Management of Early Stage Non–Small-Cell Lung Cancer | 6 |
INTRODUCTION
Treatment for early stage non–small-cell lung cancer (NSCLC) is no longer “one-size fits all” with stage being the only determinant of the most effective therapy. Tumor histology, size, and location, as well as numerous epidemiologic factors, each contribute significantly to prognosis and therapy. For the majority of patients with early stage NSCLC, anatomic resection by lobectomy or more extensive surgery, provides the greatest chance for cure and is the initial treatment of choice. This approach has been challenged in patients with medical comorbidities, advanced age, and/or small or indolent tumors. Adjuvant chemotherapy has been shown to improve survival in those with completely resected stage II/III, and large (≥4 cm) stage IB tumors. This chapter outlines treatment strategies for patients with stage I and II NSCLC, including surgical approaches, adjuvant chemotherapy, and ablative therapy (e.g., stereotactic body radiation therapy [SBRT], radiofrequency ablation [RFA], microwave ablation [MWA], and cryotherapy).
SURGERY
Early stage NSCLC, defined as stage I and stage II disease, is most commonly treated with surgery as the initial modality. The current tumor node metastasis (TNM) staging guidelines by the American Joint Committee on Cancer (AJCC), seventh edition, define these as tumors up to 7 cm in size with or without ipsilateral hilar lymph node involvement, but without mediastinal lymph node disease. Tumors greater than 7 cm are considered to be stage II in the absence of lymph node involvement (1). A preoperative diagnostic biopsy of a highly suspicious pulmonary nodule is not necessarily required prior to definitive resection. There are two key components to surgery for early stage NSCLC, complete resection of the primary tumor and evaluation of draining lymph node basins in the ipsilateral hilum and mediastinum. Surgical intervention for NSCLC is not without risk and complications occur in up to 30% of patients. Appropriate assessment and mediation of interventional risk have evolved dramatically in the past decade.
Preoperative Assessment
Patients with NSCLC have more tobacco-related comorbidities than patients with other solid tumors and, therefore, physiologic assessment is essential to determine appropriate treatment strategies. The goal of preoperative assessment is to identify patients at increased risk for operative complications and long-term disability. The evaluation focuses heavily on cardiac and pulmonary physiology. Risk assessment can be complex, with subtleties related to patient age, cognition and mobility, tumor size and location, and the mode of intervention. Therefore, high-risk patients are best approached in multidisciplinary fashion.
Coronary artery disease (CAD) is more common in patients with NSCLC than the general population. The underlying rate of CAD in patients with NSCLC is 11% to 17% and the risk for major cardiac complication following lung resection is 2% to 3% (2). The American Heart Association/American College of Cardiology recommend the revised cardiac risk index (RCRI) tool for assessing cardiac risk in most patients undergoing noncardiac surgery. This has been further refined in a thoracic surgery-specific population through the development of the thoracic RCRI (ThRCRI), which also takes into account the extent of resection (3). Any patient with a score greater than 1.5, a newly suspected cardiac condition, limited exercise tolerance, or requiring cardiac medications should undergo a formal evaluation by a cardiologist prior to surgical intervention.
Pulmonary function tests (PFTs), primarily the forced expired volume in 1 second (FEV1), is the tool used most frequently for preoperative pulmonary assessment. Diffusion capacity for carbon monoxide (DLCO) is less commonly measured, but equally predictive of outcome. However, the two values do not always correlate with each other, so both FEV1 and DLCO should be measured as a routine part of preoperative planning. Impaired FEV1 and DLCO are both independent predictors of pulmonary morbidity, but their associated predicted postoperative (ppo) values appear to be more accurate guides. The ppoFEV1 and ppoDLCO should be calculated in all patients with abnormal lung function (FEV1 or DLCO <80% predicted). Calculations for ppoFEV1 and ppoDCLO can be based on either lung perfusion scan or planned extent of anatomic resection.
