Combined radiofrequency ablation and high–dose rate brachytherapy for early-stage non–small-cell lung cancer

Brachytherapy 10 (2011) 253e259

Combined radiofrequency ablation and highedose rate brachytherapy for early-stage nonesmall-cell lung cancer Michael D. Chan1,*, Damian E. Dupuy2, William W. Mayo-Smith2, Thomas Ng3, Thomas A. DiPetrillo1 1

Department of Radiation Oncology, The Warren Alpert Medical School, Brown University, Providence, RI Department of Diagnostic Imaging, The Warren Alpert Medical School, Brown University, Providence, RI 3 Department of Surgery, The Warren Alpert Medical School, Brown University, Providence, RI

2

ABSTRACT

PURPOSE: This retrospective analysis reports the results of patients with early-stage inoperable nonesmall-cell lung cancer treated with radiofrequency ablation (RFA) followed by adjuvant highedose rate (HDR) brachytherapy. METHODS AND MATERIALS: Seventeen medically inoperable patients with biopsy-proven Stage I nonesmall-cell lung cancer were treated with RFA followed by single fraction HDR brachytherapy. Brachytherapy catheters were inserted immediately after RFA, and one fraction of HDR brachytherapy was delivered on the same day. Doses of brachytherapy ranged from 14.4 to 20 Gy (median, 18 Gy). Patients were followed clinically and radiographically to determine tumor control and toxicity profile. RESULTS: Median followup time was 22 months. Of the 17 patients, 3 patients have recurred locally. Each of the patients with local recurrences was originally treated for T2 disease. In total, three of seven cases with T2N0 disease experienced local recurrences, whereas all 9 patients with T1 disease were controlled locally. Five of the 17 patients required a chest tube posttreatment, and 1 patient developed an empyema. There were no deaths within 1 month of treatment. CONCLUSIONS: RFA followed by HDR brachytherapy yields excellent local control with an acceptable toxicity profile for patients with otherwise inoperable early-stage lung cancer. Ó 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords:

Lung cancer; Radiofrequency ablation; HDR brachytherapy

Introduction The role of radiofrequency ablation (RFA) in the definitive management of inoperable nonesmall-cell lung cancer (NSCLC) is currently being defined. Several series have shown durable local control with the use of RFA as a single modality for early-stage NSCLC. However, encouraging these early series may be, the local control rate with RFA alone for NSCLC may be as low as 60%,

Received 30 March 2010; received in revised form 12 July 2010; accepted 19 July 2010. Financial disclosures: Dr. Dupuy receives grant support from the following sources: Angiodynamics, Veran Medical, Biotex, BSD Medical, and Medwaves. Dr. Dupuy also serves as a speaker and consultant for Convidien and as a consultant for Ethicon Endosurgery. * Corresponding author. Department of Radiation Oncology, The Warren Alpert Medical School, Brown University, 593 Eddy Street, Providence, RI 02903. Tel.: þ1-401-444-8311; fax: þ1-401-444-5335. E-mail address: [email protected] (M.D. Chan).

which is still inferior to what has been reported in surgical series (1e3). In 2006, Dupuy et al. (4) reported a series of 24 patients treated with a combination of RFA and adjuvant external beam radiation therapy to a dose of 66 Gy. Local control in that series was 91% at a mean followup of 2 years, representing a better local control rate than previously seen in published series of RFA in the definitive management of NSCLC (4). Local control in this series in fact was comparable to the reported results in some surgical series (5). With the improved local control of adding external beam radiotherapy to RFA comes the potential for increased toxicity of treating normal lung tissue with ionizing radiation. Previous series have demonstrated higher rates of toxicity in patients receiving adjuvant radiotherapy after surgical resection of lung cancer (6). Although the toxicities in the previous series using the combination of radiotherapy and RFA do not show excessive toxicity, a common cause of noncancer death in these cases is a pulmonary

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decline (4). The patient population treated with RFA for early-stage NSCLC is generally selected because of a particularly compromised pulmonary reserve that renders them nonsurgical candidates. Highedose rate (HDR) brachytherapy immediately after RFA represents a novel approach to optimize local control while also optimizing normal-tissue sparing. This approach exploits the ability of HDR brachytherapy to deliver a onetime hypofractionated dose of radiotherapy with a fraction size similar to what is delivered with stereotactic body radiotherapy (7). At the same time, brachytherapy, governed by the inverse square decay of an iridium source, significantly decreases the integral dose to the normal lung parenchyma as compared with external beam irradiation (8, 9). The purpose of this report is to evaluate the feasibility and safety of combined RFA and HDR brachytherapy in medically inoperable patients with Stage I NSCLC and to report the local control in the interim term.

