Radiofrequency Ablation—A New Treatment Option for Non-small Cell Lung Cancer Patients

Lung cancer is the most common cancer worldwide, with an estimated five-year survival rate of 15% for the majority of histologies (e.g. non-small cell). Surgery is the primary treatment for resectable non-small cell lung cancer (NSCLC). The five-year survival rates after surgical treatment are 63–67% in stage IA, 46–57% in stage IB, 52–55% in stage IIA, 33–39% in stage IIB, and 19–23% in stage 111A.^1–3 However, only one-third of patients are surgical candidates due to their advanced stage at presentation or medical co-morbidities.⁴ In these patients, the treatment options rely on radiotherapy (RT) with or without chemotherapy. In a meta-analysis determining the effectiveness of radical RT for stage I/II medically inoperable NSCLC patients, overall five-year survival ranged 0–42%, with complete response rates of 33–61% and local failure rates ranging 6–70%.⁵ The role of chemotherapy in NSCLC has primarily been for patients with more advanced disease alone or in conjunction with radiotherapy. Recently, two large studies evaluating the addition of chemotherapy to surgery for stage I and II NSCLC showed a 12–15% improvement in survival in the chemotherapy group compared with surgery alone.^6,7 Clearly, even in early-stage disease, systemic failures can be problematic.
The fact that many patients are not candidates for resection or radiation has led to alternative modalities that could accomplish tumor destruction. Percutaneous image-guided thermal ablation with radiofrequency (RF) energy has been used as a minimally invasive approach for a variety of solid tumors, including liver, kidney, bone, and adrenal gland.^8–11 The technique for thermal ablation utilizing RF was first described in animal lung tumor models in 1995 and was reported in human lungs in 2000.^12,13 Since 2000 the worldwide experience of RF ablation (RFA) of lung neoplasms has grown (see Table 1) as a minimally invasive option for non-surgical candidates, not only for local control but also for symptom palliation.

