Lung stereotactic body radiotherapy (SBRT) delivers an

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1 Original Article Stereotactic Body Radiotherapy in Patients with Previous Pneumonectomy Safety and Efficacy Robert Thompson, MD,* Meredith Giuliani, MBBS,* Mei Ling Yap, MD,* Soha Atallah, MD,* Lisa W. Le, MSc, Alexander Sun, MD,* Anthony Brade, MD,* B. C. John Cho, MD,* Andrea Bezjak, MD,* and Andrew Hope, MD* Introduction: There are limited treatment options for patients with prior pneumonectomy and a new lung malignancy. The safety and efficacy of stereotactic body radiotherapy in this subpopulation has not been well defined. Methods: Postpneumonectomy patients treated with lung SBRT were identified from a prospective single institution database. Treatment toxicity was recorded prospectively using the Common Terminology Criteria for Adverse Events version 3.0. Disease recurrences were categorized as local, regional, or distant metastatic disease. Overall survival was calculated using the Kaplan-Meier method. Results: Of 406 patients, 13 postpneumonectomy patients were identified and 14 tumors were treated with SBRT. Median age was 69 years. Three lesions were biopsy confirmed. The SBRT doses were 60 Gy/3 (n = 1), 54 Gy/3 (n = 1), 48 Gy/4 (n = 7), 60 Gy/8 (n = 2), and 50 Gy/10 (n = 3). Median follow-up was 24 months. Two patients had grade 3 radiation pneumonitis 3 and 4 months post-sbrt; they died 3 and 1 months later, respectively, one of myocardial infarction and the other of progressive dyspnea thought to be related to congestive heart failure. There were no local failures, one regional failure, and three distant failures. Median survival was 29 months, 1 and 2 year overall survival were 69% (95% confidence interval: %) and 61% (95% confidence interval: 39 95%), respectively. Conclusions: SBRT in patients with prior pneumonectomy poses challenges because of limited lung reserve. However, local control and long-term survival can be achieved using SBRT in this inoperable population. Careful consideration must be given to radiation planning to minimize the risk of radiation pneumonitis. Key Words: Stereotactic body radiation therapy, Stereotactic ablative body radiotherapy, Pneumonectomy, Local control, Radiation pneumonitis (J Thorac Oncol. 2014;9: ) *Radiation Medicine Program, Princess Margaret Cancer Centre; Department of Radiation Oncology, University of Toronto; and Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON. Address for correspondence: Dr Meredith Giuliani, 610 University Ave, Toronto, ON M5G2M9. Meredith.Giuliani@rmp.uhn.on.ca Disclosure: Drs Bezjak, Hope and Giuliani have received travel funding from Elekta and Dr Bezjak has received program funding from Elekta in the past. All other authors declare no conflict of interest. Copyright 2014 by the International Association for the Study of Lung Cancer ISSN: /14/ Journal of Thoracic Oncology Volume 9, Number 6, June 2014 Lung stereotactic body radiotherapy (SBRT) delivers an ablative dose of radiation that encompasses the tumor while minimizing dose to surrounding structures. SBRT delivers higher doses per fraction than conventional radiation, typically in three to five fractions. SBRT has been shown to be safe and efficacious in the treatment of early stage non small-cell lung cancer in the inoperable patient population with local control rates greater than 90% The most common toxicities after SBRT are fatigue and, less often, pneumonitis. 2 Radiation pneumonitis occurs in approximately 10% of patients treated with lung SBRT. 12 Therapeutic options for patients previously treated with a pneumonectomy who subsequently develop a malignancy within their remaining lung are limited. Pneumonectomy reduces lung function 13 and results in a significant and sustained decrease in physical functioning. 