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Innovative Therapy and Technology
Lung cancer remains the number one cause of cancer-related deaths in men and women, and the incidence continues to rise with approximately 175,000 new cases diagnosed annually in the United States. In this chapter, we review several innovative therapies for patients who are at high risk for primary and metastatic lung tumors. Application of these new therapies continues to evolve, and in most cases, surgical resection remains the mainstay of therapy. Lobectomy has been considered the standard treatment modality for early-stage non–small cell lung cancer (NSCLC) for years, with sublobar resection being suboptimal because of an increased potential for recurrent disease. More recent data on small tumors (less than 2 cm) with good margins (with margin distance at least the diameter of the tumor) show the local recurrence rate has lowered to near that of lobectomy. However, most patients with NSCLC present with advanced disease, and a significant number of patients with early-stage disease are unable to undergo pulmonary resection because of compromised cardiopulmonary function or other reasons. The new alternatives to traditional surgical treatment allow additional options when surgery is not clearly of benefit or when the patient is not a candidate for traditional resection. As with other recent advances, such as video-assisted thoracoscopic surgery (VATS), these newer, less invasive approaches may allow surgeons to treat patients with thoracic malignancies even in the setting of marginal pulmonary reserve.
The two principal ablative modalities discussed in this chapter for inoperable or high-risk patients are radiofrequency ablation and stereotactic radiosurgery. Another ablative modality, microwave ablation, is also being evaluated, although current clinical experience with this novel approach is limited. We also briefly discuss some newer technologies for ablation, including irreversible electroporation. The main goal of these less invasive therapies is to locally destroy the pulmonary or thoracic neoplasm while preserving the surrounding normal tissues. In addition, we discuss intrathoracic chemoperfusion for pleural malignancies.
It is important that thoracic surgical oncologists stay abreast of new therapies, design clinical trials, and critically evaluate and report the results. The introduction of new technology should not change the paradigm of who treats thoracic malignancies. Failure of surgeons to adapt to new technology will lead to fragmentation in the care of the patient with a thoracic malignancy. However, for the time being, the current evaluable data support the concept that most localized thoracic malignancies should ideally still be treated by minimally invasive surgical resection. Thus, failure to involve an experienced thoracic surgical oncologist in the design of clinical trials will increase the risk of compromising patient care.
Radiofrequency Ablation
Radiofrequency ablation (RFA) is a thermal ablative modality, which uses high-frequency alternating current to generate heat and coagulate tissue. RFA systems typically have three components: (1) a generator, (2) an active electrode that is placed within the tumor, and (3) a dispersive electrode (Bovie pad) placed on the thighs of the patient ( Fig. 46-1 ). As the radiofrequency energy moves from the active electrode to the dispersive electrode and back, ions within the tissue oscillate with the changing direction of the current, resulting in frictional heating of the tissue. As the temperature within the tissue rises to greater than 60° C, cell death occurs as a result of protein denaturation and coagulation necrosis. Moreover, the dispersion of energy beyond the vicinity of the active electrode is minimal, allowing for focused delivery of energy to the target lesion with minimal injury to the surrounding normal tissue. The advantages of this minimally invasive ablative approach include lower morbidity and mortality in comparison with the more invasive approaches, lower costs per treatment, lower costs to set up a program and the associated technology, reduced hospital stay, and the ability to complete treatment without multiple sessions. The goal of RFA in the treatment of lung tumors is complete coagulation necrosis of the lesion with a small margin of extension into adjacent normal pulmonary parenchyma.
Initial experience with RFA has been primarily in the treatment of liver tumors, both as an adjunct to resection and as primary therapy. Due to low complication rates, RFA may supplant other thermal ablative modalities (e.g., cryotherapy). Pulmonary RFA also has a low rate of major complications, which include sepsis, respiratory infection, bleeding, infection at the operative puncture site, and prolonged air leak. In a large international, multicenter study of 2320 patients who underwent percutaneous RFA for liver malignancies, the mortality rate was 0.3%, and the overall complication rate was 7.1%.
