|Year : 2013 | Volume
| Issue : 4 | Page : 680-685
Repeat stereotactic body radiation therapy for patients with pulmonary malignancies who had previously received SBRT to the same or an adjacent tumor site
Vladimir Valakh, Curtis Miyamoto, Bizhan Micaily, Philip Chan, Toni Neicu, Shidong Li
Temple University School of Medicine, Department of Radiation Oncology. Philadelphia, PA, USA
|Date of Web Publication||11-Feb-2014|
Department of Radiation Oncology, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA
Source of Support: None, Conflict of Interest: None
Objectives: Retrospective analysis of patients with recurrences at or closely adjacent to the site of prior lung stereotactic body radiation therapy (SBRT) who received repeat SBRT.
Materials and Methods: Nine patients with non-small cell lung cancer (n = 8) or oligometastatic colonic adenocarcinoma (n = 1) were treated with image-guided lung SBRT to a median of 60 Gy (range, 30-60) in a median of 3 fractions (3-5). Patients developed in-field relapse (n = 3) or recurrence adjacent (≤3.5 cm away) to the previous tumor location (n = 6) and received 2 nd lung SBRT to a median of 60 Gy.
Results: Median follow-up after 2 nd SBRT was 22 months (4-40). All completed prescribed course of repeat SBRT and acute toxicity was limited. There was no grade >3 late toxicity. 3 (33.3%) patients developed Grade 3 late reactions: 2 pulmonary and 1 chest wall pain. Late pulmonary toxicity included 2 (22.2%) patients with Grade 3 and 3 (33.3%) with Grade 2. One patient (11.1%) had late Grade 3 and 1 (11.1%) Grade 2 chest wall pain. 1 (11.1%) developed Grade 2 late brachial plexopathy. No myelopathy was observed. Two patients developed progression of tumors treated by 2 nd SBRT. Local recurrence free survival and overall survival was 75% and 68.6%, respectively at 2 years. Relative volume of ipsilateral lung receiving 5 Gy (V5) and V10 were lower for 2 nd SBRT.
Conclusion: Repeat image-guided SBRT for patients with small peripheral recurrences was feasible and severe toxicity was not observed. Additional studies are needed to evaluate the safety and efficacy of lung reirradiation using 2 nd SBRT.
Keywords: Lung cancer, recurrence, reirradiation, stereotactic body radiation therapy, stereotactic radiotherapy
|How to cite this article:|
Valakh V, Miyamoto C, Micaily B, Chan P, Neicu T, Li S. Repeat stereotactic body radiation therapy for patients with pulmonary malignancies who had previously received SBRT to the same or an adjacent tumor site. J Can Res Ther 2013;9:680-5
|How to cite this URL:|
Valakh V, Miyamoto C, Micaily B, Chan P, Neicu T, Li S. Repeat stereotactic body radiation therapy for patients with pulmonary malignancies who had previously received SBRT to the same or an adjacent tumor site. J Can Res Ther [serial online] 2013 [cited 2019 Dec 15];9:680-5. Available from: http://www.cancerjournal.net/text.asp?2013/9/4/680/126481
| > Introduction|| |
Stereotactic body radiation therapy (SBRT) is a safe and effective treatment for medically inoperable patients with early non-small cell lung cancer (NSCLC). ,, In addition, use of SBRT has been reported for recurrent NSCLC and for extrathoracic malignancies with limited lung metastases. , With reported local control rates of 84-97% a small proportion of patients treated with SBRT develop in-field recurrences. ,,,, Furthermore, some distant failures after SBRT occur in the lung parenchyma adjacent to the original tumor site and therefore are located in the previously irradiated tissue.
Management of a lung malignancy recurring at the site of previous SBRT or close to it poses a significant therapeutic challenge. Case series of surgical salvage for local recurrences after SBRT have been reported for initially operable. , Some patients with underlying cardiopulmonary dysfunction, which prohibited thoracotomy at the time of SBRT may be reassessed and deemed to be surgical candidates at the time of isolated local relapse.  However, operable patients likely represent a small minority of SBRT relapses. Although chemotherapy may be used for locally recurrent lung malignancies after SBRT  use of systemic therapy alone is not likely to result in definitive local control.