14 In a retrospective review, Donington et al. 15 showed that, for selected patients with a single lung, a further wedge resection, segmentectomy, or lobectomy may be possible but these carry an operative complication rate of approximately 40% and operative mortality of 8%.. SBRT represents an attractive alternative to surgical resection for these patients. Here we report on our institution s experience with SBRT postpneumonectomy, focusing particularly on the safety and efficacy of this therapy. PATIENTS AND METHODS Patients treated with lung SBRT after pneumonectomy were identified from a prospective database with research ethics board approval. Our institution has maintained a prospective database of patients treated with lung SBRT since October Thirteen out of 406 patients treated with SBRT during the period of October 2004 to August 2013 were identified as having had a previous pneumonectomy. Radiotherapy The Pinnacle (Philips Medical Systems, Fitchburg, WI) radiation therapy planning system was used to create all treatment plans. Four-dimensional computed tomography (4DCT)-based planning was used. The gross tumor volume was contoured on the exhale, inhale, average, and maximum intensity projection phases. These four GTVs were combined 843

2 Thompson et al Journal of Thoracic Oncology Volume 9, Number 6, June 2014 to create an internal target volume. The planning target volume was created based on a 5 mm expansion of the internal target volume. Kilovoltage cone-beam CT imaging was used for every radiotherapy fraction to confirm patient position. Radiotherapy dose and fractionation were determined by the treating oncologist and were based upon multiple clinical considerations including the target location, size, and previous radiotherapy plan details if applicable. Treatment plans were optimized to minimize dose to surrounding lung and other organs at risk including spinal cord, ribs, and mediastinal structures (Fig. 1). The following dose-parameters were obtained from the radiation plans: the volume of lung that received 5 Gy (V5), 10 Gy (V10), and 20 Gy (V20) as a percentage of the total lung volume excluding the target volume; mean lung dose (MLD); mean heart dose; and maximum heart dose. Toxicity and Outcomes Patients were followed after SBRT according to an institutional prospective protocol. They were seen for clinical review at 6 weeks, 3, 6, 9, 12, 18, and 24 months after SBRT. CT scans of the chest were performed at 3, 6, 12 and 24 months or more frequently if needed. They were then seen at least once a year with a CT scan. Toxicity was recorded prospectively as per the Common Terminology Criteria for Adverse Events version Pulmonary function tests (PFTs) were performed before SBRT for all patients. Post- SBRT PFT data was obtained. Tumor recurrences or failures were categorized as local failure, regional nodal failure, or distant failure. Statistical Analysis Patient demographic and dosimetric information were summarized using descriptive statistics. The overall survival (OS) time was calculated from the date of diagnosis to date of death or censored at the last follow-up date. The Kaplan-Meier method was used to construct the OS curve. The survival time of the patient who received two SBRT treatments was counted from the diagnosis date of the first tumor. The cause-specific survival was also calculated using the Kaplan-Meier method. RESULTS Patient Demographics Thirteen patients were identified as having received SBRT between August 2006 and July 2012, after a previous pneumonectomy; one patient had two lesions treated with SBRT. Most patients (10 of 13) were male. The median patient age was 69 (range, 49 85) years. Eleven patients had a previous pneumonectomy for non small-cell lung cancer and a presumed new lung primary malignancy. One patient had a pneumonectomy for malignant mesothelioma (Patient no. 11) and another patient had a pneumonectomy for oligometastatic transitional-cell bladder carcinoma (Patient no. 13). The mean time between pneumonectomy and SBRT was 6.8 years (range, years). Five patients had previous adjuvant thoracic radiation therapy (Table 1). The mean dose was 49 Gy (range, Gy). Of those patients, the mean time between previous thoracic radiation and lung SBRT was 6 years (range, 2 months to 12 years). Tumor Characteristics Eleven lesions were peripherally located per the RTOG 0236 study criteria 2 and three lesions were centrally located. Our institutional policy is to recommend a biopsy, unless the procedural risk of a biopsy is deemed to be high. Three lesions were biopsy confirmed through either fine needle aspiration or core biopsy. In the remaining patients, biopsy was not performed because of excessively high procedural risk. Positron-emission tomography with fluorodeoxyglucose was used for all presumed new primary lung malignancy patients (n = 12). In those cases without a biopsy, a diagnosis was established based upon serial lesion growth on chest CT and positron-emission tomography scan features characteristic of lung malignancy. Before SBRT, each patient s clinical case was reviewed by a multidisciplinary tumor board including thoracic surgeons, medical oncologists, and radiation oncologists. The mean tumor volume was 9.5 cm 3 (range, cm 3 ; Table 1). Radiotherapy Five patients were treated with volumetric-modulated arc therapy and the remaining patients were treated with static FIGURE 1. Images of the lung nodule pre- and post-sbrt and the radiation plan. (A) The pretreatment computed tomography thorax demonstrating the solitary pulmonary nodule. B) The radiotherapy plan. The red area is the gross tumor volume, the green area is the planning target volume, the blue line is the 4560 cgy isodose line (95% of the prescription dose), the purple line is the 2000 cgy isodose line and the teal line is the 1000 cgy isodose line. C) The 18 month posttreatment computed tomography thorax demonstrating resolution of the pulmonary nodule. 844 Copyright 2014 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 9, Number 6, June 2014 SBRT in Patients with Pneumonectomy TABLE 1. Patient, Tumor, and Prescription Dose Patient No. Previous Pneumonectomy TNM Stage Pneumonectomy-SBRT Interval (Years) Previous Chest RT Pre-SBRT FEV1 (Liter) Pre-SBRT FVC (Liter) Lesion Location New Lesion GTV (cm 3 ) SBRT Dose 1 T2N1M0 NSCLC 4.4 No P Gy/4 fx 2 T3N3M0 NSCLC 7.0 Yes P Gy/8 fx 3 T3N0M0 NSCLC 12.7 No P Gy/4 fx 4 T3N1M0 NSCLC 4.4 No C Gy/10 fx 5 T1N2M0 NSCLC 6.0 Yes P Gy/3 fx 6 T2N1M0 NSCLC 20.0 No P Gy/4 fx 7 T2N1M0 NSCLC 1.1 No C Gy/10 fx 8 T3N0M0 NSCLC 9.1; 11.0 No; yes P; P 3.1; Gy/8 fx; 48 Gy/4 fx 9 T2N1M0 NSCLC 6.0 Yes P Gy/4 fx 10 T3N0M0 NSCLC 1.9 No P Gy/3 fx 11 T2N0M0 (mesothelioma) 4.4 Yes P Gy/4 fx 12 T2N2M0 NSCLC 11.8 No P Gy/4 fx 13 Oligometastatic bladder TCC 2.2 No C Gy/10 fx P, peripherally located tumor; C, centrally located tumor as per the RTOG 0236 protocol; Gy, Gray; fx, fraction; GTV, gross tumor volume; NSCLC, non small-cell lung carcinoma; TCC, transitional-cell carcinoma; SBRT, stereotactic body radiotherapy; FEV1, forced expiratory volume in 1 second;rt, radiation therapy; FVC, forced vital capacity. Patient no. 8 was treated with lung SBRT twice. beams, mean number of beams 8.5 beams (range, 7 9 beams) including one patient who was treated with volumetric-modulated arc therapy on a second tumor. The most common dose delivered and fractionation were 48 Gy/4 (n = 7; Table 1). Outcomes Median follow-up time was 24 months (range, 7 54 months). There were no local failures. There was one regional failure that manifested at 6 months as nodal enlargement on CT scan and confirmed by pathology, and three distant failures (lung, thigh, and retroperitoneum) at 3, 15, and 20 months. The 1-year cause-specific survival was 82% (95% confidence interval [CI]: %; Fig. 2). Median survival was 29 months, 1-year OS was 69% (95% CI: %), 2-year OS was 61% (95% CI: 39 95%), and 3-year OS was 36% (95% CI: 16 85%; Fig. 3). Toxicity Two patients had at least grade 3 radiation pneumonitis (RP). Patient number 5 developed grade 3 RP at 3 months after SBRT, was treated with steroids, and was improving but subsequently died