Several centers around the world have published reports demonstrating the safety and feasibility of RFA for lung tumors. Animal models, to investigate the feasibility of RFA for the treatment of lung tumors, have been used to develop treatment algorithms for humans. In a study by Goldberg and colleagues using a rabbit model of lung sarcoma, seven lesions were treated with RFA for 6 minutes at 90° C, and the remaining four tumors were left untreated as controls. The authors noted computed tomography (CT) evidence of coagulation necrosis surrounding the tumor, manifested radiographically by increased opacity enveloping the lesion. This was followed temporally by the development of central tissue attenuation consistent with cavitation. Histologic analysis revealed that at least 95% of the tumor nodules were necrotic, although some rabbits (43%) had residual tumor nests at the periphery of the tumor. Pneumothorax was the only procedure-related complication, occurring in 29% of treated rabbits and 25% of controls. In another study, Miao and colleagues implanted VX2 sarcomas into the lungs of 18 rabbits (12 treated and 6 controls). The lesions were then treated with RFA using a cooled-tip electrode. Absolute tumor eradication was achieved in 33% of the rabbits. A partial response was observed in 41.6% of rabbits that survived longer than 3 months. On histopathologic evaluation, the ablated lesions retained their fundamental tissue architecture with evidence of coagulation necrosis. Surrounding edema and inflammation were noted in the normal adjacent pulmonary parenchyma. One to 3 months after treatment, the ablated tumor became an atrophied nodule of coagulation necrosis within a fibrotic capsule.
The timing and progression of these postablation changes becomes an important issue when evaluating postprocedure treatment response in patients with pulmonary tumors. Some investigators have performed RFA followed by resection to evaluate the efficacy of the ablation procedure. In one multicenter study of 15 patients, ablation was possible in 13 cases. In these 13 patients, median tumor kill was 70%, with seven patients achieving 100% ablation. Five of the final six cases exhibited 100% ablation. Nguyen and colleagues published the results of an ablate-and-resect study in which vital immunohistochemical stains were used to assess tumor cell viability. In seven tumors studied with this technique, more than 80% nonviability was documented. Three patients (38%) demonstrated 100% nonviability. All three tumors were less than 2 cm in diameter. A single ablation with a 3- or 3.5-cm active electrode was performed, such that the larger tumors may have been inadequately ablated. Schneider and colleagues reported their series of ablate-and-resect pulmonary metastasectomies. Eighteen patients underwent RFA and subsequent thoracotomy and resection for 18 diverse solid tumor metastases. Lesion size ranged 0.7 to 2.5 cm. The resected specimens were evaluated for tumor viability with immunohistochemistry. Complete ablation was achieved in 39%. More than 90% ablation was achieved in 50% of the resected lesions, and the authors considered this to be a successful ablation, asserting that subsequent growth of the residual lesion (had it not been resected) was unlikely. An incomplete ablation (with less than 90% ablation) was documented in the remaining 11%. In another study, by Ambrogi and colleagues, a total of nine patients underwent RFA either by the CT-guided approach or by thoracotomy followed by resection. Complete ablation was noted in six of the nine patients (67%). These studies demonstrate that although RFA can produce effective ablation, 100% tumor cell death is not universally achieved and resection remains the treatment of choice for those able to tolerate surgical intervention.
Several U.S. Food and Drug Administration–approved devices are available for the performance of RFA, including (1) LeVeen (Boston Scientific, Boston, MA), (2) RITA (AngioDynamics, Latham, NY), and (3) Valleylab (Covidien, Boulder, CO). The Boston Scientific and Covidien devices are impedance-based systems in which the endpoint of treatment is determined by a significant rise in tissue impedance, indicating an inability of the target lesion to maintain further conduction and, therefore, ablation. The RITA system is a temperature-based device, which elevates the tumor temperature to predetermined lethal levels for a designated period of time. The Boston Scientific and AngioDynamics ( Figs. 46-2 and 46-3 ) active probes consist of an expandable needle system, whereas the Covidien system consists of either a single needle or three parallel needles ( Fig. 46-4 ) that are placed within the tumor. The Covidien electrode consists of a proximal insulated portion and a distal uninsulated active tip. The electrode is irrigated with a continuous infusion of cold saline and for this reason is sometimes referred to as a “cool-tip” electrode. The dissolved saline ions enhance conduction and therefore theoretically decrease the required time to achieve effective ablation.
