagus is no longer a contraindication to surgical resection.8 As in the case of the spine, encouraging survival results can be achieved even after resection of up to four vertebral bodies.31 The prognostic factors associated with improved survival are the extent of resection, the status of the mediastinal lymph nodes and the involvement of the great vessels in the thoracic outlet.32

FIGURE 2

Vertebral body replacement in a T4 tumour with infiltration of the spinal column.

9-1-7-fig2.jpg

Lobectomy or less in T1a non-small-cell lung cancer?

In those at increased perioperative risk, elderly patients in particular, parenchyma-sparing anatomical resections are increasingly the subject of recent publications. In a retrospective review of 1221 stage I NSCLC patients, Okada et al.33 found no difference in 5-year survival rates between parenchyma-sparing anatomical segmentectomy and lobectomy, when the tumour size did not exceed 31 mm. These results were confirmed in a prospective trial on 565 patients,34 but also in other retrospective trials.35,36 However, wedge resection was associated with worse survival than lobectomy.36 Thus, Reveliotis et al.37 concluded that segmentectomies are preferable to wedge resections when considering local recurrence and cancer-related survival, that sublobar resections are superior to lobectomy in terms of lung parenchyma preservation and that high-risk patients (in terms of age and cardiopulmonary reserve) with tumours < 2 cm should undergo anatomical segmentectomy.

In the face of an increasing proportion of patients with impaired respiratory reserve, in recent years, the basic principle of histologically confirmed radical removal of the primary tumour along anatomical boundaries has been further developed, thus also applying the concept of anatomical segmentectomy for T1a tumours in patients with good lung function. Thus, in stage Ia patients with tumour < 2 cm, extended segmentectomy has been shown to offer similar results regarding local recurrence and 5-year survival.36,38 To further evaluate the oncological and functional suitability of anatomical segmentectomy in patients with clinical stage Ia disease, two international prospective multicentre studies are currently under way.37 Another aspect of treatment selection is the histological profile of the tumour.37 In the case of adenocarcinomas without solid components on computerized tomography (CT) (ground glass opacity) and without vascular invasion, a wedge resection might be considered an appropriate therapeutic option.39,40

A final word of caution: in a recent population-based analysis evaluating 14 473 cases from the US Surveillance Epidemiology and End Results (SEER) database, Whitson et al.41 concluded that lobectomy is still clearly superior to segmentectomy in terms of overall survival and cancer-specific 5-year survival, even after adjusting for patient- and tumour-related factors.41

The role of the surgical access

Since the first reported thoracoscopic [video-assisted thoracoscopic surgery (VATS)] lobectomy42 more than 20 years ago, in many thoracic surgical centres around the world VATS lobectomy has become almost the standard of care for early-stage NSCLC.43 With increasing experience in specialized centres, today even locally advanced tumours are resected thoracoscopically.44,45

The obvious advantages of a small access without spreading the ribs are the reduction of surgical trauma, a much lower frequency and intensity of intercostal neuropathy and better postoperative respiratory mechanics. The significantly lower incidence of postoperative complications after VATS lobectomy has been confirmed by a recently published propensity-matched analysis from the European Society of Thoracic Surgeons database, comparing 2721 patients with VATS lobectomy with a well-matched group of 2721 patients undergoing open lobectomy.46 However, one supposed advantage of VATS lobectomy over open lobectomy, namely the superior compliance with adjuvant chemotherapy after VATS lobectomy, could not be confirmed; in a Danish cohort of 1968 patients with stage 1 NSCLC, no significant difference could be found between VATS lobectomy and open lobectomy in terms of adjuvant chemotherapy compliance, duration of chemotherapy or delay between surgery and chemotherapy.47

Minimally invasive resection seems to be advantageous, especially in patients of advanced age. In a retrospective matched case–control study carried out in 2008, which evaluated 333 NSCLC patients (82 matched patients in each group) aged 70 or older, VATS lobectomy patients experienced significantly lower complication rates and a shorter length of stay than open lobectomy patients. Moreover, in the VATS lobectomy group the perioperative mortality was zero (compared with 3.6% in the open group).48 However, in a recent prospective cohort study evaluating determinants of outcome after surgical treatment of NSCLC (open lobectomy, n = 585; VATS lobectomy, n = 220 cases), multivariate analysis showed that the incidence of pulmonary complications was predicted correctly by postoperative FEV1 (forced expiratory volume in 1 second) and DLCO (diffusion capacity of the lungs for carbon monoxide) only, and not by surgical approach.49