• Perfusion: ppoFEV1 or ppoDLCO = preoperative FEV1 or DLCO × (1 – fraction of total perfusion of the resected lung)
• Anatomic: ppoFEV1 or ppoDLCO = preoperative FEV1 or DLCO × (1 – no. of functional segments resected/total no. of functional segments)
Postoperative predicted FEV1 and DLCO greater than 40% portend a good prognosis for resection, but the inverse is not necessarily true; patients with ppoFEV1 or ppoDLCO less than 40% may require additional evaluation in the form of cardiopulmonary exercise testing, and alternative treatment strategies may need to be considered. Commonly used low-technology exercise tests include stair climbing and a shuttle walk. Peak oxygen consumption (VO2 max) is the most specific cardiopulmonary test and values less than 10 mL/kg/min are considered prohibitive for surgery, while values greater than 20 mL/kg/min indicate low risk for perioperative complications (2).
Lobectomy
Open Lobectomy
The majority of open lobectomies are performed using a posterior lateral thoracotomy, entering the pleural cavity through the 5th intercostal space. Median sternotomy and anterior thoracotomy can also be used, but exposure to the pulmonary hilum is suboptimal. Local control and overall survival following anatomic lobectomy for early stage NSCLC have improved over the past 50 years with substantial improvement in operative morbidity and mortality. In the American College of Surgeons Oncology Group (ACOSOG) Z0030 trial, 5-year disease-free survival was 68% for patients with resected early stage disease (4). Completeness of resection and lymph node involvement are the primary predictors of long-term survival. By definition, lobectomy involves individual identification and division of the lobar arteries, veins, and bronchus. In the modern era, most lobectomies are completed with endoscopic staplers. Resections by thoracotomy carry significant risk, with up to 37% of patients experiencing a postoperative complication (5). Most of these are minor, such as atrial arrhythmia or a prolonged air leak, but more serious complications, including respiratory failure, can occur and increase in frequency with decreasing baseline pulmonary function. The operative mortality following lobectomy is reported to be 1% to 3% (5,6), with pneumonia and respiratory failure as the most common causes of death.
Systematic Mediastinal Nodal Evaluation
Resection of the draining lymph nodes is vital for pathologic NSCLC staging, and is an integral part of surgical therapy. The demonstration of a survival improvement with adjuvant chemotherapy following resection of stage II and III NSCLC (7) places added importance to adequate intraoperative lymph node evaluation. Hilar and mediastinal lymph nodes are assigned stations as defined by the AJCC seventh edition TNM lung cancer staging system (1). The definitions of lymph node classifiers (N) remained essentially unchanged from the previous version and will remain unchanged in the next proposed system (see Appendix B). All interlobar and intralobar lymph nodes (stations 10–14, N1) encountered during dissection of the hilum and fissure are removed and sent for pathologic evaluation.
A thorough evaluation of mediastinal lymph nodes is essential and can be performed as a systematic sampling in which one or several lymph nodes are biopsied at each of the ipsilateral mediastinal stations (stations 2R, 4R, 7, and 9R on the right; levels 5, 6, 7, and 9L on the left), or a formal mediastinal lymphadenectomy in which all associated nodes and soft tissues between anatomic landmarks are removed. The collection and evaluation of at least 10 hilar and mediastinal lymph nodes are recognized as a quality measure for NSCLC resections by the American College of Surgeons Commission on Cancer, but controversy remains as to whether lymph node sampling or full dissection is superior, and if there is any survival benefit for the more aggressive approach. The ACOSOG randomized trial (ACOSOG Z0030) looked specifically at lymph node dissection versus sampling in greater than 1,000 patients with early stage NSCLC undergoing resection and failed to identify significant differences in morbidity or survival between the approaches (4). However, the authors cautioned that the trial focused on patients with clinical stage I disease and the results may not apply to those with higher stage tumors that would be more prone to metastasize.
