Minimally Invasive Techniques
Although surgical resection, chemotherapy, and external beam radiation are still viewed as the primary standard of care for early-stage lung cancer, newer minimally invasive percutaneous ablative techniques, such as radiofrequency ablation (RFA), microwave ablation, laser ablation, and cryoablation, are currently being examined as viable treatment alternatives, especially for nonsurgical candidates.
Radiofrequency Ablation
RFA has been the most widely applied thermal ablation method for lung neoplasms. It provides some procedural advantages over traditional therapies and a safety profile similar to percutaneous image-guided lung biopsy with the most common adverse effects being pneumothorax and pain.37 Almost all RFA procedures can be performed in an outpatient setting, mostly with the patient receiving conscious sedation. The lack of significant ionizing radiation and well-defined zones of tissue destruction can allow multiple applications over time. Disadvantages over surgery include relying on minimally invasive staging techniques, such as PET and CT, which are less accurate compared with pathological staging, and knowing when a negative margin has been achieved since the tumor is left in situ (Figure 4).
In early-stage lung malignancies, RFA is usually performed to achieve definitive therapy for patients who are not candidates for surgery, either because of comorbid contraindications to surgery, such as poor cardiopulmonary reserve, or because the patients refuse to undergo a surgical operation. Clinical criteria for RFA candidacy are summarized in Table 3. In more advanced disease, RFA is used more as a palliative measure to achieve tumor reduction before chemotherapy or radiation; to palliate local symptoms related to aggressive tumor growth, such as chest pain, chest wall pain, or dyspnea; to treat hematogenous painful bony metastatic disease; or to treat tumor recurrence in patients who are not suitable for subsequent radiation therapy or surgery.
Since RFA is a local therapy, the clearest indication for its use is in incidental or screen-detected stage I disease where the tumor is smaller than 3 cm and there is no evidence of regional or distant spread by staging CT and/or PET scanning. The gold standard therapy for patients with a known 70% 5-year survival is lobectomy.36 However many patients with stage I tumors are poor surgical candidates because of severe underlying cardiopulmonary disease. In patients with localized disease that can be safely treated with RFA, preliminary results suggest that tumor control can be achieved.38
Conventional External Beam Radiation
In a meta-analysis determining the effectiveness of radical radiotherapy for treating stage I/II medically inoperable NSCLC, the overall 5-year patient survival rate ranged from 0% to 42%, with complete response rates of 33% to 61% and local failure rates ranging from 6% to 70%.39 Current external beam radiotherapy survival data in patients with stage IA NSCLC are reported to be as high as 51% at 2 years.40 Traditional external beam radiotherapy fails to provide adequate local control because of patient-related and tumor-related factors. Many patients with underlying pulmonary comorbidities and poor performance status cannot tolerate the treatment effects to the uninvolved lung.
Stereotactic radiation therapy technologies (eg, Cyberknife, tomotherapy, etc.) have been developed in the hope of providing greater and more accurately delivered target doses with lower toxicity to the surrounding normal tissues. McGarry and colleagues41 reported results from a phase 1 trial of stereotactic body radiation therapy in patients with medically inoperable stage I NSCLC.
In this study, the local failure rate was 21%, which was clearly related to the total dose given, since local failures were less common with total doses above 16 Gy. Pulmonary toxicity was found to be much greater in central lesions with stereotactic body radiation therapy. In a combined multi-institutional Japanese study,42 the outcomes of 245 patients were analyzed. There was variation in the dose schedule used at different institutions, but among patients who received a biological effective dose of 100 Gy or more, the local recurrence rate was only 8%. Shorter treatment times with the stereotactic technique may reduce the chance of tumor repopulation between treatments. Furthermore, since NSCLC tends to be radioresistant, the higher biologically effective doses that are given with stereotactic radiotherapy should improve local control. The pulmonary toxicity is reported to be lower with stereotactic radiotherapy compared with conventional external beam radiation treatment. In a recent report by Timmerman and colleagues43 of the first 70 patients undergoing stereotactic body radiation therapy, the median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in a total of 14 patients for whom the median time of observation was 10.5 months. Patients treated for peripheral tumors had a 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors. They concluded that central tumors should not be treated with this stereotactic regimen because of these significant delayed toxic effects.