Methods and materials This is a retrospective review of 17 patients with medically inoperable NSCLC who underwent an institutional review board-approved prospective trial using combined RFA and brachytherapy from March 2003 to October 2005. Informed consent was obtained from all patients before the procedure. Informed consent for participating in this retrospective study was waived by the institutional review board. Patient confidentiality protocols were followed to assure compliance with Health Insurance Portability and Accountability Act regulations. Patients were referred for these procedures, as they were not the surgical candidates because of comorbid conditions (n 5 16) or because of their refusal of surgery (n 5 1). Before the procedure, all patients were evaluated clinically by an interventional radiologist and a radiation oncologist. Positron emission tomography (PET) and CT were obtained for staging purposes in 15 of 17 patients. The remaining 2 patients were staged with CT of the chest and abdomen. The feasibility and appropriateness of RFA was assessed, and risks and benefits of the procedure were discussed with the patients. Patient characteristics Patient and tumor characteristics are summarized in Table 1. Seventeen tumors with a mean size of 3.0 cm (range, 1.8e4.1 cm) were treated in seven males and 10 females. Tumor histologies were found to be four adenocarcinomas, five squamous cell carcinomas, one bronchoalveolar carcinomas, and seven NSCLCs (not subclassified). RFA technique The procedures were carried out after an overnight fast using conscious sedation with i.v. midazolam hydrochloride (1e4 mg) and fentanyl (25e200 mg). Further, local

Table 1 Clinical characteristics Characteristics

Number

Sex Men Women

7 10

Mean age  SD at RFA (y)

74  8.8

Clinical stage T1 T2

10 7

Histology Squamous Adenocarcinoma Bronchoalveolar Uncharacterized NSCLC Size Mean (cm) Range Reasons for inoperability Chronic obstructive pulmonary disease Multiple medical comorbidities Previous lung resection Age O80 y

5 4 1 7 3.0 1.8e4.1 6 5 3 3

SD 5 standard deviation; RFA 5 radiofrequency ablation; NSCLC 5 nonesmall-cell lung cancer.

anesthesia was achieved with subcutaneous and extrapleural buffered 1.5% lidocaine. All patients were monitored by dedicated nursing personnel using departmental protocol. RFA was performed under CT fluoroscopic guidance by placement of an internally cooled RFA electrode system (Cool-tip; Covidien, Boulder, CO). The RFA generator (Cosman coagulator-1; Covidien, Boulder, CO) produces a maximum output of 200 W and cooling of the electrode is performed with a peristaltic pump that recirculates ice-cold fluid (80 mL/min) and keeps the electrode’s tip temperature below 20 C. When cluster RFA electrodes were used (16 patients), four 180-cm2 grounding pads were used. When a single electrode was used (1 patient), two grounding pads were used. During the procedure, the tip of the radiofrequency electrode was placed at the deepest margin of the tumor. Axial and craniocaudal placement of the radiofrequency electrode was confirmed with CT fluoroscopy. If after the first application, the maximum intratumoral temperature did not exceed 60 C, an additional application was performed at the same position. This was repeated for a maximum time of 12 min at any given electrode position. All treatments were performed by one of the two radiologists, each of whom had a minimum of 5 years experience performing RFA. Treatment parameters were as follows: the average impedance was 71 U (range, 42e117 U), power deposition was 167 W (range, 120e196 W), and current was 1.7 A (range, 1.3e2.0 A). The average treatment time was 6.8 min (range, 1e12 min). The average posttreatment maximum