Recent findings suggest that VATS lobectomy is associated with lower complication rates than open procedures because patients’ cellular immunity is impaired to a lesser extent and for a shorter period.50 Better immune competence could also explain why long-term survival after VATS lobectomy is the same as or better than survival after open lobectomy. In a retrospective study of 208 patients who underwent VATS lobectomy and 208 propensity score-matched patients who underwent open lobectomy, long-term survival was found to be similar in both groups, thus strongly suggesting that VATS lobectomy is non-inferior to open lobectomy, even though the latter is still considered the gold standard procedure. As regards the accuracy of lymph node evaluation, in this series open lobectomy allowed more accurate lymph node staging.51 In a recent meta-analysis of 23 studies (21 retrospective and two prospective), VATS lobectomy was not only non-inferior to open lobectomy in terms of overall survival, but clearly superior. The authors also found that VATS lobectomy was associated with a significantly lower complication rate and a similar distant recurrence rate, but also a higher local recurrence rate.52 The largest study so far analysed the records of patients in a multi-institutional registry of eight institutions in the People’s Republic of China. Comparison of outcomes among 1458 patients who underwent VATS lobectomy and 1458 propensity-matched patients who underwent open lobectomy led to the conclusion that long-term survival was similar after VATS lobectomy or open lobectomy.53

The role of mediastinal lymphadenectomy

The justification for complete mediastinal lymphadenectomy is the theoretical presence of occult lymph node metastases or skip metastases. Thus, complete lymphadenectomy should be performed in all patients, even those with early-stage disease.54 Whether or not the extent and technique of mediastinal lymph node dissection can affect survival is addressed in a number of publications, but remains controversial.5557 However, because of the need for complete resection and reliable staging, systematic mediastinal lymphadenectomy plays a central role in the multimodal treatment of NSCLC.58,59

The European Society of Thoracic Surgeons has devised specific guidelines for pre- and intraoperative lymph node staging based on a meta-analysis of the relevant literature.60 These guidelines recommend en bloc resection of stations 2R and 4R, 3a/3p, 7, 8 and 9 on the right side, and stations 5, 6, 4 L, 7, 8 and 9 on the left side. In addition, the most distant mediastinal node resected should be identified. The IASLC also requires systematic lymph node dissection as an essential component of intraoperative staging.25

Accordingly, systematic lymph node dissection – and not lymph node sampling – is required in all cases to ensure complete resection. Izbicki et al.61 found that systematic mediastinal lymph node dissection increased the percentage positive mediastinal lymph nodes. This has been confirmed by two Japanese trials,62,63 in which systematic mediastinal lymphadenectomy detected up to 32% positive lymph nodes, whereas node sampling detected at most 17% of positive lymph nodes. Thus, selective lymph node biopsy or lymph node sampling is justified only if resection is not possible. In peripheral squamous carcinoma patients with T1 tumours, however, a lobe-specific systematic nodal dissection can be acceptable, under the condition that the interlobar and hilar nodes are negative. The minimal requirement in this special circumstance is the removal of three mediastinal lymph node stations, including station 7, with a minimum number of six lymph nodes excised.60

Lymphadenectomy and survival

Whether or not complete mediastinal lymphadenectomy results in not only optimized staging but also a survival benefit remains controversial. In a series of 471 patients with stage Ia–IIIa NSCLC, Wu et al.64 found a statistically significant survival benefit for complete lymphadenectomy versus lymph node sampling (48.37% vs. 36.98% 5-year survival). In an interesting recent trial, Xu et al.65 examined the impact of lymph node dissection in a cohort of 203 stage Ia NSCLC patients. The authors divided the cohort into groups according to the total number of resected lymph nodes, the number of lymph node stations and the number of mediastinal stations, and found that an increase in the total number of resected lymph nodes and of lymph node stations was correlated with an increased disease-free survival. However, they could not detect any difference in survival between resection of fewer than 20 lymph nodes and resection of more than 20 lymph nodes (provided at least six lymph node stations had been resected), which suggests that the completeness of resection depends more on the comprehensiveness of accessed lymph node stations than on the absolute number of resected lymph nodes.

In contrast, Lardinois et al.66 and Sakurai et al.67 found that lymph node sampling, compared with complete lymph node dissection, resulted in no difference in overall survival, but a decrease in disease-free survival and an increase in local recurrence rate. In the randomized ACOSOG Z0030 trial investigating the role of lymphadenectomy in resection of T1 and T2 N0 or N1 tumours with no hilar involvement, there was no difference in long-term and disease-free survival or in local, regional or distant recurrence between lymph node sampling and complete lymph node dissection.68 These data are confirmed by a systematic review and meta-analysis published in 2014, which clearly found no difference in overall survival, recurrence rate or complication rate between lymph node sampling and complete mediastinal lymph node dissection in early-stage NSCLC. As for the role of lymphadenectomy in higher stages, the published evidence remains conflicting; thus, there remains a need for further and, preferably, prospective trials.69

However, Vielva et al.54 stress that, even though it has not been conclusively proven that complete mediastinal lymph node dissection confers a survival benefit, there appears to be no contraindication to complete lymphadenectomy; thus complete lymphadenectomy, even in patients with early-stage NSCLC, may be justified, if only for heuristic reasons. Established principles, such as complete mediastinal lymph node dissection, must be fully maintained along with minimally invasive techniques (VATS lobectomy).