A course of repeat external beam radiation therapy can be an attractive treatment option for recurrence after SBRT at or near to a previously irradiated site, provided a tumoricidal dose is administered and severe normal tissue toxicity is avoided. In lung reirradiation, use of SBRT may potentially reduce additional radiation dose to surrounding noninvolved structures compared with conventional techniques. SBRT has been recently studied as a method of reirradiation for recurrent NSCLC in patients who were previously treated with conventionally fractionated radiation. , In this study, we report early results of repeat image-guided SBRT for nine patients with pulmonary recurrence at or closely adjacent to the site of prior SBRT.
| > Materials and Methods|| |
This study was registered with the Institutional Review Board and qualified for exemption from full board review. A retrospective analysis of a single-institutional database containing 118 lung SBRT patients treated between December 2006 and November 2011 was performed. Among those, we identified nine patients who received a second course of lung SBRT for either isolated in-field recurrence (n = 3) or a malignant mass closely adjacent (≤3.5 cm away) to the previously treated tumor location (n = 6). The eligibility cut-off of 3.5 cm distance was chosen because for all included patients there was overlap between at least 25% isodose lines from 1 st and 2 nd SBRT courses. A total of 8 patients had non-small cell lung carcinoma while one had oligometastatic colonic adenocarcinoma. Tissue confirmation of malignancy was obtained in 9/9 patients (100%) prior to the 1 st SBRT treatment. Diagnosis of recurrent malignancy was established based on the presence of new or enlarging mass on computerized tomography (CT) with corresponding abnormal fluorodeoxyglucose uptake on positron emission tomography (PET), with the maximum standardized uptake value consistent with that of a neoplasm. All nine recurrent tumors were located peripherally, >2 cm away from the proximal bronchial tree, the great vessels and the esophagus. Median interval between 1 st and 2 nd SBRT courses was 46 weeks (range, 4-109 weeks). No patients received systemic chemotherapy during the interval between 1 st and 2 nd SBRT. All maintained good or excellent performance status before repeat SBRT. Patient and disease characteristics are summarized in the [Table 1].
All patients were treated with linear accelerator-based image-guided SBRT. CT for virtual simulation was performed in supine position using immobilization system which consists of an extended vacuum cushion, a box frame and an abdominal compression device. Axial images with 3-mm slice thickness were obtained using AcQSim CT scanner v. 8.0 m (Philips Medical System Inc., Cleveland, OH, USA) to include the entire lungs. With the patient remaining in the same position, an additional CT of the target area was acquired using slow scan settings to allow for tumor motion assessment. Gross tumor volume (GTV) was outlined on the fast CT data set using lung window and level settings. Both fast and slow simulation CT data sets as well as staging PET/CT were then fused and used for the internal target volume (ITV) delineation by the treating radiation oncologist. A uniform 3 mm margin was then added to ITV to generate the planned target volume (PTV).
SBRT treatment planning was carried out using conformal arcs (9/18 plans, 50%) or step-and-shoot IMRT (9/18, 50%) techniques. We used 6-MV photon beams on Elekta Synergy® S (Elekta, Stockholm, Sweden) linear accelerator with a 4-mm-thick multi leaf collimator. All treatment planning was performed using Pinnacle software, v. 9.0 (Philips Medical System Inc., Cleveland, OH, USA). Inhomogeneity correction was used for all cases. The goal of treatment planning was to deliver the prescribed dose to the periphery of the PTV. Doses at the isocenter ranged from 110% to 125% of the prescribed dose respectively. Non-coplanar beam arrangement was not used. SBRT was administered twice per week and no routine premedication was given. Onboard kilovoltage cone beam CT was used for image guidance for all treatments. At the time of planning for 2 nd SBRT course, composite radiation plans were created whenever interval radiographical changes in the thoracic tissues permitted accurate reconstruction of the previous dose distribution. The goal of 2 nd SBRT planning was to keep the combined maximum point dose for the spinal cord below 50 Gy in 2 Gy per fraction BED equivalent (α/β=3) and the dose to other organs at risk as low as possible. An example of radiation dose distribution on a composite treatment plan is shown by [Figure 1].
