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* From the Departments of Diagnostic Imaging (Drs. Dupuy, Ganghi, and Mayo-Smith), Radiation Oncology (Dr. DiPetrillo), Medicine (Drs. Ready and Donat), and Thoracic Surgery (Dr. Ng), Rhode Island Hospital and Brown Medical School, Providence, RI.
Correspondence to: Damian E. Dupuy, MD, Department of Diagnostic Imaging, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903; e-mail:ddupuy{at}lifespan.org
Abstract
Purpose: The standard treatment of stage I non-small cell lung cancer (NSCLC) is surgical resection. Some patients are poor surgical candidates due to severe comorbid medical conditions. Radiotherapy alone has historically been used in this patient population with limited success. Radiofrequency ablation (RFA) is an image-guided, thermally mediated ablative technique recently applied to lung tumors. Combination therapy with both these treatments has not been previously performed. We report our experience with combined CT-guided RFA and conventional radiotherapy in 24 medically inoperable patients with a minimum of 2-year study follow-up in surviving patients.
Patients and methods: Twenty-four consecutive, medically inoperable patients with biopsy-proven, stage I NSCLC were treated with CT-guided RFA followed by radiotherapy to a dose of 66 Gy. RFA was performed with a single or cluster cool-tip F electrode; 21 patients were staged before therapy using fluorodeoxyglucose-positron emission tomography.
Results: There were 14 women and 10 men (median age, 76 years; range, 58 to 85 years). The histologic subtypes were squamous cell (n = 13), adenocarcinoma (n = 5), and undifferentiated (n = 6). All patients received RFA followed by three-dimensional conformal radiotherapy. There were no treatment-related deaths or grade 3/4 toxicities. Pneumothorax requiring chest tubes developed in three patients (12.5%). At a mean follow-up period of 26.7 months (range, 6 to 65 months), 14 patients (58.3%) died, with cumulative survival rates of 50% and 39% at the end of 2 years and 5 years, respectively. Ten of the deaths were cancer related. Two patients had local recurrence (8.3%), while nine patients had systemic metastatic disease. Three patients died of respiratory failure with no evidence of active disease, and one patient died of a cerebrovascular accident at 18-month follow-up. Pleural effusions developed after treatment in six patients (25%), which proved to be malignant in one patient.
Conclusion: RFA followed by conventional radiotherapy is feasible in this population of medically inoperable stage I NSCLC patients. Procedural complication rates are low, and no additional major toxicities were seen despite the addition of RFA. Local control and survival rates appear to be better than with radiotherapy alone.
Key Words: non-small cell lung cancer • radiofrequency ablation • radiotherapy • treatment
Lung cancer statistics in the United States estimate that lung cancer will be diagnosed in 172,570 people in 2005.1 As the leading cause of cancer death among men and women in the United States, the associated death rate for lung cancer is 28%, surpassing mortality rates of colon, prostate, and breast cancer combined.1 This startling fact underscores the importance of improved methods to treat this aggressive form of cancer. Its ominous prognosis is reflected by the overall 5-year survival rates for previously untreated patients with primary non-small cell lung cancer (NSCLC) after surgical treatment (according to pathologic stage): 63 to 67% in stage IA, 46 to 57% in stage IB, 52 to 55% in stage IIA, 33 to 39% in stage IIB, and 19 to 23% in stage IIIA.23 With NSCLC, 30% of patients present with disease confined to the parenchyma, 30% with spread to intrathoracic lymph nodes, and 40% with metastatic disease.4
In cases of regional disease, a combination of surgery, chemotherapy, and/or external beam radiation therapy (XRT) prevails as standard treatment. For patients with localized disease not involving the mediastinum, surgical resection remains the best treatment option. Coexistent morbid medical conditions are the main reason why this group of patients is not suitable for surgery. In patients who are not surgical candidates, treatment options rely primarily on XRT with or without chemotherapy. In small cell lung cancer and in other cases in which radiotherapy cannot be or is not administered, chemotherapy may be administered alone. However, utilization of the best current therapies results in an overall 5-year relative survival rate for all stages combined to be only 15%.1 The poor response of lung cancer to current treatment methods necessitates research into alternative modalities.
