Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Before 1980, radiotherapy was considered the only real recourse in advanced disease. In 1995, a landmark meta-analysis of trials conducted in the 1980s and early 1990s demonstrated a survival benefit with platinum-based chemotherapy. Newer chemotherapy agents and improved supportive care measures have allowed more patients to benefit from chemotherapy with reduced toxicity. Concurrent platinum-based chemotherapy and radiotherapy has improved the survival in stage III disease, and recently chemotherapy has also demonstrated improved survival in resected early-stage disease. The majority of patients still present with advanced unresec disease for whom the prognosis remains poor, but for key subpopulations the outlook has improved markedly since the emergence of targeted therapies directed against the epidermal growth factor receptor and vascular endothelial growth factor receptor pathways. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of many ongoing studies, and there is an abundance of new agents undergoing clinical trials. Together, these developments have moved us away from the nihilism of 20 years ago into an era of unprecedented optimism in taking on the many remaining challenges of managing NSCLC in the 21st century.
The thoughtful paper by Weiss and colleagues highlights many of the important clinical and translational science advances of the past 2 decades that have shaped our knowledge and management approaches to non-small-cell lung cancer (NSCLC). The authors have chosen their topics of discussion carefully and have been cautious not to "overreach" in their assessment of realized gains vs persisting challenges. The acknowledgement that a trimodality approach in stage IIIA disease "cannot be recommended as standard" and the assessment that "the best [multimodality therapy approaches] in [stage IIIB disease] ... continue to be explored" are fair presentations of the current state of the art.
Several other issues might have been chosen for greater emphasis, but space is always the enemy of the engaged author. As a commentator, I will briefly discuss a few additional topics that may add modestly to the scope of the Weiss manuscript.
Lung Cancer in Women
As the authors note early in their paper, the American epidemic of lung cancer is driven in larger measure than ever before by new diagnoses in women. While the overwhelming etiologic agent in both women and men remains the self-administered, inhaled carcinogens of tobacco smoke, the resulting disease in women is different in many ways. The histology is more often adenocarcinoma, the age of onset is earlier, the frequency of "never smokers" (though not necessarily smoke-unexposed given the prevalence of secondhand smoke) is higher, and EGFR mutation frequency is increased.
Moreover, emerging evidence suggests that sensitivity to carcinogens is different in women than in men. The CYP1A1 gene product is associated with activation of inhaled procarcinogens. CYP1A1 gene expression in lung tissue is greater in female than in male smokers. At the same time, the absence of carcinogen-detoxifying enzymes such as GSTM1 may have greater effects in lung tissue in women.
As noted by Patel, "It is incumbent upon us to have a better understanding of the genetic, metabolic, and hormonal factors that affect the way women react to carcinogens and lung cancer. This information could affect the way patients who smoke are screened and evaluated as well as the way smoking cessation and lung cancer prevention programs are directed."
Endoesophageal/Endobronchial Ultrasound-Guided Staging
In their discussion of staging, the authors focus on the role of imaging and mediastinoscopy in the determination of operability. They also allude to the potential of video-assisted thoracic surgery (VATS) to reach additional lymph node stations. However, they fail to discuss two effective nonsurgical staging strategies-endoscopic (endoesophageal) ultrasound (EUS) with guided fine-needle aspiration (FNA) and endobronchial ultrasound (EBUS) with guided transbronchial FNA. These techniques have clear efficacy in assessing the extent of intrathoracic spread of lung cancer. Endoscopic ultrasound has been available for nearly 2 decades and is a staple of evaluation for esophageal, gastric, and pancreatic disease. For a variety of reasons, it is less widely applied to the evaluation of patients with lung cancer. EBUS has a substantially shorter track record but is increasingly practiced by interventional pulmonologists.
Both EUS and EBUS can be done in the outpatient setting using conscious sedation and offer increased accuracy over computed tomography (CT) and positron-emission tomography (PET). They each substantially increase the number of potentially sampled lymph node stations compared to cervical mediastinoscopy alone (ie, EUS enables sampling of nodal stations 5, 7, 8, 9; EBUS facilitates sampling of both right- and left-sided nodal stations 2, 4, 10, and 11, as well as level 7). In experienced hands, EUS can also be used to biopsy suspicious left adrenal masses, pericardial and left-sided pleural fluid, and even selected accessible liver lesions (B. Hoffman, personal communication).