Clinical Applications of RFA for Primary Lung Neoplasms

RFA of lung neoplasms is a technique, the clinical applications of which are just beginning to be developed. It has some advantages over traditional RT and chemotherapy. Its safety profile is similar to percutaneous image-guided lung biopsy. Almost all RF procedures can be performed in an out-patient setting, mostly with conscious sedation. Multiple applications can be performed in a single session or over several sessions.
RFA of lung malignancies is performed with two basic rationales. In the first group it is used with an intention of achieving definitive therapy. These are patients who are not candidates for surgery because of co-morbid medical conditions. This cohort could potentially derive significant benefit from a minimally invasive alternative therapy. In the second group it is used as a palliative measure:
• to achieve tumor reduction before chemotherapy;
• to palliate local symptoms related to aggressive tumor growth, such as chest pain, chest wall pain or dyspnea;
• for hematogenous painful bony metastatic disease; and
• tumor recurrence in patients who are not suitable for repeat radiotherapy or surgery.
The most promising application for RFA is in the treatment of primary NSCLC.With the overall five-year survival rate for all stages of NSCLC being less than 15%, newer treatment modalities are needed. RFA is a local therapy and potentially can be utilized for incidental or screen detected stage I disease, where the tumor size is less than 3cm and there is no evidence of regional or distant tumor spread by staging computed tomography (CT) and/or positron emission tomography (PET) scanning. Currently, the gold standard of therapy for such patients is lobectomy with a five-year survival rate of 65–70%. Current studies report overall five-year survival rates from 53% to 82% when both anatomic (lobectomy) and non-anatomic (limited/wedge resection) are included.^14,15 Wedge resection is associated with an increased risk of local recurrence when compared with lobectomy but appears to be a viable compromise for patients with cardiopulmonary impairment when considering the operative risks.¹⁶ RFA ± RT can be offered as a limited local therapy in patients who are poor surgical candidates, thus providing them with additional local control and possible benefit in survival.¹⁷
Utilization of RFA for lung tumors has been gaining momentum in the past few years, as an increasing amount of much required data is reported confirming the safety and efficacy of this technique. Although RFA has been used in a heterogeneous cohort of lung tumor patients, the initial results are encouraging. In medically inoperable patients with NSCLC, Herrera et al. report rates of 40% for partial response, 60% for stable disease with no evidence of disease progression, and death from an unrelated cause.¹⁸ Cosmo et al. treated 40 lung neoplasms with RFA and had a local relapse rate of 2.5% in a mean follow-up of eight months.¹⁹ Kotaro et al. treated 99 malignant thoracic tumors (three primary and 96 secondary) with complete ablation of 91% of the tumors after the first RFA and 9% local recurrences or residual tumors that were treated with repeat RFAs.²⁰ Jeong et al. treated 32 malignant lung masses (27 NSCLC and five metastasis) with CT-guided RFAs. In their study, lung cancers smaller than 3cm had a higher complete necrosis rate when compared with larger tumors (100% versus 8%).They also found an increased mean survival in patients with complete necrosis versus partial necrosis (19.7 versus 8.7 months).²¹
Pulmonary RFA alone for the treatment of primary lung cancer is not validated at this time, given the prospective surgical data demonstrating a three- and 2.4-fold increase in local–regional recurrence rate with local treatment wedge resection and segmental resection, respectively, compared with lobectomy.²² However, for less than 2cm stage IA NSCLC, several studies comparing limited resection (segmentectomy) and lymph node (LN) assessment versus lobectomy have shown equivalent five-year survival rates (87.1% versus 93%) and local recurrence.^23–25 These recent studies and the data by Jeong et al. lead to the speculation that for tumors less than 2cm in size,RFA might provide an alternative for local disease control. The explanation for recurrence includes inadequate resection of the primary tumor, as well as presence of microscopic lymphatic disease within the ipsilateral hilar nodes. Unfortunately, detection of these deposits is not possible by the current imaging methods and RF technology does not allow the treatment regimen to extend extensively into the normal lung parenchyma, yet for patients who are non-surgical candidates due to co-morbid conditions, poor cardiopulmonary reserve or prior RT with recurrence in the treatment field, RFA provides an alternative treatment modality.
RFA can also be used in conjunction with other treatment modalities. In addition to the previously mentioned combination with external beam radiotherapy (EBRT) there are studies that focus on combining RFA with brachytherapy in patients with either metastatic lung malignancies or prior treatment that precludes additional EBRT.²⁶ The rationale is to enhance the local control by magnifying the cytoreduction and the effect of radiation by destroying the central hypoxic area of the tumor. CT can be utilized for brachytherapy catheter placement and the entire treatment can be accomplished in one day.Tumors that tend to be more encapsulated with a sharper lung/tumor interface (e.g. well differentiated squamous cell carcinoma) may be more suitable for candidates for local therapy alone.
The cytoreductive effect of RFA in lung cancer shows promise for symptom palliation. Patients with inoperable lung cancer and tumor size too large for radical RT have a poor prognosis with limited therapeutic options. The majority of lung cancer patients die from their cancer, and the most common symptoms from which they clinically manifest are cough, dyspnea, hemoptysis, and pain.²⁷ Symptom palliation is therefore an important part of treatment, yet current medical literature reflects failure, with 50% of patients dying without adequate pain relief.²⁸ Jeong et al. demonstrated 80% relief in mild hemoptysis, but less than ideal relief of chest pain, dyspnea, and coughing. Conventional treatment of osseous metastatic disease involves RT and chemotherapy. RT has been shown to palliate respiratory symptoms and improve quality of life in NSCLC patients, but if the symptomatic areas were included in the prior radiation field they can be difficult to treat.²⁹ RFA has been shown to provide substantial decrease in pain from skeletal metastasis and improved quality of life.^30,31

Conclusion

To date, RFA has shown promise for the treatment of lung cancer either alone or in combination with traditional therapies. The advantages of RFA include precise control, relatively low cost, decreased morbidity and mortality compared with surgery, and its use in the out-patient setting. There are many questions as to which patients may benefit most and what imaging tests are best to monitor treatment efficacy. Local control and symptom palliation are clearly areas of important clinical application. However, to achieve a greater utilization and a true paradigm shift toward the use of alternative methods, such as RFA, future controlled multicenter trials are necessary. ■