Two animal studies compared the relative efficacy of the various probes by assessing the region of ablation in a liver model. A recent Japanese report of RFA for treatment of 342 pulmonary tumors in 128 patients cites tumor size greater than 2 cm and use of the single-needle VL probe to be associated with local progression on multivariate analysis. Further analyses comparing the array probe and the internally cooled electrode for tumors showed that the use of the internally cooled electrode was an independent risk factor for local progression (hazard ratio [HR] 3.39; 95% confidence interval [CI], 1.56-7.38).
Patient Selection
For stage I NSCLC, RFA should be reserved for those patients who are believed to be at increased risk for pulmonary resection and for those who refuse surgery. Occasionally, RFA may be a reasonable therapy for a medically inoperable patient with more advanced cancer (e.g., satellite nodules) localized to the lung. The efficacy of RFA is low for nodules greater than 5 cm in diameter. RFA is also not recommended for central lesions or those abutting the mediastinum. Other patients who may be considered for treatment with RFA include those with advanced-stage disease who have responded to definitive radiation and chemotherapy but have a persistent solitary peripheral focus of cancer, and for those who present with a recurrent isolated cancer after previous lung resection. Leung and colleagues demonstrated that thermally ablative techniques, including RFA, applied to a previously irradiated field have the potential to enhance survival in patients with recurrent NSCLC.
RFA is also a suitable option for some patients with limited peripheral pulmonary metastases. Similar to resection, this treatment should be reserved for those patients with a limited number of metastases, disease localized to the chest, controlled or controllable primary sites, and for those patients who are believed to be at increased operative risk for resection of their pulmonary metastases. In some situations, complete resection of all pulmonary metastases is not possible, and RFA can be used as an adjunct intraoperatively. We have found RFA to be of use when a wedge resection of a peripheral nodule was performed and resection of other deeper nodules would have required a lobectomy or pneumonectomy. To preserve pulmonary parenchyma, some of these tumors were treated with intraoperative RFA via open thoracotomy. We recently reported the outcomes of RFA therapy for high-risk patients with pulmonary metastasis. Although surgical resection still remains the standard of care, we find RFA to be safe and feasible in selected patients or as a parenchymal-sparing approach in combination with surgical resection. Table 46-1 outlines suggested selection criteria for the use of RFA.
TABLE 46-1
Selection Criteria for Radiofrequency Ablation
| Inclusion Criteria | Exclusion Criteria |
|---|---|
| NSCLC stage I or II * ; poor surgical candidate | Tumor abutting hilum or large pulmonary vessel |
| NSCLC stage II (satellite nodule same lobe) or stage III/IV (nodule in another lobe or lung); poor surgical candidate | Malignant effusion |
| Stage IIIa or IV with solitary pulmonary nodule remaining after standard therapies | Pulmonary hypertension |
| Limited pulmonary metastases and recurrent disease; primary disease controlled or controllable; poor surgical candidate | More than three tumors in one lung |
| Target lesion ≤ 5 cm | Target lesion > 5 cm |
NSCLC, Non–small cell lung cancer.
* Patients with stage II should receive additional therapy because N1 disease will not be treated with radiofrequency ablation.
Operative Technique
In our initial experience, RFA was performed via an open thoracotomy in some patients. This approach provides the most controlled method for RFA application but negates the most attractive attribute of the technology, that is, its nonoperative applicability. Surgical resection remains the standard of care for early-stage NSCLC. RFA should be used as an adjunct to surgery or as a suboptimal substitute in patients unable or unwilling to undergo resection. Situations may arise, such as that described previously, in which a patient presents with two or more tumors, some amenable to resection and others to RFA. Although VATS has been postulated to be an attractive approach for the application of RFA, optimal needle deployment within the tumor in the setting of a collapsed lung is often difficult.
The most common method of pulmonary RFA entails percutaneous CT-guided administration. Either general or local anesthesia can be used when performing CT-guided RFA. Our preference is to use general anesthesia. This allows needle deployment, ablation, and biopsies (if required) to be performed in a more controlled manner. Additionally, some patients with cardiopulmonary compromise may have difficulty maintaining optimal body position if awake or sedated. Patient positioning is extremely important during CT-guided RFA. It is advantageous to position the patient in such a way that the target lesion is accessed with minimal penetration of normal lung parenchyma. This decreases the risks of hemorrhage and prolonged air leak. Positioning is also important to ensure adequate clearance of the RFA probe within the scanner. The maximum number of lesions that can be ablated in a single setting is debatable. As a general rule, however, ablation of more than three lesions in one setting is not recommended.