The rate of nodal upstaging is an important measure of the quality of NSCLC treatment. In a recent propensity-matched analysis of 963 patients with clinical stage I NSCLC, Berry et al.70 found that rates of regional lymphadenectomy and nodal upstaging as well as overall survival and disease-free survival were similar in patients undergoing VATS lobectomy and those undergoing open lobectomy; however, a criticism of this study is that patients who underwent VATS lobectomy that was subsequently converted to open lobectomy (7%) were included in the VATS lobectomy group for evaluation, thus possibly compromising the validity of the results.71 In contrast, a study by Danish Lung Cancer Registry of 1513 stage-operated patients with NSCLC clinical stage I (VATS lobectomy, n = 717; open lobectomy, n = 796) found that nodal upstaging was significantly more frequent after VATS lobectomy than after open lobectomy (8.1% vs. 13.1%). Multivariate survival analysis, however, revealed no difference in overall survival, thus relativizing the role of nodal upstaging in survival.72 A significantly reduced rate of nodal upstaging after VATS lobectomy was also been found in a study of 2830 patients from the Kentucky Cancer Registry (1964 open lobectomy cases, 500 VATS lobectomy cases), although VATS lobectomy patients had an improved survival rate in this series.73 In a landmark study evaluating 11 500 patients with clinical stage I NSCLC, nodal upstaging from N0 to N1 was significantly lower in the VATS lobectomy group. However, the frequency of upstaging from N0 to N2 was similar in both groups.74

Indeed, there is no doubt that some lymph nodes stations are technically difficult to reach in the course of thoracoscopic en bloc lymph node dissection. In addition, in a higher percentage of cases lymphatic drainage is not limited to the locoregional lymph node stations on the ipsilateral side, but can also skip the locoregional lymph nodes or even reach the contralateral side. In a preliminary study in which pleural lymph flow was visualized by injection of indocyanine green, a fluorescent dye, direct lymph flow to the ipsilateral mediastinum, thus skipping the locoregional lymph nodes, was observed in 3 of 14 patients (21.4%).75 In a large CT-based study investigating the pattern of lymph node involvement in 400 patients with primary complex histoplasmosis – a model for lymphatic metastatic spread – the most commonly affected lymph node station for the right upper lobe was the right lower paratracheal node, for the left upper lobe the subaortic node, and for the left lower lobe the left pulmonary ligament lobe. These lymph node stations were also the most common sites of skip lymph node involvement. In the case of the right lower lobe and the middle lobe, however, the subcarinal node was the most commonly affected node, but was rarely affected by skipping.76 In an anatomical study of lymphatic drainage in 260 adult cadavers, direct lymphatic drainage to the mediastinum was observed in 22.2% of right lung segments and in 25% of left lung segments. In five cases, direct contralateral lymphatic drainage was observed, originating from basal segments of lower lobes in four cases.77

In fact, involvement of the lower lobes seems to be associated with a worse prognosis. In a retrospective study of 76 patients with clinical N2/3 stage III disease who received induction chemoradiotherapy followed by surgery, lower lobe disease (right, 11 cases; left, seven cases) was associated with a significantly shorter disease-free survival and overall survival.78 In a much larger retrospective trial evaluating a total of 978 NSCLC patients, multivariate analysis found that tumour location in the left lower lobe was an independent prognostic factor (in addition to well-established prognostic factors such as T stage and N stage).79

In the context of bilateral lymph node disease, some authors have reported that hyperradical resection, comprising bilateral mediastinal lymphadenectomy performed by median sternotomy and modified radical neck dissection, results in surprisingly good survival rates, even in patients with N3 disease.80 It is not clear, however, if bilateral lymph node dissection has a direct therapeutic effect or if it only optimizes nodal staging.

At our department, these technical and oncological arguments prompted us to implement combined thoracoscopic lobectomy and bilateral mediastinal lymphadenectomy via cervical access [video-assisted mediastinal lymphadenectomy (VAMLA)] in a single procedure. VAMLA, which was first described in 2002,81 enables removal not only of lymph nodes 2–4R, 2–4L and 7 via en bloc resection, but also the peribronchial lymph nodes N1 on the right side (10R and 11R).82

A theoretical advantage of a combined video-thoracoscopic and video-mediastinoscopic approach is that it reduces the duration of single-lung ventilation by about 1 hour, thereby possibly reducing several undesirable functional and immunological effects of single-lung ventilation. In a pilot study comparing 18 VAMLA + VATS lobectomy patients with 14 VATS lobectomy patients, both the number of the dissected mediastinal lymph node stations and the weight of the resected mediastinal specimen were significantly higher in the VAMLA + VATS lobectomy group; however, operation duration and complication rate remained similar.83 In a much larger trial carried out in 2015, which evaluated 649 patients undergoing surgery for left-sided NSCLC (225 VAMLA + VATS lobectomy patients; 424 VATS lobectomy patients), operative times were significantly shorter, the total number of removed lymph nodes was significantly greater and nodal upstaging was higher in the VAMLA + VATS group than in the VATS group, but complication rates were similar.84 However, it is still not clear if these immediate benefits translate into an improved long-term survival. Randomized prospective trials are needed to answer this question.

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