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temperature was 77.1 C (range, 62e87 C) and average number of applications per session was 1.9 (range, 1e5). Brachytherapy technique Brachytherapy began after the completion of the RFA. The RFA electrode was removed and a 5-French vascular sheath was placed in the center of the lesion with an 18-gauge vascular access needle (Cook Inc., Bloomington, IN) under CT guidance (Fig. 1). The access needle was then removed and a 6-French Nucletron brachytherapy catheter (Cook Inc., Bloomington, IN) was placed into the tumor (Fig. 1). Helical CT imaging was then performed for 3-dimensional planning. Post-RFA CT images revealed satisfactory placement of brachytherapy catheters and dummy seeds in all the patients. Treatment planning was performed on the Plato treatment planning system (Cook Inc., Bloomington, IN). The target volume was determined from 3-mm helical slices with a pitch of 1. Dose was prescribed to include the gross tumor volume as defined on CT with a 5-mm clinical target volume (CTV) margin with the intent of delivering 18 Gy to the margin of CTV. Dose points were placed at 5 mm intervals on the surface of the CTV (Fig. 2). The dose optimization was performed on distance with less than 0.3 dwell time gradient. The dose was delivered in a single fraction with highe dose rate iridium-192 source after which the catheter was promptly removed. Doses of brachytherapy ranged from 14.4 to 20 Gy (median, 18 Gy). Brachytherapy was delivered within 1.5 h of completion of RFA.

Fig. 2. Isodose distribution for highedose rate lung brachytherapy. P4 and P5 represent dose calculation points 5 and 10 mm from the gross tumor volume (GTV). Prescription dose is 18 Gy and is prescribed to a depth of 5 mm beyond the GTV. Lower isodose lines are also depicted to demonstrate tissue-sparing effect of lung brachytherapy.

because thermal lesions are denser than surrounding soft tissue because of coagulated protein. Complete response to treatment was defined as complete lack of tumor enhancement, whereas residual disease was defined as a focus of enhancing soft tissue O9 mm in size. Enhancement was considered significant if it was greater than 15 HU. Followup information was obtained by review of followup imaging procedures and clinical charts. Fludeoxyglucose PET or PET/CT followup was also obtained in 6 patients after treatment (range, 3e12 months after therapy). A typical tumor response on fludeoxyglucose PET and CT are depicted in Fig. 3. An example of a tumor recurrence is depicted in Fig. 4.

Followup A chest radiograph was obtained immediately after the RFA procedure and 2 h after the brachytherapy catheter removal to assess for pneumothorax. Patients were discharged home the same day if there were no complications. Noncontrast/contrast enhanced CT was performed at 1 month and then subsequently every 3 months after the treatment or sooner if clinically indicated. An initial noncontrast study was necessary to quantify contrast enhancement

Salvage Three patients received a second application of RFA alone after disease failure in the lung after RFA and HDR brachytherapy. Two patients received salvage RFA alone after recurring locally at 9 and 24 months after original treatment with RFA and HDR brachytherapy for a T2N0 NSCLC. A third patient developed what appeared to be a second primary tumor 2.5 years after being treated for

Fig. 1. (A) Vascular access needle placed under CT guidance. (B) Brachytherapy catheters in place.

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Fig. 3. A 65-year-old patient with Stage I squamous cell carcinoma of the right upper lobe. (A) Axial CT image shows a 2.8-cm right upper lobe lung mass. (B) Axial CT obtained at a 2-month interval posttherapy shows cavitation and surrounding consolidation at the site of radiofrequency ablation (RFA) and brachytherapy. (C) Coronal positron emission tomography image obtained after fludeoxyglucose administration at a 35-month followup shows minimal linear activity at the site of prior RFA consistent with scarring.

a T1N0 NSCLC. The second primary tumor was in a different lobe of the lung from the original tumor and was treated with RFA alone.

Results

patients developed distant metastases at first failure at a median time of 16 months after RFA with brachytherapy. Sites of distant failure included lung, brain, bone, and liver. Two-year local control was 83% (Fig. 5). There were three local recurrences. All local recurrences occurred in patients with T2 disease. There were no recurrences among the 9 patients with T1N0 disease.

Survival With a median followup of 22 months, the 17 patients treated with RFA and adjuvant HDR brachytherapy had a 2-year actuarial survival of 53% (Fig. 5). The median survival of this cohort was 21 months. Eleven patients had died by the time of the analysis. Three patients were alive with disease at the time of the analysis, and 3 patients were alive without evidence of disease recurrence. One patient had died of pneumonia within 30 days of his treatment. One patient died of a pathologically proven second primary cancer.

Salvage

Failure pattern

Toxicity

Two-year disease-specific survival was 76%. The predominant mode of first failure was distant. Six of 17

Toxicities are summarized in Table 2. Eleven of 17 patients developed a pneumothorax status after RFA with

Of the 3 patients who received a second application of RFA at time of failure, 2 patients remained clinically stable and without evidence of tumor recurrence at 2 and 16 months. The remaining patient developed three additional nodules within the lungs within 2 months. This patient was alive with stable metastatic lung cancer and receiving Tarceva (Genentech, San Francisco, CA) at last followup, approximately 9 months after salvage RFA.