Video-Assisted Thoracoscopic Surgery Lobectomy
Video-assisted thoracoscopic surgery (VATS), like thoracotomy, is a surgical approach and not a unique therapeutic intervention. The VATS approach to lobectomy typically involves two to three port sites and a 5 to 8 cm access incision. The distinction between VATS and mini-thoracotomy is the lack of rib spreading and the use of thoracoscopic visualization as opposed to visualization through the access incision (8). The rigid nature of the thoracic cavity makes it particularly well suited to scope-based approaches. The use of “pleuroscopy” has been reported since the early 20th century (9), but the practicality of thoracoscopic techniques increased dramatically in the 1980s with improvements in video technology and the introduction of double lumen endotracheal tubes to facilitate single-lung ventilation. Initial reports of VATS lobectomy appeared in the 1990s, documenting their safety and outlining techniques (10–13). Subsequently, numerous large series have reported recurrence and survival data equivalent to that achieved with open lobectomy (14–18). These studies have demonstrated that VATS lobectomy is a safe procedure with a rate of conversion to open lobectomy of 5% to 10%. Importantly, it has also been found that the conversion from VATS to open lobectomy is not associated with increased perioperative morbidity or mortality (19).
VATS lobectomy is the same oncologic operation as open lobectomy, including removal of the entire lobe that contains the tumor with individual ligation of vessels and the bronchus, and systematic evaluation of hilar and mediastinal lymph nodes. Most large VATS lobectomy series describe a similar pattern of perioperative complications as open lobectomy, but at reduced rates (14–16). The most widely recognized benefits of VATS are reduction in pain and length of hospital stay. The patients who appear to benefit the most from minimally invasive techniques are those at high risk due to marginal lung function. Multiple analyses from the Society of Thoracic Surgeons’ General Thoracic Surgery database (STS-GTSDB) have demonstrated similar rates of cardiopulmonary complications and death after VATS and open lobectomy for standard-risk patients, but significant decreases in these poor outcomes in high risk patients who undergo VATS as opposed to open thoracotomy (20,21).
One downside of VATS when compared to open lobectomy may be a decrease in the thoroughness of hilar lymph node evaluation. Analysis of clinical stage I tumors from the STS-GTSDB found similar rates of N0 to N2 upstaging with VATS and open lobectomy (4.9% vs. 5.0%), but a lower rate of N0 to N1 upstaging with VATS (6.7% vs. 9.3%) (22). Forty percent of lobotomies reported in the STS-GTSDB are currently performed thoracoscopically (8), but this database is heavily weighted toward academic centers and large practices, so it is thought that the actual rate of VATS lobectomy use in the United States is likely lower. Dense pleural adhesion and the inability to tolerate single-lung ventilation are the only definitive contraindications to VATS resections. Dense mediastinal scarring, central tumors, and tumors larger than the access incision are relative contraindications. Emerging technologies include single-port lobectomy and spontaneous breathing, nonintubated techniques, but thus far there are few reports of lobectomy using these procedures.
Robotic-Assisted Lobectomy
The main advantage of robotic technology for anatomic lung resections mirrors that of the VATS approach, namely smaller, non–rib-spreading incisions resulting in less operative trauma, and decreased pain and length of hospital stay. The benefits of a robotic approach over VATS include binocular visualization, wristed instruments that allow for more precise dissection, and no requirement for an access incision. Additionally, given the totally portal nature of the procedure, carbon dioxide insufflation of the hemithorax can be used to further collapse the lung providing a larger working area.
Robotic lobectomy requires similar positioning as the open or VATS approach with the patient in the lateral decubitus position. There are three or four access ports for the robot and one assistant port for suctioning, stapling, and retraction. The dissection of the hilum and fissure is performed in a similar manner as with the VATS and open approaches with the bronchovascular structures being dissected and individually divided with staplers. Initial series reporting on robotic lobectomy for NSCLC have demonstrated the safety and feasibility of this approach, without increased morbidity or mortality (23–25). While large longitudinal studies addressing long-term oncologic outcomes are needed, initial reports show comparable stage-specific survival rates with VATS and robotic approaches (26,27). Cost comparisons between robotic and VATS techniques are difficult due to the larger upfront cost of a robotic system; however, both approaches appear to have an overall cost benefit compared to open thoracotomy due to the significant decrease in hospital length of stay (28).
Sublobar Resection
Sublobar resections have always been a compromise procedure for patients with early stage NSCLC who lack the pulmonary function to tolerate lobectomy. However, since the 1950s lobectomy has been the standard-of-care for treatment of resectable early stage NSCLC, even for patients with small tumors (<2 cm). In 1996, the Lung Cancer Study Group (LCSG) reported the only randomized trial that compared lobectomy to lesser resections for early stage NSCLC (29). This study found a threefold increase in local recurrence with sublobar resection compared to lobectomy. The main concerns regarding these results are that this trial completed accrual in 1988, prior to the introduction of FDG-PET, and that CT scans were obtained in less than 30% of patients. So while this trial has guided surgical care for 20 years, its findings are becoming less relevant due to improvements in the radiographic diagnosis and staging of lung cancer and advancements in our understanding of the biology of this disease.
