Historically, SCLC has been considered a nonoperative disease. Early randomized studies suggested no benefit to surgery over radiation or chemotherapy only. The Medical Research Council trial published in 1973 evaluated only patients with SCLC involving the bronchus, and complete resection was performed in only 34 of 71 (48%) patients.44 The Lung Cancer Study Group, Eastern Cooperative Oncology Group (ECOG), and European Organization for Research and Treatment of Cancer published an intergroup trial in 1994, which randomized patients with limited SCLC who had responded to five cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine), but again these included only patients who had bronchoscopically visible disease. While most of the surgical patients (54 of 70, 77%) underwent complete resection, 35 (50%) surgical patients had cN2 disease, 24 (34%) had pN2 disease, and 12 (17%) were unresectable at the time of surgery.45 Neither of these studies demonstrating lack of benefit of surgery in “limited” SCLC included patients with early SCLC as defined by modern-day staging techniques, including PET-CT, brain MR, and endobronchial ultrasound (EBUS) or mediastinoscopy for nodal evaluation.
Resection is recommended for early-stage SCLC. Early-stage SCLC comprises a small proportion of an already rare entity. Ten to fifteen percent of lung cancers are SCLC, and only 3% to 7% of these patients present with stage I or II disease, as determined in a SEER database study of all patients diagnosed with lung cancer between 1988 and 2005 and followed for at least 3 months.46 Resection offers benefit for tumors that prove to be combined or mixed SCLC/NSCLC (10%–30% of SCLC cases). In addition, resection offers the best local control in limited disease. The same SEER database analysis46 found lobectomy alone (47% 5-year overall survival) to be superior to radiation therapy (17% 5-year overall survival), a finding which was significant on multivariable analysis (HR = 0.56; 95% CI = 0.41–0.76). Other studies have demonstrated similar survival for lobectomy in early-stage SCLC.47 The National Comprehensive Cancer Network (NCCN) currently recommends lobectomy with mediastinal nodal sampling or dissection for patients with clinical stage I disease to be followed by adjuvant chemotherapy, even if nodes are pathologically negative.48 Patients treated with complete resection should also undergo prophylactic whole brain irradiation following adjuvant chemotherapy if performance status and neurocognitive function are not impaired, given the high propensity of SCLC to metastasize to the brain.
Surgical resection is recommended for pulmonary carcinoid, which can be found at all levels from the trachea to the lung periphery.49 The prognosis for resection of low-grade TC is excellent, with 82% 10-year survival in Wilkins series that spans a 50-year experience49 as well as in a modern Australian series.50 Most surgeons advocate a parenchymal-sparing approach, which often mandates sleeve resection (bronchus, carina, or even trachea) to preserve lung for tumors that are frequently central. Peripheral carcinoids can be managed with sublobar resection, including segmentectomy or wedge resection, with good results, as supported by a recent SEER database evaluation of 3270 pulmonary carcinoid patients, in which sublobar resection compared well to lobectomy when assessed for noninferiority in multivariable analysis.51
Non–small-cell Lung Cancer
The remaining primary epithelial lung malignancies are NSCLC, including adenocarcinoma, SCC, and others, such as LCC. Treatment for most NSCLCs depends on stage, with surgical resection generally the treatment of choice for early-stage disease. Chapter 71 describes the standard lobectomies for NSCLC isolated to individual lobes. SCCs are frequently central and may necessitate sleeve resection or even pneumonectomy if there is involvement of hilar vessels or bronchi.
In contrast to the other forms of NSCLC, adenocarcinomas are remarkably heterogeneous and recent advancements in molecular genetics, histopathology, and imaging have had significant impact on the treatment of these tumors. Adenocarcinoma represents the most common histology among NSCLC and lung cancer in the United States.6 Tumors previously identified as BAC, and now defined as AIS or MIA, often demonstrate indolent behavior and favorable long-term survival.52 Increased understanding of these aspects of tumor biology and the advent of targeted biologic therapy for certain genetic mutations53 have revolutionized the treatment of patients with AIS, MIA, and adenocarcinoma. These tumors frequently present as nonsolid or subsolid nodules on low-dose chest computed tomography, presenting a conundrum for treating clinicians. Given indolent and multicentric behavior for subsolid nodules, parenchymal-sparing sublobar resection is likely the best surgical approach,54 but these lesions are frequently not palpable, making wedge resection difficult if possible at all. Anatomic segmentectomy would be preferred, but when a nonsolid adenocarcinoma crosses segmental boundaries, it may necessitate lobectomy, which is suboptimal in the setting of potentially multicentric disease. Whether to follow these preinvasive and early invasive adenocarcinomas with surveillance imaging and when to treat with surgery, radiation, or biologic therapy are areas ripe for further research.55
Chapter 68 introduced the seventh edition staging system for NSCLC. As discussed above in this chapter, treatment for most early-stage NSCLCs involves surgical resection with lobectomy, segmentectomy, or wedge resection. More advanced stage disease warrants consideration of multimodality therapy, including chemotherapy and external beam radiation.