Three single-institution experiences with EUS in staging patients with NSCLC have recently been reported. Sawhney et al studied 65 NSCLC patients who were considered potential surgical candidates. PET and EUS were performed. Findings were verified either by follow-up surgery or serial radiographic monitoring. PET scans provided an accurate assessment of mediastinal nodal status in 77% of patients, whereas EUS-FNA was correct in 94%. The authors concluded that "the use of EUS obviated a surgical procedure in 55% of patients with radiologic evidence of mediastinal metastases and in 22% of patients without evidence of mediastinal metastases."
Tournoy and colleagues evaluated 67 patients with a prestudy diagnosis of presumed lung cancer. All had mediastinal nodal enlargement and/or a suspicious left-adrenal lesion by body imaging. Using EUS-FNA, malignancy was documented in 47 patients (70.1%). The accuracy of EUS-FNA for malignancy was 100%, compared to 75% for PET (P = .001). The number of invasive surgical procedures indicated in these patients was reduced by two-thirds through the use of the EUS-FNA approach.
Eloubeidi et al used EUS-FNA to stage 35 patients following a positive CT and/or PET scan but a negative mediastinoscopy. With EUS-FNA, 13 of the 35 (37.1%) were shown to have N2 or N3 nodal involvement. The investigators calculated that use of EUS-FNA before cervical mediastinoscopy in selected patients could save on the order of $11,000 per patient.
Institutional experiences with EBUS have only recently begun to reach the peer-reviewed literature. However, the added utility of this procedure for staging patients with NSCLC is already evident. For example, Yasufuku et al studied the relative efficacy of CT, PET, and EBUS-FNA (or transbronchial needle aspiration, TBNA) as preoperative strategies in 102 (proven or presumed) NSCLC patients considered candidates for definitive surgical management. TBNA allowed assessment of 147 mediastinal and 53 hilar nodes in the 102 patients. In 24 of 102 patients, at least one nodal sampling was positive for malignant cells. The diagnostic accuracy of EBUS-FNA was 98%, compared to 72.5% for PET and 60.8% for CT. Sensitivities were 92.3%, 80%, and 76.9% respectively.
Plat et al tested the ability of EBUS-TBNA to provide a pathologic diagnosis in 33 consecutive patients with PET-positive N1 or N2 nodes. Diagnostic tissue was obtained in 27 patients (82%) via TBNA. In 25/33 (76%), no additional mediastinal staging was required. These authors concluded that "Transbronchial needle aspiration after endobronchial ultrasound localization should be considered as the primary method of evaluation of lymph nodes positive by ... [FDG-PET] ... and may replace the majority of surgical mediastinal staging/diagnostic procedures."
Perhaps even more provocative is a recent report by Herth et al concerning the utility of EBUS-TBNA in patients with NSCLC but no mediastinal node > 1 cm by chest CT. They studied 100 such patients, evaluating lymph node areas 2 (R+L), 4 (R+L), 10 (R+L), 11 (R+L), and 7. All patients had subsequent surgical staging of the mediastinum. One hundred nineteen nodes ranging in size from 5 to 10 mm by EBUS imaging were sampled. A pathologic diagnosis of cancer was obtained in 19 patients. All 19 positives were confirmed by subsequent surgical excision and pathologic evaluation. Of the remaining 81 patients, 2 (2.5%) were also found to have N2 disease at surgical exploration despite the negative EBUS evaluation (overall sensitivity = 92.6%; negative predictive value = 96.3%). Whether routine EBUS should become a standard part of staging in selected patients (or even all patients) with NSCLC but no evidence of enlarged mediastinal nodes by CT imaging will require additional evaluation.
Molecular Predictive and Prognostic Factors
In their manuscript, Weiss et al review the available data on the utility of platinum-based adjuvant chemotherapy among patients with completely resected NSCLC. They point out the absence of single-study randomized data showing a significant survival advantage produced by adjuvant chemotherapy after resection of a T1/2, N0 NSCLC. They also briefly describe the recent report by Olaussen and colleagues, who retrospectively correlated the absence of ERCC-1 (excision repair cross-complementation group-1) in tumor tissue (measured by immunohistochemistry) with a favorable impact of adjuvant chemotherapy.