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Fig. 4. A 64-year-old patient with Stage IB squamous cell carcinoma of the right upper lobe. (A) Axial CT image shows brachytherapy catheter and dummy seeds in 3.0-cm right upper lobe lung mass placed after radiofrequency ablation. (B) Axial CT obtained at a 27-month followup shows residual scarring at the site of RFA and brachytherapy and a nodular density (arrow) at the periphery of the previous treatment volume consistent with local recurrence.

brachytherapy. Of these patients, 5 required placement of a chest tube. One patient developed shortness of breath 3 weeks after procedure and was found to have pneumonia

with a small parapneumonic effusion. The patient was treated with empiric antibiotic therapy and subsequently recovered. Two additional patients developed pleural effusions after treatment. These were managed conservatively. One patient developed an empyema 12 months after undergoing RFA with brachytherapy. There were no treatment-related deaths. There were no cases of clinical radiation pneumonitis.

Discussion RFA is an emerging treatment option for the definitive management of medically inoperable early-stage NSCLC. An estimated 20% of patients with early-stage NSCLC are not surgical candidates and instead are treated with alternative modalities, such as RFA (10). The major advantages of RFA are its minimal invasiveness and its ability to spare normal lung parenchyma. Candidates for RFA are generally high-risk surgical candidates or patients who lack the pulmonary reserve to tolerate a major lung resection. In fact, patients with pretreatment forced expiratory volume in 1 sec of as low as 0.2 L have been treated successfully with RFA (10). Because of the significant comorbidities in the lung cancer patient population treated with RFA, the 2-year overall survival of 53% in this current series should be Table 2 Types and severities of complications after treatment

Fig. 5. (A) KaplaneMeier plot of overall survival and (B) Recurrencefree survival in 17 patients treated with radiofrequency ablation and highe dose rate brachytherapy. Two-year actuarial survival was 53%. Two-year actuarial local recurrence-free survival was 83%. Median followup was 22 months.

Toxicity

Number

Pneumothorax Chest tube Pleural effusion Empyema Radiation pneumonitis Intrapulmonary hemorrhage Treatment-related deaths

11/17 5/17 3/17 1/17 0/17 0/17 0/17

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viewed in the context of an ill population with a high rate of intercurrent death. A major disadvantage of RFA as a single modality for NSCLC is its suboptimal local control, which has been reported in the literature as low as 60% at 2 years (1e3). In comparison, when the Lung Cancer Study Group published its randomized trial comparing lobectomy with subtotal lobectomy in 1995, the local control at 5 years in the lobectomy arm was 95% (5). The local control in the subtotal lobectomy arm was 85% (5). On the other hand, local control rates for definitive radiotherapy have been reported to be between 50% and 70% at 3 years (11). Because RFA is a relatively recent approach in the treatment of early-stage lung cancer, long-term followup is still pending. Some series have combined the results of primary lung tumors and lung metastases. It is notable that primary NSCLC have a decreased local control as opposed to lung metastases. This may be because of a longer natural history of NSCLC as compared with metastastic patients or a more infiltrative natural history of primary lung cancers (2). With the intent to maximize local control achieved by RFA for NSCLC, Dupuy et al. (4) reported a series of 24 patients treated with the combination of RFA with external beam radiotherapy and achieved a local control of 91% at 2 years. In this current series, the reported local control rate of 83% is improved from previously reported series of RFA alone Table 3. One factor that has been shown to affect local control and ultimate likelihood of the cure achieved by RFA is the bulk of disease (2, 12). Ambrogi et al. (2) reported a series of 88 lung tumors treated with RFA alone, of which 40 were primary lung cancers. This series found local control to be decreased in tumors that were greater than 3 cm. Likewise, in this current series, the only local failures seen were in patients with T2 tumors. This finding suggests that for larger tumors, RFA alone is likely insufficiently encompassing the tumor in the respective treatment volumes. For T1N0 NSCLC, there were no local failures attesting to the high rate of local control for this population when treated with RFA with HDR brachytherapy. The major advantage of HDR brachytherapy over external beam radiation is the simultaneous normal tissue sparing and conforming of a high dose of radiotherapy around a specified target volume. In a pathologic evaluation of microscopic tumor extension from NSCLC, Giraud et al. (13) found that 95% of microscopic extension of primary NSCLC would be encompassed in a margin of 8 mm for