|Figure 1: Axial (a) and coronal (b) images illustrating a radiation treatment plan, which combines dose from 1st and 2nd stereotactic body radiation therapy treatments. Total prescribed dose was 60 Gy for each of the two courses of SBRT. Green shaded structures are the planned target volumes. The innermost (red) line is the 100 Gy isodose; blue, purple, orange and green lines represent 80, 60, 40 and 20 Gy, respectively|
Click here to view
All dose prescriptions are listed in the [Table 2]. For 1 st SBRT median total prescribed dose was 60 Gy (range, 30-60 Gy) administered in the median of 3 fractions (range, 3-5 fractions) over a median of 13 calendar days. Median biological equivalent dose (BED 10 ) was 132 Gy (60-180). For 2 nd SBRT a median of 60 Gy (30-60) was given in a median of 4 fractions (3-5) over a median of 9 days. Median 2 nd BED 10 was 132 Gy (60-180). Four patients had a history of additional radiotherapy to the thorax other than 2 courses of SBRT described in this study [Table 2]. For this report, all SBRT plans were retrospectively loaded onto a treatment planning computer, accuracy of all contours was verified by a radiation oncologist and dose volume histogram (DVH) data were extracted. Lung contours excluded GTV.
Follow-up evaluation consisted of an office visit with a physical examination every 3 months for the first 2 years. Scheduled follow-up CT scans of the chest were obtained at 3 months intervals. Follow-up whole body PET/CT scans were obtained at the discretion of treating radiation oncologists. None of the patients were lost to follow-up. Median follow-up duration after 2 nd SBRT was 22 months (range, 4-40). Description of toxicities that occurred after 2 nd SBRT were obtained from the medical records and retrospectively scored according to the Common Terminology Criteria for Adverse Events v. 4.03 manual. Side-effects occurring ≥ 90 days after completion of SBRT were classified as late.
Statistical analysis was performed using SPSS Statistics 20.0.0 (International Business Machines, North Castle, NY, USA). We used the Kaplan-Meier method to estimate survival. Wilcoxon signed rank test was employed to compare DVH data and the significance level was set at P = 0.05. Adverse events were characterized as crude rates.
| > Results|| |
Results of DVH analyses for both 1 st and 2 nd SBRT courses are displayed in the [Table 3]. We retrieved and compared the PTV, the maximum point PTV dose, relative volume of the ipsilateral lung receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20) and dose to 1000 cm 3 of the ipsilateral lung (D 1000cc ). Average V5 and V10 were lower for the second course of SBRT and the differences were statistically significant. There was a strong statistical trend toward lower average PTV volume for 2 nd SBRT [Table 3].
All nine patients completed the prescribed course of repeat SBRT without interruption. Acute toxicity was limited to one patient with Grade 2 chest wall pain, one patient with Grade 1 dyspnea and one patient with Grade 1 radiation dermatitis.
There was no Grade 4 or 5 late toxicity. A total of 3/9 (33.3%) patients had any Grade 3 late toxicity. 2 (22.2%) patients had late Grade 3 pulmonary toxicity (dyspnea) at 7 and 29 months after 2 nd SBRT, treated with intravenous and enteral corticosteroids as inpatient and these events were documented as chronic obstructive pulmonary disease exacerbations by admitting physicians. For both patients with Grade 3 pulmonary toxicity indication for SBRT reirradiation was recurrence near the previous SBRT site. Other three patients (33.3%) had Grade 2 late pulmonary toxicity managed as an out-patient without corticosteroids. One patient (11.1%) had late Grade 3 and 1 (11.1%) had late Grade 2 chest wall pain. 1 (11.1%) developed Grade 2 late brachial plexopathy, which resolved on continued follow-up. Plexopathy [patient 1 in [Table 2] likely resulted from previous SBRT to the remote region of the ipsilateral lung (apical tumor treated to 48 Gy/4 fractions). The maximum point dose to the proximal brachial plexus was 51.33 Gy. Volume of brachial plexus receiving >EQD2 (3) 60 Gy was 2.34 cm 3 . Contribution from two SBRT courses included in this study was <50 cGy. No instances of myelopathy were observed in the study.