Less invasive therapies that can accomplish tumor destruction or complete eradication without the use of general anesthesia may complement, improve, or replace existing therapies. One such ablative tumor therapy that may add to the treatment regimen in this complex group of patients is radiofrequency ablation (RFA). Percutaneous image-guided tumor RFA is an expanding minimally invasive modality for the local treatment of solid malignancies.5678 First reported in 2000,5 RFA of human lung tumors may be a promising treatment option for nonsurgical candidates given the suboptimal outcomes with current treatment options. The insertion of an radiofrequency electrode into the defined tumor bed and establishment of an electric field to a reference electrode that oscillates with generated alternative radiofrequency currents ultimately creates a conduit for frictional heating.67 This tissue heating consequently induces coagulation necrosis and cell death in a controlled and predictable manner. We have applied this to a group of medically inoperable NSCLC patients followed by conventional XRT, as there is a potential synergistic effect of these two therapies. To our knowledge, this novel combination approach has not been previously reported in the literature.
Materials and Methods
This study was approved by the hospital internal review board. Twenty-four consecutive adult patients with biopsy-proven NSCLC were enrolled. All patients either refused surgical resection or were deemed medically inoperable due to comorbid medical conditions (eg, FEV1 of 50% of predicted, congestive heart failure). Patients were deemed poor surgical candidates by an interdisciplinary group consisting of a pulmonologist, thoracic surgeon, medical oncologist, and radiation oncologist. This institutional pulmonary tumor board considers advanced age (> 80 years) and dementia as relative contraindications to lobectomy. Staging was performed with CT scan and bone scan in all patients and positron emission tomography (PET) scanning in 21 patients. PET scanning was performed when available to improve staging, since inclusion criteria for treatment was T1-T3,N0,M0 tumor stage. PET scanning was considered necessary for routine pretreatment staging, as the presence of positive nodes and metastatic disease would have altered patient therapy. Radiation was performed with 33 fractions of 2 Gy per fraction for a total of 66 Gy. All radiation treatments were three-dimensionally planned to encompass the tumor plus a 2-cm margin. No ipsilateral nodes were treated. Patients were followed at 3-month intervals with contrast-enhanced CT scans and PET (17 patients) at 6-month intervals after completion of XRT. Follow-up pulmonary function tests and clinical examination were performed at 6 months, and follow-up clinical examinations were done at 6-month intervals.
RFA Technique
RFA was performed under conscious sedation with IV midazolam and fentanyl. Patients were monitored with continuous pulse oximetry, with ECG with BP performed every 5 min. CT was used to localize the tumor. Standard surgical prepping and draping was performed. Local anesthesia included 1.5% lidocaine both intradermally and deeper into the tissues adjacent to the pleural surface. When possible, the radiofrequency electrode was positioned with the electrode shaft parallel to the longitudinal axis of the tumor. The tip of the radiofrequency electrode was positioned against the deepest margin of the tumor for the first treatment. This treatment strategy allows the optimal heat distribution for any given tumor. Axial and craniocaudal placement of the radiofrequency electrode was confirmed with CT fluoroscopy (5-mm collimation, 10 mA). The electrode was coupled to a radiofrequency generator and perfusion pump (Radionics CC-1; Valley Lab; Boulder, CO). If after the first treatment the maximum intratumor temperature did not exceed 60°C, than an additional treatment was performed at the same position. This was repeated for a maximum time of 12 min at any given electrode position. The electric current was grounded by applying four grounding pads (in the horizontal configuration; 1,800 cm2/each) to the opposite chest wall.