at 6 months of a myocardial infarction. This patient s V5, V10, V20, and MLD were 43%, 25%, 11%, and 820 cgy, respectively. The mean and maximum heart doses were 272 cgy and 1899 cgy, respectively. Patient number 12 had dyspnea and pleuritic chest pain at 2 weeks, which progressively worsened to grade 3 RP at 4 months and subsequently died at 5 months after SBRT with progressive dyspnea thought be related to cardiac dysfunction. This patient s V5, V10, V20, and MLD were 21%, 12%, 6%, and 460 cgy, respectively. The mean and maximum heart doses were 209 cgy and 1740 cgy, respectively. Of the patients with no grade 3 RP, the mean V5, V10, V20, and MLD were 28 % (range, 5 52%), 17% (range, 4 30%), 7% (range, 2 15%), and 549 cgy (range, cgy), respectively. The mean and maximum heart doses for these patients were 361 cgy (range, cgy) and 2098 cgy (range, cgy), respectively (Table 2). Seven patients had asymptomatic radiographic changes of the lung and one patient had a symptomatic, grade 2, rib fracture. Four patients had grade 1 fatigue and 2 patients had a grade 1 skin reaction. Pulmonary Function Testing The mean pre-sbrt forced expiratory volume in 1 second (FEV1) was 1.4 liter (range, liter) and forced vital capacity was 2.2 liter (range, liter). Ten of 13 patients FIGURE 2. Kaplan-Meier plot of cause-specific survival. Copyright 2014 by the International Association for the Study of Lung Cancer 845

4 Thompson et al Journal of Thoracic Oncology Volume 9, Number 6, June 2014 FIGURE 3. Kaplan-Meier plot of overall survival. had a posttreatment PFTs. The median time from completion of SBRT to posttreatment PFT was 7 months (range, 5 23 months). The mean change in FEV1 was 0.1 liter (range, 0.5 to 0.1 liter), indicating a decrease in FEV1 with SBRT. Similarly, the mean change in forced vital capacity from before to after SBRT was 0.1 liter (range, 0.4 to 0.2 liter). DISCUSSION Managing patients with a lung tumor in their solitary lung caused by previous pneumonectomy is a major challenge. The ability to make a diagnosis is limited by the high-risk nature of a biopsy and treatment options are limited because of reduced lung reserve. Despite careful clinical review of each patient and their diagnostic imaging by a multidisciplinary team, there is a chance that, of the patients without biopsy-confirmed disease, some may have had an alternative cancer diagnosis such as small-cell lung carcinoma or a benign histology. As most patients after pneumonectomy have limited pulmonary function, transbronchial core biopsy or percutaneous needle biopsy carries increased risk and these risks often preclude pathologic diagnosis. At our center, biopsies are considered, and the recommendation is to place a pre-biopsy chest tube to address the risk of a peri-procedural pneumothorax, but this is not common practice. Even with this method, only 3 patients were biopsied because the risks of the procedure outweighed the benefits of diagnostic confirmation. The only published data on lung SBRT after previous pneumonectomy was from Haasbeek et al. 11 and updated by Senthi et al. 17 who reported on 27 patients, previously treated with pneumonectomy, with a second primary lung cancer treated with radiotherapy including conventional fractionation, hypofractionation, or SBRT. After a median follow-up of 52 months, their results demonstrated a local relapse rate of 8% and a median OS of 39 months. They used previously defined criteria based on disease recurrence time, location, and histology from Martini et al. 18 to distinguish a second primary lung cancer from a recurrence. Eleven patients in our study had contralateral lung malignancies that fulfilled these criteria. In contrast, two other patients included in this analysis had altogether different diagnoses: mesothelioma and oligometastatic bladder cancer. Despite these differences, our results are similar to those of Senthi et al. 17 in terms of OS and local control. The possible adverse effects of SBRT after pneumonectomy