Another molecular technique for assessing tumor tissue-based risk of relapse after complete resection in patients with early-stage lung cancer has been reported by Potti et al. These investigators have developed "metagene" expression profiles from the resected lung cancer tissue somewhat analogous to the OncotypeDx panel now used to refine recurrence risk assessments in certain subgroups of completely resected breast cancer patients. Using the metagene approach, the investigators have been able to separate small groups of early-stage lung cancer patients into "high and low recurrence risk" subgroups more effectively than other known prognostic factors. Further prospective testing of this approach is ongoing. Hopefully, the use of metagene expression (or similar) profiles to designate high-risk individuals, combined with ERCC-1 testing and other (yet to be defined) predictive markers, will substantially increase the selective utility of adjuvant therapy after lung cancer resection.
Mortality Rates After Right Pneumonectomy
One other element in the management of patients with operable NSCLC perhaps worthy of additional comment beyond the discussion by Weiss et al is the surgical mortality rate associated with right pneumonectomy. Surgical experience with lung resection is correlated with outcome. Silvestri et al studied the outcome of 1,583 lung resections for cancer performed by thoracic or general surgeons in South Carolina between 1991 and 1995. Approximately 70% of the board-certified thoracic surgeons performed more than 10 lobectomies during this interval compared to 25% of the board-certified general surgeons. Among patients undergoing lobectomy, surgical mortality was significantly higher (P = .04) in individuals operated on by general surgeons (38/711; 5.3%) than in those operated on by thoracic surgeons (21/705; 3.0%). A similar pattern of deaths after pneumonectomy (20/99 [22%] vs 8/68 [11.8%]) was seen.
Even for patients with lung cancer operated on by an experienced surgeon in a high-volume facility, right pneumonectomy can be a treacherous procedure. In this regard, Darling et al reviewed the Toronto General Hospital experience of 187 pneumonectomies (68 right; 119 left) performed between 1990 and 2000. Among 11 postpneumonectomy in-hospital deaths (total rate = 5.9%), 7 (10.3%) occurred after right-sided procedures compared to 4 (3.3%) after left pneumonectomy. Bronchopleural fistulae were significantly more common after right than left lung removal and were correlated with in-hospital deaths.
An even more troubling outcome after right pneumonectomy was reported by Martin et al for the thoracic surgical group at Memorial Sloan-Kettering Cancer Center. They reviewed their experience between 1993 and 1999 with NSCLC patients (N = 470) who were treated with induction chemo- or chemoradiotherapy followed by thoracotomy. Among these 470 patients, 97 (20.6%) underwent pneumonectomy. The overall postpneumonectomy mortality rate was 11.3% (11/97). All the postpneumonectomy deaths occurred in the group of patients undergoing right-sided procedures (11/46 [23.9%]). The authors concluded that "pulmonary resection after neoadjuvant therapy is associated with acceptable overall morbidity and mortality. However, right pneumonectomy is associated with a significant increased risk and should be performed only in selected patients."
The risk of death after right pneumonectomy has been demonstrated further in the findings of the North American Intergroup Trial 0139. In that two-arm trial randomizing stage IIIA NSCLC patients to definitive chemoradiation or induction chemoradiation (total radiation dose = 45 Gy) and then resection, 29 patients underwent right pneumonectomy. Among these 29, there were 11 (37.9%) treatment-related deaths. In 25 patients undergoing left pneumonectomy, the treatment-related death rate was 12%. These risks are in stark contrast to the treatment-related death rate of ~1% in the 98 patients randomized to the surgery arm of study 0139 who underwent lobectomy, rather than pneumonectomy, as their definitive surgical management.
To date, no prospective, randomized, phase III trial data have demonstrated significantly improved survival when surgical resection (of any extent) is added to chemoradiation for patients with N2 disease. Whether the use of trimodality therapy including lobectomy will eventually be shown to significantly improve survival over chemoradiation is uncertain. What is known is that right pneumonectomy, especially after induction therapy, is a hazardous undertaking. In aggregate, these data argue strongly against the use of right pneumonectomy as part of a trimodality approach to N2 disease-indeed, this is as close to an absolute contraindication to the inclusion of a surgical component as one can find.
-Mark R. Green, MD
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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