adenocarcinoma and 6 mm for squamous cell carcinoma. These results suggest that a limited target volume for adjuvant radiation therapy is possible and that a more conformal means of delivering adjuvant radiation therapy, such as brachytherapy may be advantageous. The risk of radiation-induced pneumonitis has been shown in several series to be related to the integral dose of radiation received by the total lung. Several surrogates for pneumonitis risk have been identified, including volume of lung receiving 20 and 5 Gy of radiation and mean lung dose (14e16). In each case, brachytherapy reduces the volume of normal lung dose irradiated as compared with the most conformal external beam radiation plan (8, 9). Accordingly, there were no cases of clinically evident radiation-induced pneumonitis in this current series. Perhaps the most relevant radiation-induced toxicity in this particular patient population is radiation-induced fibrosis. As patients with NSCLC treated with RFA often have severely compromised pulmonary reserve, the amount of normal lung that is exposed to high doses of ionizing radiation may, in fact, factor into the patients’ quality of life after treatment. The degree to which high doses of radiation affects pulmonary reserve has not been well studied, but one series has reported that the loss of pulmonary function after external beam radiotherapy may be related to the pretreatment reserve (17). With often little pulmonary reserve to spare, patients treated with RFA for early-stage NSCLC may not have the reserve to tolerate the added toxicity of external beam radiotherapy. RFA with HDR brachytherapy was reasonably well tolerated in this series, although procedure-related pneumothorax remained problematic. The incidence of patients who experienced a pneumothorax or need for subsequent chest tube placement was only slightly higher than previously reported in the literature for RFA alone (1, 3). The one Grade 4 toxicity was in a patient who experienced an empyema, but this was 12 months after the procedure and may or may not have been related. None of the patients who were not dependent on oxygen before therapy became oxygen dependent as a result of the treatment. Patients additionally had the potential advantage of having a biopsy and treatment on the same day. One advantage of RFA in the treatment of NSCLC is its ability to be repeated in the salvage setting. Three of the patients in this series experienced a lung cancer recurrence that was salvaged with a second RFA procedure. Although

Table 3 Local control Author

Number

Disease

Treatment modality

Local control % (2 y)

Hiraki et al. (12) Fernando et al. (1) Ambrogi et al. (2) Dupuy et al. (4) Lee et al. (18)

25 9 28 24 10

NSCLC (!4 cm) IA/IB NSCLC NSCLC/metastases (!3 cm) IA/IB NSCLC IA/IB NSCLC

RFA RFA RFA RFA þ EBRT (66 Gy) RFA

60 63 61 92 60 (1 y)

NSCLC 5 nonesmall-cell lung cancer; RFA 5 radiofrequency ablation; EBRT 5 external beam radiation therapy.

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retreatment of a lung cancer local recurrence with radiation therapy is feasible, it can be complicated by the cumulative dose tolerances of normal tissues to radiation. A local recurrence after RFA can be treated again with RFA in the same tumor bed. Likewise, a solitary distant recurrence can be treated with RFA alone and not risk the destruction of significant amounts of normal lung parenchyma as a result.

[7]

[8]

[9]

Conclusion This report represents the first series of RFA with adjuvant HDR brachytherapy in the literature showing the feasibility of such an approach with little increased toxicity over RFA alone. Local failure remains a problem for patients with T2 tumors, but salvage therapy with durable response is still possible. References [1] Fernando HC, De Hoyos A, Landreneau RJ, et al. Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates. J Thorac Cardiovasc Surg 2005;129:639e644. [2] Ambrogi MC, Lucchi M, Dini P, et al. Percutaneous radiofrequency ablation of lung tumours: Results in the mid-term. Eur J Cardiothorac Surg 2006;30:177e183. [3] de Baere T, Palussiere J, Auperin A, et al. Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: Prospective evaluation. Radiology 2006;240: 587e596. [4] Dupuy DE, DiPetrillo T, Gandhi S, et al. Radiofrequency ablation followed by conventional radiotherapy for medically inoperable stage I non-small cell lung cancer. Chest 2006;129:738e745. [5] Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615e622; discussion 622e613. [6] Shennib H, Bogart J, Herndon JE, et al. Video-assisted wedge resection and local radiotherapy for peripheral lung cancer in high-risk

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