must be carefully considered. In this study, a small decline in pulmonary function parameters of 0.1 liter on average was seen for both FEV1 and FVC. In several larger analyses of PFTs after SBRT, there was no statistically significant decline in FEV1 and FVC Upon analysis of the two patients who had grade 3 RP, it appears that patient no. 5 received higher lung doses than the rest of the cohort and this may have contributed to her pulmonary toxicity. However, patient no. 12 received a dose similar to the patients with no grade 3 RP. In a retrospective review of 13 patients who received lung intensity modulated radiation therapy (IMRT) in 1.8 Gy daily fractions post-extrapleural pneumonectomy for mesothelioma, Allen et al. 23 reported six cases of fatal pneumonitis. In their dosimetric analysis, they reported a median V5, V20, and MLD for the patients who had pneumonitis of 99%, 18%, and 15 Gy, respectively, when compared with 90%, 11%, and 13 Gy, respectively, for the patients who did not develop pneumonitis. The lung radiation doses in our study, even for the two patients with grade 3 RP, were substantially lower than those in the study by Allen et al. 23 Limitations of this study are that only three patients had biopsy proven malignancy. It is possible some patients were treated for benign disease which would favorably bias these results. In addition, there were insufficient events of grade 3 or greater radiation pneumonitis to perform a dosimetric analysis to determine an optimal cutoff for lung parameters including the mean lung dose for patients with single lung SBRT. We report two patients who experienced at least grade 3 toxicity. To the best of our knowledge, they did not have toxicity related deaths; TABLE 2. Toxicity and Dosimetric Data V5 (%) V10 (%) V20 (%) MLD (cgy) Mean Heart Dose (cgy) Maximum Heart Dose (cgy) Patients with grade 3 RP Patient no Patient no All other patients 28* (5 52) 17* (4 30) 7* (2 15) 549* ( ) 361* ( ) 2098* ( ) *Mean values. V5, V10, V20: volume of lung (%) receiving 5, 10, and 20 Gy, respectively. MLD, mean lung dose; cgy, centigray; RP, radiation pneumonitis. 846 Copyright 2014 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 9, Number 6, June 2014 SBRT in Patients with Pneumonectomy however, they did die of cardiopulmonary complications and we cannot be certain these were not related to the SBRT. At present, patient mean lung dose should ideally not exceed 450 cgy in the remaining lung, and even at these low doses, there is a risk of serious complications as these patients lack pulmonary reserve. However, it is important to explore novel treatment options in patients after pneumonectomy. With improvements in interventional radiology, more patients may be candidates for biopsy safely. In addition, with greater experience with SBRT, more patients may be safely treated. With advances in treatment for patients with lung carcinoma, second malignancies in these patients are an increasing clinical concern. Patients remain at risk of second primary cancers with no decreased incidence over time. 24 CONCLUSION SBRT is a therapeutic option for patients with a single lung and a new lung lesion that is presumed to be cancerous. Careful consideration must be given to radiation planning to minimize the risk of radiation pneumonitis. REFERENCES 1. Chang JY, Shirvani SM, Jr. BWL, et al. Primary Lung Cancer. In: Lo SS, Teh BS, Lu JJ, et al., eds. Stereotactic Body Radiation Therapy. Berlin Heidelberg: Springer-Verlag; 2012: Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303: Hara R, Itami J, Kondo T, et al. Clinical outcomes of single-fraction stereotactic radiation therapy of lung tumors. Cancer 2006;106: Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/ II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. 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J Thorac Cardiovasc Surg 2013;145:75 81; discussion 81. Copyright 2014 by the International Association for the Study of Lung Cancer 847