One of the common reasons for conventional external beam radiotherapy failure is poor local control. From a theoretical standpoint, upfront cytoreduction with an ablative technique may improve the chances of localcontrol. Hypoxic cells are more resistant to radiation therapy. The usually more central hypoxic regions of a tumor can be destroyed with an ablative technique such as RFA. Residual tumors, if present, would tend to be at the periphery, which would then be in a more suitable environment for radiation to work effectively because of increased blood flow and oxygenation. The addition of adjuvant chemotherapy to control residual microscopic disease after surgery or ablation may also improve local control.44
Local resection via wedge or sublobar resection may provide better local control than radiation, but this should be reserved for smaller tumors (<2.0 cm). The 5-year cancer-specific survival rates of patients with pathologic stage I disease with tumors 20 mm or smaller and 21 to 30 mm in diameter were 92.4% and 87.4% after lobectomy, 96.7% and 84.6% after segmentectomy, and 85.7% and 39.4% after wedge resection, respectively, in a recent study.45 In treating patients with early-stage disease, very local therapy, such as wedge resection or RFA, may not remove all cancerous cells. Combining radiation with local therapy may provide the necessary local control in these patients with tumors larger than 2 cm. In fact, several studies have shown improved local control rates when combining RFA or wedge resection with radiation (external or brachytherapy).8,45,46 Notable advantages and disadvantages of the minimally invasive treatment options are shown in Table 4.
Conclusion
Our ability to treat early-stage lung cancers with less invasive modalities requires an improved understanding of many facets of lung cancer, including tumor biology, minimally invasive staging, synergistic effects of combination therapy, and appropriate treatment follow-up. Technological advances in imaging, proteomics, tumor ablation, stereotactic radiation techniques, and treatment monitoring will play a significant role in this evolution. Applying these techniques to poor surgical candidates is expected to both help this group of patients and improve our understanding of the possible treatment effects, appropriate imaging follow-up, and possible synergy between these treatments and chemotherapy.
Dr. Dupuy: A significant number of patients who are not operative candidates have resectable disease. These patients get triaged primarily to radiation oncology. The big decision for the radiation oncologist is whether you go with radiation, ablation, or both.
Dr. Lynch: We need to determine the pros and cons of those three possibilities.
Dr. Dupuy: We assess the likelihood of metastatic disease based on size. If a lesion is smaller than 2 cm, we're more likely to do ablation alone because the likelihood of metastatic disease is much smaller. If it's larger than 2 cm, we're likely to augment ablation with either external beam or interstitial brachytherapy.
Dr. Lynch: What about conventional external beam radiation alone?
Dr. Dupuy: Conventional external beam radiation is probably not the way to go any more now that other techniques are available that are definitely better. Dr. Lanuti: I think that conventional external beam is being replaced by stereotactic radiation therapy. There are so few patients who are candidates for standard external beam therapy. Patients with early-stage lung cancer should be considered for stereotactic techniques or RFA if they are not surgical candidates.
Dr. Lynch: But there is a role for conventional radiation in combination with another approach.
Dr. Harpole: Yes. If you don't have a stereotactic machine in your community and you have a tumor less than 5 cm that was node negative on PET, doing combination therapy with radiation plus chemotherapy will serve the patient much better than radiation alone because you're not going to sterilize a tumor by radiation alone.
Dr. Lynch: What about stereotactic radiosurgery?
Dr. Dupuy: The jury is still out on whether stereotactic radiation is going to completely replace external beam radiation, although it probably will. The problem is the data aren't totally clear. The Japanese data indicate that stereotactic radiotherapy is better than surgery, but Bob Timberman's work and the RTOG are a bit more conservative, because there is a considerable grade 3 and grade 4 toxicity with the stereotactic technique.