Recently, there has been a resurgence of interest in the intentional use of sublobar resections for small and indolent clinical stage I NSCLC. The primary advantage of sublobar resection is the preservation of pulmonary parenchyma, which should translate into better postoperative pulmonary function, improved quality of life, and increased ability to tolerate a second curative procedure for a subsequent bronchogenic carcinoma.
Several recent, single institution, retrospective analyses that compared sublobar resection to lobectomy in patients with limited cardiopulmonary reserve contradict the earlier findings from the LCSG study, demonstrating that in well-selected patients with stage I NSCLC sublobar resection achieves similar survival rates as lobectomy. Most series highlight important requirements to assume an equivalent outcome between sublobar resections and lobectomy, including
• Tumor size less than 2 cm
• Indolent histologic subclassification
• Segmentectomy rather than wedge resection
• Surgical margins of at least 2 cm or as large as the tumor
Increased rates of detection of small peripheral tumors and ground-glass opacities (GGOs) associated with favorable histology have led to the increasing use of sublobar resections in many centers to include patients with adequate physiologic reserve (30). Both American and Japanese series have demonstrated that adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), which can be identified preoperatively by a high GGO-to-solid ratio on CT, represents an entity with improved survival and reduced rates of lymph node involvement and distant metastatic spread (30–32). The selection of medically fit patients with very favorable tumors based on peripheral location, small size, and a high GGO-to-solid ratio for intentional sublobar resection is gaining acceptance in the international community. Reviews by Yamada, Yamato, and Wantanabe have each reported 100% survival and no evidence of recurrence when intentional sublobar resection was used in patients with pure GGOs less than 3 cm in size (33–36).
A prospective, randomized multi-institutional phase III trial is being conducted by the Alliance Cooperative Group (CALGB 140503) to determine the effectiveness of an intentional sublobar resection protocol for small (<2 cm) peripheral tumors. A similar trial recently completed accrual in Japan (JCOG0802/WJOG4607). Both trials are similar in design to the LCSG trial, with lobectomy being compared to sublobar resection (wedge resection or segmentectomy), but with a smaller tumor size requirement and use of modern staging studies. Results of these studies will hopefully provide important insights into the role of lung-sparing resections for small, peripheral stage IA tumors.
ADJUVANT THERAPY
Platinum-Based Adjuvant Therapy
Despite complete resection, disease recurrence remains a significant problem for patients with early stage NSCLC, especially within the first 5 years after surgery. Cisplatin-based adjuvant chemotherapy is the standard-of-care following surgery for patients with stage II, III, and high-risk stage IB NSCLC (37). The goal of adjuvant therapy is to eliminate occult metastatic disease, thereby decreasing the recurrence rate and improving survival.
Several large, randomized clinical trials have demonstrated a survival benefit, ranging from approximately 5% to 15%, for adjuvant chemotherapy (38–40). These studies used cisplatin-based, two-drug regimens and enrolled mostly patients with stage IB-IIIA NSCLC. The lung adjuvant cisplatin evaluation (LACE) meta-analysis (7) evaluated pooled data of five large, randomized, controlled adjuvant chemotherapy trials that were performed since 1995: Adjuvant Navelbine International Trialist Association (ANITA) (38), Intergroup trial JRB.10 (39), International Adjuvant Lung Trial (IALT) (40), Big Lung Trial (BLT) (41), and Adjuvant Lung Project Italy (ALPI) (42). These studies accrued a total of 4,585 patients who had undergone complete resection for stage I (7% stage IA, 31% stage IB), stage II (35%), and stage III (27%). With a mean follow-up of 5.2 years, adjuvant chemotherapy resulted in a 5.4% increase in overall survival (HR 0.89). The advantage of adjuvant chemotherapy was not seen in all stages and appeared to be detrimental in patients with stage IA disease. Of note, some of these studies allowed the use of postoperative radiation (PORT), which has been shown to have a negative impact on outcomes in patients with early stage NSCLC, particularly those with N0 disease (43).