Adjuvant Chemotherapy Following Surgical Resection
Stage is the major factor influencing whether a patient who undergoes surgical resection for NSCLC should receive adjuvant chemotherapy. Early trials suggested no benefit to adjuvant chemotherapy following resection. The ECOG compared concurrent radiation and cisplatin–etoposide with radiation alone following resection of stage II or IIIA NSCLC and found no statistically significant difference in overall survival or recurrence.56 The Adjuvant Lung Project, Italy randomized 1209 patients who underwent complete resection for stage I, II, or IIIA NSCLC to an adjuvant cisplatin-based regimen (MVP) or observation and likewise found no statistically significant difference in overall or progression-free survival between the two groups57 following resection for more advanced disease. In the largest randomized-controlled study of adjuvant chemotherapy following surgery, the International Adjuvant Lung Cancer Trial randomized 1867 patients with stage I, II, or III disease to cisplatin-based chemotherapy or observation. Patients receiving adjuvant chemotherapy experienced a significantly higher overall and disease-free survival.58 Two additional international multicenter randomized studies demonstrated similar benefit for adjuvant cisplatin–vinorelbine doublets: the National Cancer Institute of Canada/National Cancer Institute of the United States Intergroup JBR.10 trial for patients with stage IB or II NSCLC59 and the Adjuvant Navelbine International Trialist Association (ANITA) Trial for patients with Stage IB, II, or IIIA disease.60 Of note, the ANITA investigators performed subgroup analyses and survival benefit for adjuvant cisplatin–vinorelbine was only demonstrated with the stage II and IIIA patients (not in stage IA), but the authors felt the numbers were small and the study was not sufficiently powered to evaluate differences for the individual stages.
Therefore, it is generally agreed that for stage II disease (and for those with stage III disease diagnosed upon final pathology following resection), treatment should include anatomic surgical resection followed by adjuvant chemotherapy. Adjuvant chemotherapy is not recommended following resection for stage IA NSCLC. For stage IB disease, the role of adjuvant chemotherapy was evaluated by the Cancer and Leukemia Group B (CALGB) 9633 trial, in which 344 patients with stage IB NSCLC were randomized to receive carboplatin–paclitaxel or observation following lobectomy or pneumonectomy, and no difference in overall survival was found between the groups.61 On unplanned subgroup analysis, the investigators found a survival benefit of adjuvant chemotherapy for patients with tumors 4 cm or larger, but overall, the study was felt to be underpowered to detect subtle differences in survival given the relatively long survival of these patients compared to those with more advanced disease.
Superior Sulcus (Pancoast) Tumors
Although a few patients with superior sulcus (Pancoast) tumors will have stage II disease (if the lesion is 7 cm or smaller and the hilar and mediastinal nodes are negative), most will have stage IIIA or IIIB disease, depending on the status of the mediastinal nodes. Practice has evolved over time,62 but superior sulcus tumors are generally treated with induction chemoradiation followed by surgical resection, using the Southwest Oncology Group (SWOG) protocol of cisplatin–etoposide with 45 Gy concurrent radiation followed by en bloc resection of the tumor with lobectomy.63
Stage IIIA NSCLC is a heterogeneous disease that includes four types of pathology: (1) bulky N2 disease; (2) microscopic N2 disease found on preoperative staging; (3) microscopic N2 disease found at the time of or following resection; and (4) T3N1 tumors (hilar nodal disease with tumor involving the chest wall or mainstem bronchus within 2 cm of the carina). Even among individual specialties, such as medical oncology64 or thoracic surgery,65 there is little consensus regarding how to treat patients with stage IIIA NSCLC. For patients with bulky N2 disease, this is particularly controversial.