Results
Patient data are summarized in Table 1 . There were 10 men and 14 women (mean age, 76 years; range, 58 to 85 years). All 24 patients underwent CT-guided RFA as an outpatient with no bleeding complications. One patient had intraprocedural hemoptysis that was self-limited and did not require additional imaging or intervention. All tumors were successfully treated with RFA, achieving post-RFA temperatures > 60°C (mean/range, 76.4°C/62 to 85°C). The mean baseline impedance was 72 ohms (range, 42 to 110 ohms). The mean current was 1.6 amps (range, 1.2 to 2.0 amps), and the mean treatment time was 6.8 min (range, 2 to 12 min). There were a total of seven pneumothoraces (29%). Three patients required chest tube drainage for clinically significant pneumothorax either during the procedure or immediately following the procedure after a 2-h chest radiograph follow-up. All but one pneumothorax was managed with a Heimlich valve on an 8F pigtail catheter in an outpatient. One patient had an air leak requiring a 20F surgical chest tube, wall suction, and 7 days of hospitalization. No acute respiratory compromise occurred as a result of RFA. All 24 patients completed a full course of XRT. There were no cases of acute pulmonary toxicity secondary to the radiotherapy. Radiographic evidence of radiation fibrosis developed at 6 months in two patients, but they remained asymptomatic. Pretherapy and posttherapy pulmonary function testing revealed no significant worsening of pulmonary function.
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Surgical resection remains the cornerstone of treatment for early stage NSCLC at present. Lobar resection with systematic hilar and mediastinal lymph node sampling is the standard surgical treatment for stage I NSCLC.9 However, not all patients with early stage NSCLC are eligible for surgical therapy due to comorbid medical conditions. XRT is typically used for patients believed to be at too high risk for any pulmonary resection.10 A previous study9 of 71 node-negative patients who received at least 60 Gy showed 3-year and 5-year survival rates to be 19% and 12%. In a meta-analysis11 determining the effectiveness of radical radiotherapy for stage I/II medically inoperable NSCLC patients, overall 5-year survival ranged from 0 to 42%, with complete response rates of 33 to 61% and local failure rates ranging from 6 to 70%. McGarry et al12 showed a median survival time of 19.9 months and 14.2 months with radiotherapy alone and no treatment, respectively, in early stage NSCLC. The difference between groups was not statistically significant (p = 0.447). These studies illustrate the overall poor prognosis in this group of patients who are too frail or sick for surgical resection.
One of the reasons for radiotherapy failure is poor local control. The inability to accomplish this is multifactorial. From a theoretical standpoint, it stands to reason that upfront cytoreduction with an ablative technique may improve the chances of local control. Hypoxic cells are more resistant to radiation therapy. The central hypoxic regions of the tumor can be destroyed with an ablative technique such as RFA. Residual tumor, if present, would tend to be at the periphery, which would then be in a more suitable environment (eg, increased blood flow and increased oxygen) for radiation to work effectively. The addition of adjuvant therapy to residual microscopic disease after surgery may also improve local control.13 Local resection via wedge or sublobar resection may provide better local control than radiation or no treatment, but only if the tumors are small (< 2.0 cm). The 5-year cancer-specific survival rates of patients with pathologic stage I disease with tumors 21 to 30 mm and > 30 mm in diameter were 87.4% and 81.3% after lobectomy, 84.6% and 62.9% after segmentectomy, and 39.4% and 0% after wedge resection, respectively, in a recent study.14 Clearly, very local therapy, either wedge resection or RFA, may not remove all cancerous cells. Combining radiation to local therapy may provide the necessary local control in this group of patients with early stage disease. In fact, several studies151617 have shown improved local control rates when combining brachytherapy and limited resection. Tumor size still appears to be a significant factor in the treatment response to this combined modality, as seen by the difference in the cumulative survival rates between stage IA and stage 1B patients.
As a first step, we have applied this to a group of early stage lung cancer patients who were not surgical candidates. Thus far, the local control data, albeit small, and safety information are highly encouraging. We could achieve good local control with this combined modality. Only 2 of the 24 patients (8.3%) had some suspicious imaging evidence of local tumor progression that possibly could be related to pneumonia or radiation changes. Radiation therapy alone can lead to pulmonary toxicity. The most common side effect of radiation alone is pneumonitis, which has been reported to occur in 5 to 15% of patients.18 Radiation pneumonitis, when it occurs, is a significant and potentially life-threatening complication of radiation. None of our patients had radiation pneumonitis. Posttreatment pleural effusions developed in 25% of patients, which were benign and self-limited in five of six patients. These effusions were likely reactive in nature and related to the therapy. The cumulative survival at the end of 3 years and 5 years with this combined modality appears encouraging, but it is based on a small number of patients. Therefore, it is necessary to evaluate this new treatment regimen in a larger multicenter trial to achieve statistical power.