A more comprehensive review of trials evaluating the role of adjuvant chemotherapy in early stage NSCLC again demonstrated an absolute survival benefit of 4% at 5 years (44). This meta-analysis included 26 randomized trials that compared outcomes of surgery with or without adjuvant chemotherapy, and 12 trials that compared surgery and radiation with or without adjuvant chemotherapy. Again, a survival advantage was not seen for patients with stage IA disease, and data remains controversial for stage IB. Based on subset analyses of two adjuvant chemotherapy trials, it appears that adjuvant chemotherapy may be beneficial for patients with larger stage IB tumors ≥4 cm (39,45).
The current standard treatment for patients with completely resected high-risk stage IB (≥4 cm), II, or IIIA NSCLC is a cisplatin-based, two-drug regimen for 12 weeks. Preexisting comorbidities, performance status, and time since surgery should be taken into account in the decision to pursue adjuvant chemotherapy. The combination of cisplatin plus vinorelbine was used in the majority of the positive adjuvant trials, but is associated with a relatively high rate of severe toxicities. The National Comprehensive Cancer Network (NCCN) guidelines for adjuvant chemotherapy now include other platinum-based, two-drug regimens that contain pemetrexed, docetaxel, or gemcitabine based on studies in advanced NSCLC that demonstrate equivalent efficacy with less toxicity (46). Since all of the positive adjuvant trials utilized cisplatin-based regimens, this agent should be favored, but carboplatin may be substituted in patients in whom cisplatin is contraindicated or poorly tolerated.
Targeted Adjuvant Therapy
Recently, efforts have focused on the potential role of newer targeted therapies and immunotherapy in the adjuvant setting. Clinical trials are currently underway to evaluate the role of these novel strategies in search of options that are more effective and less toxic than standard chemotherapy. The phase III Eastern Cooperative Oncology Group (ECOG) 1505 study evaluated chemotherapy with or without bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), in the adjuvant setting (47). In this trial, patients with completely resected stage IB, II, or IIIA NSCLC were randomized to cisplatin-based chemotherapy with or without bevacizumab, and there were no significant differences in overall survival (HR 0.99) or disease-free survival (HR 0.98) between the two groups.
Studies evaluating the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the adjuvant setting have suggested a trend in the improvement of disease-free survival, but no advantage in overall survival, so their use as adjuvant therapy remains controversial. The phase III RADIANT trial randomized patients with completely resected NSCLC, regardless of EGFR mutation status, to adjuvant erlotinib versus placebo and found no statistically significant differences in disease-free or overall survival (48). However, among the subgroup of patients whose tumors harbored sensitizing EGFR mutations, there was a nonsignificant trend toward improved disease-free survival in the erlotinib group (HR 0.61). Further studies are currently evaluating adjuvant EGFR TKIs in patients with EGFR-mutated NSCLC.
The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an ongoing randomized, phase III study that is evaluating the role of individualized, genotype-directed therapy in the adjuvant setting. Patients with completely resected stage IB, II, or IIIA NSCLC undergo tumor analysis for EGFR mutation and ALK gene arrangement. If either of these driver-mutations is identified, then the patient can be randomized to receive appropriate targeted therapy (erlotinib or crizotinib, respectively) or placebo for 2 years following completion of standard adjuvant chemotherapy. In light of the recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway in patients with advanced-stage NSCLC, a third arm has been added to the ALCHEMIST study in which patients whose tumors are EGFR and ALK wild-type are randomized to receive nivolumab, an anti-PD-1 monoclonal antibody, or undergo standard surveillance without further therapy. As our understanding of the genomic heterogeneity and complexity of NSCLC advances, further definition of which patients are more likely to benefit from these novel adjuvant therapy strategies should follow.