Treatment Response
RFA incites an inflammatory response that can persist for up to 3 months, making it difficult to determine radiographically whether the mass represents scar or viable cancer. The mass may initially appear larger on radiographic imaging and subsequently decrease in size. Ablated lesions may demonstrate central cavitation ( Fig. 46-5 ) or develop bubble lucencies, both of which are radiographic indicators of effective ablation. Other centers have used CT densitometry protocols to evaluate for persistent or recurrent disease. Densitometry involves the injection of contrast and subsequent CT images of the ablated nodule at 45, 180, and 300 seconds after the injection of contrast material. These densitometry techniques are time consuming and typically valuable only for those patients with single tumor nodules. The Response Evaluation Criteria in Solid Tumors has been modified to evaluate treatment responses objectively ( Table 46-2 ). CT scans are obtained at 3-month intervals to assess lesion size and characteristics. Whenever possible, positron emission tomography (PET) scans are also obtained to aid in the determination of tumor response. The American College of Surgeons Oncology Group (ACOSOG) completed a multicenter study evaluating RFA in high-risk patients with stage IA NSCLC. This study (Z4033) addresses such issues as response assessment by standardizing the follow-up protocol. The preliminary results have been presented, and final results are awaited.
TABLE 46-2
Modified RECIST
| Response | CT Mass Size | CT Mass Quality | PET |
|---|---|---|---|
| Complete (Two of the following) |
Lesion disappearance (scar) less than 25% of original size | Cyst/cavity formation Low density of entire lesion |
SUV < 2.5 |
| Partial (One of the following) |
More than 30% decrease in the LD of target lesion | Central necrosis or central cavitation with liquid density | Decreased SUV or area of FDG uptake |
| Stable lesion (One of the following) |
Less than 30% decrease in the LD of target lesion | Mass solid appearance, no central necrosis or cavitation | Unchanged SUV or area of FDG uptake |
| Progression (Two of the following) |
Increase of more than 20% in the LD of target lesion | Solid mass, invasion of adjacent structures | Higher SUV or larger area of FDG uptake |
CT, Computed tomography; FDG, fluorodeoxyglucose; LD, largest diameter of lesion; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors; SUV, standard uptake value of 18 F-FDG on PET scan.
Clinical Results
In our initial experience with RFA at the University of Pittsburgh, we treated 33 tumors in 18 patients. Tumor pathologies included metastatic carcinoma ( n = 8), sarcoma ( n = 5), and NSCLC ( n = 5). The mean age was 60 (range, 27 to 95) years. Our principal finding was the lack of effectiveness in treating tumors greater than 5 cm in size. Using the Response Evaluation Criteria in Solid Tumors, we found a radiographically determined response rate of 66% for tumors less than or equal to 5 cm in size, compared with only 33% in patients with tumors greater than 5 cm. A multicenter study summarizing the results of 493 percutaneous RFA procedures for pulmonary nodules concluded that RFA was safe, with negligible morbidity and mortality (0.4%), and is associated with a gain in quality of life.
We reported our experience with RFA for the treatment of stage I NSCLC. Nineteen patients underwent RFA over a 3-year period. Median age was 78 years (range, 68 to 88). An initial complete response was observed in two patients (10.5%), partial response in 10 (53%), and stable disease in 5 (26%). Early progression occurred in two patients (10.5%). During follow-up, local progression occurred in eight nodules (42%), and the median time to progression was 27 months. There was no procedure-related mortality, although six deaths occurred during follow-up. The median follow-up in the remaining patients was 28 (range, 9-52) months. The probability of survival at 1 year was estimated to be 95% (95% CI, 0.85-1.0), and the median survival was not reached.
We have published a study of 100 patients who underwent image-guided RFA for lung malignancy. The median age was 73.5 years (range, 26 to 95 years), and there were 46 patients with primary lung cancer, 25 patients with recurrent lung cancer, and 29 patients with metastatic disease. The median hospital stay was 2 days (range, 1 to 33 days), and the most common complication was pneumothorax. Local progression occurred in the treated lesions in 35 patients, and median time to local progression was 15 months. The mean follow-up time was 17 months, and the median overall survival for the entire group was 23 months.