The application of radiofrequency energy to pulmonary neoplasms is a revolutionary concept.78 Unlike conventional therapies such as chemotherapy and XRT, multiple applications can be performed for local control with only modest increases in morbidity largely related to the pneumothorax risk. For this group of patients with peripheral lung cancers, the safety profile is not that dissimilar than that of a lung biopsy, and only one patient required hospitalization for a persistent air leak after chest tube placement for pneumothorax. Despite many of our patients in this study with severe emphysema, the chest tube rate of 12.5% was quite acceptable when one considers that wedge resection requires several days of hospitalization while receiving chest tube drainage. The contraindications for RFA are few and include uncontrollable bleeding disorders and recent use of anticoagulants. Potential complications include pneumothorax, hemorrhage, pleural effusion, pleurisy, hemoptysis, damage to adjacent anatomic structures (although low given the predictable nature of the procedure), skin burns secondary to grounding pads (extremely rare when placed properly), or infection. Only one patient in our study had an episode of transient hemoptysis, and there were no major complications in any of the patients. One patient had a delayed empyema that was not temporally related to the RFA and may have been more likely related to an unrecognized pneumonia in the treated region. The exact treatment role of RFA in pulmonary neoplasms and its complementary applications with standard therapies remain to be precisely defined, but incorporating this new treatment into the care of medically inoperable lung cancer patients is promising. The timing (eg, radiation before vs after ablation) and type of radiation (eg, external three-dimensional conformal vs brachytherapy or stereotactic) as well as the addition of systemic radiosensitizers (eg, chemotherapy or molecular-targeted therapies) are other areas of fertile research that we are planning in the future.
A problem that is challenging after RFA is the assessment of tumor response. Unlike surgery, in which the cancer is removed, a residual mass associated with some degree of scarring is usual after RFA. PET scan results may continue to be positive, making it difficult to assess whether viable tumor or scarring is present. It is also not possible to have mediastinal lymph node evaluation for accurate pathologic staging in this group of patients due to their poor medical condition.
Our early safety and local control data of RFA when used in conjunction with conventional XRT is extremely encouraging, and continued clinical research will be necessary to precisely define which patient population will benefit most from this novel therapy. The question remains as to whether improved local control means improved survival in this group of patients. Testing this hypothesis with a large randomized study is necessary to answer this question.
Conclusion
The minimally invasive technique of RFA may have a promising impact in the treatment of nonsurgical patients, provided that control of local disease will improve quality of life, survival, and overall prognosis. It appears to be safe when used in conjunction with conventional radiotherapy. Local control and survival rates are favorable when compared to radiotherapy alone. Long-term studies with adequate follow-up elucidating the mechanism and effect of this procedure remain to be reported. We are currently embarking on a national multicenter trial in the hopes of improving survival in this group of patients.
Footnotes
Abbreviations: NSCLC = non-small cell lung cancer; PET = positron emission tomography; RFA = radiofrequency ablation; XRT = external beam radiation therapy
Received for publication June 17, 2005. Accepted for publication August 13, 2005.
References
This article has been cited by other articles:
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  R. Timmerman, R. McGarry, C. Yiannoutsos, L. Papiez, K. Tudor, J. DeLuca, M. Ewing, R. Abdulrahman, C. DesRosiers, M. Williams, et al. Excessive Toxicity When Treating Central Tumors in a Phase II Study of Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Lung Cancer J. Clin. Oncol., October 20, 2006; 24(30): 4833 - 4839. [Abstract] [Full Text] [PDF]
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 J. A. WADDLE Radiofrequency ablation of liver and lung tumors. Radiol. Technol., September 1, 2006; 78(1): 45 - 55. [Abstract] [Full Text] [PDF]
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