Cancer control and survival
Two patients developed progression of tumors treated by the second SBRT course at 6 and 9 months from completion and both ultimately died of their malignancies. For both of these patients the indication for SBRT reirradiation was in-field relapse. One additional patient developed distant recurrence in the contralateral lung. There were no other local, regional or distant recurrences in the study and the remaining six patients were alive and without evidence of ongoing malignancy at the time of the last follow-up. For the entire study, Kaplan-Meier 2 year estimates of local recurrence free survival and overall survival was 75% (95% confidence intervals, 45-100%) and 68.6% (32.1-100%), respectively [Figure 2] and [Figure 3]. Two out of three patients who received 2 nd SBRT for isolated in-field relapses developed local recurrence while 0/6 patients who retreated for new tumors adjacent to the initial site developed local recurrence after 2 nd SBRT.
| > Discussion|| |
As SBRT is used increasingly frequently for definitive treatment of lung malignancies  more patients with recurrences located at or near to the pulmonary site irradiated during SBRT are expected to present for consideration of salvage therapy. Lung SBRT patients already carry significant burden of medical comorbidities at the time of the first treatment  and selection of an appropriate second line therapy poses a formidable challenge. Observation and expectant management are appropriate options for those patients with relapse after SBRT who have poor functional status. Conversely, there is emerging evidence that for select patients with isolated local recurrence after lung SBRT, there may be a role for reevaluation by a thoracic surgeon for salvage thoracotomy and resection. ,,, However, long-term oncologic outcome and toxicities of thoracotomy after SBRT are currently not known. In any case, only a small minority of SBRT recurrences will be deemed operable due to preexisting comorbidities. While systemic chemotherapy is a traditional second line treatment for recurrent NSCLC,  durable local and overall disease control are not common with systemic therapy alone. Therefore a considerable experience with reirradiation for relapsed lung cancer initially treated with conventionally fractionated radiotherapy has accumulated. 
When lung reirradiation is considered for recurrence after SBRT, a theoretical advantage of using image-guided SBRT exists. Compared with conventional techniques, SBRT employs tight PTV margins, achieves high dose conformality and fast dose fall off, all of which may potentially result in lower dose to the surrounding critical tissues outside of PTV.  This is particularly important in the reirradiation setting, when late normal tissue toxicity is of a paramount concern. A theoretical disadvantage of SBRT for reirradiation is its use of large doses per fraction which can potentially lead to increased delayed toxicity compared with either conventionally fractionated reirradiation or hyperfractionation. Kelly et al. studied SBRT as a method of reirradiation for 36 patients with recurrent lung cancer, all of whom received prior conventionally fractionated thoracic radiotherapy to a median dose of 61.5 Gy.  Overall in-field local control was 92% at 2 years while OS was 59% and progression free survival was 26%. Authors reported no life threatening toxicity while 33% of patients had any Grade 3 toxicity. The median follow-up was short (15 months).  In a smaller report of eight patients with recurrent bronchogenic carcinoma treated with SBRT for local relapse after conventional radiotherapy, Seung and Solhjem. demonstrated no in-field recurrences and no severe toxicity with a short follow-up of 18 months. 
Peulen et al. recently has reported early results of use of second SBRT course for reirradiation after previous lung SBRT.  Twenty-nine patients retreated for 33 lesions (11 central, 21 peripheral) were included. With a short median follow-up of 12 months, incidence of severe toxicity was high. Eight subjects (27.6% of patients in the study) experienced Grade 3 or 4 late reactions and 3 (10.3%) died of causes that could be potentially attributed to repeat SBRT. Notably, all patients with Grade 4 and 5 toxicities had central tumors and authors rightfully concluded that great concerns existed with use of repeat SBRT for centrally situated SBRT relapses. As in our study, repeat SBRT for peripheral targets was not associated with Grade >3 late reactions.
In the present report of nine patients, treatment delivery of repeat SBRT was well tolerated and the incidence of normal tissue complications was encouragingly low. We have observed no life threatening adverse events thus far. At the time of this report, our overall rate of Grade 3 late pulmonary toxicities appears to be similar to that reported for SBRT to previously untreated lungs.  We were able to achieve local control of 7/9 (78%) of retreated tumors. Six of nine patients are alive and are without any clinical and radiographic evidence of ongoing malignancy, which indicates that they were correctly selected as good candidates for aggressive salvage local therapy. Both tumors that progressed after repeat SBRT were direct in-field recurrences after the first SBRT, which may be an evidence of the fact that in-field relapses carry worse prognosis than recurrences near the previous SBRT site. For two patients with local failure, the average retreatment PTV volume 48.9 cm 3 versus 14 cm 3 for seven patients whose local disease was controlled.
This study has several important limitations. Firstly, whereas the toxicity profile and oncologic outcome appear favorable, longer follow-up is needed to exclude development of additional severe late reactions and relapses. Secondly, as patients were poor candidates for lung biopsy due to comorbidities, recurrences were not histologically confirmed. Most importantly, the sample size is of nine patients are small and statistical power is of our study is low. However, clinical situation described in this report is rare and treatment options for recurrence after SBRT are extremely limited. Therefore we believe that results of this study may be considered hypothesis-generating for future investigations of safety of repeat lung SBRT.