Several randomized trials have been conducted to investigate the best multimodality approach. A recent phase III trial compared radiation to surgery following response to platinum-based induction chemotherapy for patients with histologically proved stage IIIA-N2 NSCLC. Three hundred and thirty-two patients were randomized and results suggested no difference between the two arms, with a median and 5-year overall survival of 16.4 months and 15.7% for resection and 17.5 months and 14% for radiation.66 The Lung Intergroup Trial 0139 randomized 396 patients with Stage IIIA-N2 NSCLC who underwent two cycles of cisplatin–etoposide with concurrent 45 Gy radiation per the SWOG protocol and deemed fit for surgery to undergo either surgery followed by two more cycles of chemotherapy or additional chemoradiation (for a total of four cycles and 60 Gy). Although progression-free survival was higher for the surgical arm (median 12.8 months vs. 10.5 months, p = 0.017), there was no difference in overall survival (23.6 months vs. 22.2 months, for surgery compared to radiation, p = 0.24).67 Nearly all (14 out of 16) of the treatment-related deaths in the surgical arm were following pneumonectomy, prompting a subgroup analysis for patients who underwent lobectomy and not pneumonectomy. In this subgroup, overall survival was higher for patients who underwent lobectomy following induction chemoradiation than for those who underwent definitive chemoradiation. This has led many clinicians to use caution in treating patients with stage IIIA-N2 disease with induction chemoradiation followed by pneumonectomy. The Intergroup 0139 trial also found that a single N2 nodal station (compared to multistation disease) was independently associated with higher survival among surgical patients (p = 0.009). This finding suggests that single-station disease behaves differently compared to multistation stage IIIA-N2 disease, supporting the practice of some surgeons to consider primary surgical resection with lymphadenectomy followed by adjuvant chemotherapy or chemoradiation for single-station stage IIIA-N2 disease.
There is even less consensus regarding the treatment of N3 disease, or stage IIIB. A phase II study of a trimodality approach using the SWOG protocol (two cycles of cisplatin–etoposide with concurrent 45 Gy radiotherapy) followed by resection for stable or improved disease was conducted for patients with stage IIIA-N2 and N3 disease.68 No difference for survival was found for patients with N2 versus N3 disease at diagnosis, with a 3-year survival of 26%, and the strongest predictor of long-term survival was negative nodal status on resection. The SWOG investigators also examined the role of definitive chemoradiation (four cycles of cisplatin–etoposide with concurrent 61 Gy) for patients with stage IIIB NSCLC.69 The 3-year and 5-year survival percentage for the 50 patients accrued were 17% and 15%, respectively.
A reasonable approach for the four types of N2 disease (Table 69-3) described above is (1) chemoradiation with consideration of surgical resection for bulky N2 disease depending on response to induction therapy; (2) chemotherapy or chemoradiation followed by surgical resection for micrometastatic disease found on preoperative staging; (3) surgical resection followed by chemotherapy or chemoradiation for single-station disease found at the time of surgery (particularly for the left upper lobe and station 4 L) or for multistation disease found on pathology following resection; and (4) chemotherapy or chemoradiation followed by resection if disease has not progressed for T3N1 disease, with chemoradiation followed by en bloc resection for superior sulcus (Pancoast) tumors.
Table 69-3Treatment Approach to Nodal Disease in Stage Iiia Nsclc ||Download (.pdf) Table 69-3Treatment Approach to Nodal Disease in Stage Iiia Nsclc
|Bulky N2 disease ||Chemoradiation with consideration of resection for bulky N2 disease that responds to induction therapy |
|Microscopic N2 on preoperative staging ||Chemotherapy or chemoradiation followed by surgical resection of micrometastatic disease |
|Microscopic N2 found at time of or following resection ||Surgical resection followed by chemotherapy or chemoradiation |
|T3N1 tumors (hilar nodal disease with tumor involving chest wall or mainstem bronchus within 2 cm of carina) ||Chemotherapy or chemoradiation followed by resection if T3N1 disease does not progress on induction therapy |
The role of surgery in stage IV disease is traditionally palliative, such as pleurodesis or pleurX catheter placement for NSCLC with malignant pleural effusion. There are particular circumstances, however, in which curative surgery is attempted in the setting of stage IV NSCLC. In a series of 28 patients who underwent extrapleural pneumonectomy (EPP) for pleural dissemination of NSCLC, the median survival for nine patients who had node-negative disease was 52 months (vs. 14 months for those with positive nodes, p = 0.0003), suggesting that EPP may prolong survival in NSCLC patients with node-negative malignant pleural effusion (stage IV).70 Data gathered retrospectively from 14 SWOG trials involving 2531 patients suggest that approximately 7% of patients with metastatic NSCLC present with a solitary metastasis,71 often called oligometastatic NSCLC. This represents a unique situation in which a multidisciplinary approach of chemotherapy, surgical resection of the lung primary, and treatment of the metastasis with resection, radiotherapy, or both may be used.72 Generally, this is considered for oligometastases to the brain or the adrenal, but others have reported small series (fewer than 10 patients) of pulmonary resection with metastasectomy for nonbrain, nonadrenal oligometastasis.73 The data regarding pulmonary resection and oligometastasectomy are retrospective and sparse, with most studies combining metachronous and synchronous presentation of metastases. Whether to perform surgical resection for NSCLC in the setting of oligometastatic disease should be considered on an individual basis in collaboration with other treating physicians and after thorough discussion of treatment options with the patient.