NONSURGICAL THERAPY
Stereotactic Body Radiation Therapy
Many lung cancer patients are considered medically inoperable due to cardiovascular, pulmonary, or other comorbidities. Historically, conventionally fractionated radiation therapy (RT) was used for patients too frail to tolerate surgery. Unfortunately, this approach had high rates of local and regional failure, as well as treatment-related toxicity. Over the past two decades, several nonsurgical modalities have been developed for the treatment of early stage NSCLC, including SBRT, a strategy that employs very large (ablative) doses of radiation delivered in one to five fractions using highly conformal techniques. SBRT requires the use of computerized treatment planning, precise tumor tracking, and noncolinear and noncoplanar beams which allow for a steep decrease of the radiation dose outside of the treatment volume. The earliest reports on the use of SBRT for the treatment of NSCLC appeared in the mid-1990s from Sweden and Japan (49–51), and included patients with early stage NSCLC and pulmonary metastases that were medically unfit for pulmonary resection. The first series examining SBRT for stage I NSCLC exclusively reported a 94% local control rate in 50 patients treated with 50 to 60 Gy in five to ten fractions with minimal toxicity (51).
Interest in this technology grew dramatically in 2004 following a retrospective review of 245 patients with stage I NSCLC treated with SBRT at 14 Japanese centers (52). Treatment schedules varied significantly and the report included both medically operable and inoperable patients. The overall 2-year local control rate was 86%, but was higher in patients receiving a biologically effective dose (BED) greater than 100 Gy than in those receiving BED less than 100 Gy (92% vs. 73%). The overall survival rate was 56% at 3 years and 47% at 5 years, and was significantly better in medically fit patients. The overall survival rate for medically fit patients with stage IA NSCLC treated with BED greater than 100 Gy was 90% at 3 years (52).
Between 2002 and 2008, more than 25 single institution, prospective, phase I and II trials reported results on the use of SBRT for medically inoperable patients with stage I NSCLC. Local control rates ranged from 70% to 100% and were better with doses greater than 48 Gy. Follow-up was less than 3 years in almost all series, but overall survival rates ranged from 47% to 91% at 1 year, with much of the mortality attributed to medical comorbidities. Adverse events occurred in 0% to 20% of patients in most series, with cough, dyspnea, fatigue, musculoskeletal pain, and pneumonitis being the most frequent (53–55).
In 2010, the Radiation Therapy Oncology Group (RTOG) reported the first prospective multicenter, cooperative group study of SBRT for early stage peripheral NSCLC (RTOG 0236). In this phase II trial, medically inoperable patients received 54 Gy in three fractions. Eligible patients had peripheral (≥2 cm from the central trachea-bronchial tree), biopsy-proven NSCLC ≤5 cm in maximum diameter. In 55 evaluable patients with a median follow-up of 34.4 months, the 3-year primary tumor control rate was 97.6% and the overall survival rate was 55.8% (56). The high local control rate was felt to be responsible for the study’s high survival rate compared to historic reports of conventional RT techniques.
Since publication of RTOG 0236, grouped data from multiple trials have also reported 3-year local tumor control rates greater than 90% following SBRT for peripheral NSCLC (57). SBRT has emerged as the standard-of-care for medically inoperable patients with peripheral, early stage NSCLC. However, significant practice variations exist for the treatment of large, multifocal, recurrent, or centrally located tumors, and for patients who are medically operable or lack tissue confirmation.
Toxicity of SBRT
SBRT of peripheral tumors can result in toxicity to the skin, soft tissue, and bone of the chest wall. Neuropathic pain and rib fractures occur in 10% to 15% of patients with tumors abutting the chest wall (58). There were initial concerns that lung SBRT would carry a significant risk for lung toxicity in patients with limited pulmonary reserve, but grade 3–4 pulmonary complications were reported in only 16% of patients treated on RTOG 0236 (59). On further review, most of these were prespecified changes in PFT values as opposed to symptomatic lung injury (60). Several subsequent studies have demonstrated minimal PFT changes after SBRT for peripheral lesions (61, 62). Poor pulmonary function and low FEV1 are predictors of poor survival, but do not correlate with increased treatment-related toxicity (53). Lung toxicity correlates more strongly with tumor size and location. SBRT is a safe treatment modality for stage I NSCLC in fragile, high-risk populations and poor pulmonary function should not exclude patients from SBRT.