Lanuti and colleagues published their mid-term results of a series of 31 nonsurgical patients with NSCLC who underwent a total of 38 percutaneous RFA treatments. There were no 30-day mortalities. Five treatments resulted in pneumothoraces, and three required chest tubes. Six patients developed pneumonia within 4 weeks of treatment; all were resolved with oral antibiotics. There were eight cases of postprocedure pleural effusion. These are typical morbidities. The authors report that one patient developed transient laryngeal nerve injury following ablation of a right upper lobe lesion abutting the mediastinum. We reiterate that RFA should not be applied to central lesions. Tumor size ranged from 0.8 to 4.4 cm. Local recurrence was assessed via CT and PET and found in 31.5% of all treated tumors but in 50% of tumors greater than 3.0 cm, 44.4% in tumors 2.0 to 3.0 cm, and 21.7% in tumors less than 2.0 cm. Survival at median follow-up of 17.3 months was 74%, and overall survival was 30 months. Lanuti and associates recently published the results of a study assessing the management of locoregional recurrence in NSCLC. From 2003 to 2010, 55 ablations were performed in 45 patients with a total of 21 locoregional recurrences following treatment. Mean tumor diameter was 2.3 cm (range, 0.7 to 4.5). Eighty percent of tumors that exceeded 3 cm in diameter were associated with locoregional recurrences. Overall survival was similar for patients who had locoregional recurrences compared with those who did not.
The RAPTURE study was a prospective, intention-to-treat, single-arm, multicenter, international clinical trial designed to validate the feasibility and safety of RFA for pulmonary tumors as well as to assess efficacy. A total of 105 patients with 183 tumors were treated with 137 RFA treatments. All patients were deemed to be nonsurgical candidates. There were no mortalities. Twenty-seven patients developed a pneumothorax requiring chest tube evacuation. Pleural effusions occurred in 15 patients, 4 requiring drainage. Tumor sizes ranged 0.5 to 3.4 cm. Pulmonary function was assessed before the procedure and 1, 3, 6, and 12 months after the procedure and no significant change was found. Of the 85 patients who could be assessed for tumor response, 88% exhibited complete response to treatment at 1 year. Local progression was noted in 12%. Overall survival was 70%, and cancer-specific survival was 92% at 1 year.
Huang and associates performed a study assessing the safety and efficacy of RFA for the treatment of pulmonary malignancy. Over a 7-year period, 329 patients (237 NSCLC and 92 metastasis) were treated with CT-guided RFA. The 30-day mortality rate was 0.6%, including 2 patients (one death from pericardial tamponade and another from hemoptysis), and there were postoperative complications in 113 of 329 (34.3%) patients. Complications included 63 (19.1%) pneumothorax, 15 (4.5%) pneumonia, 14 (4.2%) hemoptysis, 10 (3%) hemothorax, and 3 (0.9%) pericardial tamponade. Lesions greater than 4 cm were associated with a significantly increased risk of local progression. The median progression-free interval was 21.6 months, and 1-, 2-, and 5-year survival rates were 68.2%, 35.3%, and 20.1%, respectively. In conclusion, the authors deemed RFA to be a safe and effective procedure for the treatment of pulmonary malignancy but noted that it requires proper training and patient selection to limit complications.
ACOSOG completed a multicenter study (Z4033) that included 54 patients from 16 centers evaluating RFA in high-risk patients with stage IA NSCLC. The preliminary results of this trial have been presented. The overall survival at 1 and 2 years was 87% and 70%, respectively. One-year local recurrence–free rate was 70%, and the 2-year rate was 61%. Change in the FEV 1 and diffusion of carbon monoxide in the lung (D lco ) at 24 months was not clinically significant. The final results of this trial are awaited.
These results demonstrate feasibility, safety, and intermediate-term results of RFA for pulmonary tumors not amenable to surgical resection. Techniques to more precisely localize the lesion under image guidance for ablative therapy are evolving; one such technique is electromagnetic navigation to aid RFA. These technologies may improve the local progression rates after RFA. Further critical evaluation of ongoing clinical trials will aid in defining the impact of RFA on long-term tumor control and its potential applicability for larger tumors and more advanced disease.
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