Our results apply only to patients with small (average PTV volume 22 cm 3 ) and peripherally located recurrent tumors. Patients with large and/or more centrally located recurrences after SBRT are probably at a higher risk of severe complications after 2 nd SBRT. We used various repeat SBRT dose schedules but a superior reirradiation regimen cannot be determined based on our data. It is likely that dose per fraction and total prescribed dose need to be catered to each individual patient. While the lungs are most likely to be the dose limiting organs in repeat SBRT, our sample size is too small to access radiation tolerance of the lung in the reirradiation setting.
| > Conclusion|| |
Repeat image-guided SBRT for patients with small peripheral lung tumors was feasible and life-threatening toxicity was not observed for these nine patients. Additional studies are needed to evaluate safety and efficacy of lung reirradiation using a second SBRT course.
| > Acknowledgments|| |
The authors would like to thank Katsiaryna Mazurenka, M.A. for statistical consultation. The results of this study were presented at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology, September 6-8, 2012, Chicago, Illinois, USA.
| > References|| |
|1.||Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070-6. |
|2.||Baumann P, Nyman J, Hoyer M, Wennberg B, Gagliardi G, Lax I, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290-6. |
|3.||Nagata Y, Takayama K, Matsuo Y, Norihisa Y, Mizowaki T, Sakamoto T, 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. Int J Radiat Oncol Biol Phys 2005;63:1427-31. |
|4.||Kelly P, Balter PA, Rebueno N, Sharp HJ, Liao Z, Komaki R, et al. Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation. Int J Radiat Oncol Biol Phys 2010;78:1387-93. |
|5.||Ricardi U, Filippi AR, Guarneri A, Ragona R, Mantovani C, Giglioli F, et al. Stereotactic body radiation therapy for lung metastases. Lung Cancer 2012;75:77-81. |
|6.||Neri S, Takahashi Y, Terashi T, Hamakawa H, Tomii K, Katakami N, et al. Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers. J Thorac Oncol 2010;5:2003-7. |
|7.||Chen F, Matsuo Y, Yoshizawa A, Sato T, Sakai H, Bando T, et al. Salvage lung resection for non-small cell lung cancer after stereotactic body radiotherapy in initially operable patients. J Thorac Oncol 2010;5:1999-2002. |
|8.||Allibhai Z, Cho BC, Taremi M, Atallah S, Hope A, Hwang D, et al. Surgical salvage following stereotactic body radiotherapy for early-stage NSCLC. Eur Respir J 2012;39:1039-42. |
|9.||Bradley J. New territory: Surgical salvage for stereotactic body radiation therapy failures in lung cancer. J Thorac Oncol 2010;5:1879-80. |
|10.||Seung SK, Solhjem M. Salvage SBRT for previously irradiated lung cancer. J Cancer Ther 2011;2:190-5. |
|11.||Pan H, Simpson DR, Mell LK, Mundt AJ, Lawson JD. A survey of stereotactic body radiotherapy use in the United States. Cancer 2011;117:4566-72. |
|12.||Guckenberger M, Kestin LL, Hope AJ, Belderbos J, Werner-Wasik M, Yan D, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol 2012;7:542-51. |
|13.||Noble J, Ellis PM, Mackay JA, Evans WK, Lung Cancer Disease Site Group of Cancer Care Ontario′s Program in Evidence-based Care. Second-line or subsequent systemic therapy for recurrent or progressive non-small cell lung cancer: A systematic review and practice guideline. J Thorac Oncol 2006;1:1042-58. |
|14.||Jeremiæ B, Videtic GM. Chest reirradiation with external beam radiotherapy for locally recurrent non-small-cell lung cancer: A review. Int J Radiat Oncol Biol Phys 2011;80:969-77. |
|15.||Tipton K, Launders JH, Inamdar R, Miyamoto C, Schoelles K. Stereotactic body radiation therapy: Scope of the literature. Ann Intern Med 2011;154:737-45. |
|16.||Peulen H, Karlsson K, Lindberg K, Tullgren O, Baumann P, Lax I, et al. Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy. Radiother Oncol 2011;101:260-6. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]