Percutaneous Ablative Therapy
Percutaneous ablation is another area of evolving technology for the treatment of thoracic malignancies. Three major modalities are within this realm: RFA, MWA, and cryotherapy. All are typically performed with sedation under CT guidance, and are best suited for small tumors without nodal metastases. RFA and MWA rely on tumor cell coagulation necrosis resulting from temperatures greater than 60°C, while CRYO causes cell death as a result of freezing and thawing.
Radiofrequency Ablation
Of the three modalities, RFA has undergone the greatest amount of clinical evaluation in NSCLC. RFA is recognized for its ease of use, single-setting treatment, tolerability, and cost effectiveness, but, to date, the majority of the data supporting its use in the lung has come from retrospective, single-institution reports that have combined early stage NSCLC with lung metastases with a focus on extremely short-term outcomes. Numerous case series have demonstrated that RFA is safe and feasible for the treatment of medically inoperable patients with early stage NSCLC. The first multi-institutional, prospective evaluation of RFA for such patients was reported by Dupuy et al. in 2015 (63). Fifty-one patients with biopsy-proven T1N0 NSCLC were treated with RFA at 16 institutions; all were deemed medically inoperable by a thoracic surgeon and had clinical follow-up through 2 years. In this frail patient population, RFA demonstrated an excellent safety profile, tolerability, and preservation of pulmonary function. Local recurrences occurred in 40% at 2 years, a figure that is consistent with other series using RFA for early stage NSCLC (64,65). Local control was better for tumors less than 2 cm, but was still not equivalent to that reported for SBRT or sublobar resection. Thermal ablative technologies for NSCLC are limited by tumor size and proximity to bronchovascular structures, the esophagus, pericardium, or trachea. RFA must be used cautiously in lesions greater than 3 cm or within 1 cm of hilar structures because of the risk of incomplete ablation and damage to central structures.
Microwave Ablation
MWA is a thermal-based ablative system which generates heat and coagulation via electromagnetic waves. The theoretical advantage of MWA over RFA is that it generates higher temperatures with a steeper tissue drop off, which allows for shorter treatment times and less of a heat-sink effect. The technology is far less established than RFA and there are only scant reports of its safety and efficacy for pulmonary tumors (66).
Cryotherapy
Cryotherapy is also performed percutaneously under CT guidance, but uses an argon-based freezing system. A unique aspect of cryotherapy is that the formation of an ice ball can be followed with CT. Multiple probes and multiple freeze-thaw cycles are typically required for tumors greater than 2 cm. As with RFA, there can be an incomplete treatment effect in peripheral zones of the tumor, so a 3 to 5 mm margin is recommended. A unique advantage of cryotherapy is the ability to use it for treatment of central tumors, because it preserves collagenous structures.
Radiographic Follow-Up Postablation
All percutaneous ablative therapies result in predictable, posttreatment CT changes. Immediately following ablation, the tumor typically increases in size and takes on a ground-glass appearance with “bubble lucencies” (67). These changes resolve over the first month and by 3 months, the lesion should decrease in size and become denser. An increase in size after 3 months is suspicious for persistent or recurrent disease. Tumors adjacent to segmental bronchi have a tendency to cavitate, while those in the periphery of the lung become linear or wedge shaped with pleural tags and pleural thickening (67). One recent report also noted reversible regional lymph node enlargement with moderate increases in FDG-PET activity following RFA as a result of treatment-related inflammation (68). Close surveillance without further intervention is recommended for typical CT changes for at least 6 months after treatment.
SUMMARY
The management of NSCLC is no longer a “one treatment fits all” scenario. Novel approaches to treatment are far more personalized and take advantage of the unique characteristics of each tumor and each individual patient. For early stage disease, in which surgery can cure 50% to 80% of patients, the development of safer, less invasive strategies is essential. VATS is now recognized as having oncologic equivalence to open procedures, and investigators are reevaluating the use of sublobar resections as a means of preserving pulmonary function. The increased accuracy of CT and FDG-PET have allowed for the emergence of nonsurgical, CT-guided ablative therapies as safe and effective therapeutic options for early stage, lymph node-negative NSCLC. While still experimental for medically fit populations, these techniques are quickly gaining wide acceptance for use in compromised, high-risk populations.
