Journal of Thoracic Oncology:
A Brief Report of 10-Year Trends in the Use of Stereotactic Lung Radiotherapy at a Dutch Academic Medical Center
Peguret, Nicolas MD; Dahele, Max MBChB, MSc, PhD, FRCP, FRCR; Lagerwaard, Frank MD, PhD; Senan, Suresh MBBS, PhD, MRCP, FRCR; Slotman, Ben J. MD, PhD
Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Disclosure: Dr. Peguret is supported by a Swiss National Science Foundation grant. Drs. Dahele, Senan, Lagerwaard, and Slotman have received travel support and honoraria from Varian Medical Systems. Dr. Dahele has received travel support from Brainlab. Drs. Lagerwaard and Slotman have received travel support and honoraria from Brainlab.
Address for correspondence: Dr. Nicolas Peguret, Department of Radiation Oncology, VU University Medical Center De Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: email@example.com
This report describes clinical trends in the use of stereotactic lung radiotherapy in a large single-institution program over the last 10 years. Changes in patient, tumor, and treatment characteristics are highlighted.
Stereotactic body radiotherapy (SBRT) typically consists of a relatively small number of high-dose fractions delivered to extracranial targets and reports of its use date back to the early 1990s.1–3 Since then, it has become accepted as an effective treatment for patients with medically inoperable early-stage peripheral non–small-cell lung cancer (NSCLC) and its introduction throughout The Netherlands has been associated with improvements in population-based outcomes for early-stage NSCLC.4–6 Despite the fact that follow-up has been of limited duration, and lower rates of pathological confirmation of malignancy have been obtained in some SBRT series, recent analyses suggest that SBRT may achieve local and regional control rates that are comparable with surgery in early-stage NSCLC.7 High local control rates have also been reported for lung metastases.8 Our department started lung SBRT in 2003. This report investigates the effect of a decade of increasing experience, evolving evidence, and the increasingly widespread adoption of lung SBRT on the patterns of practice in a single Dutch academic medical center.
PATIENTS AND METHODS
Details of patients with a clinical or histological diagnosis of early-stage NSCLC, or lung metastases treated with lung SBRT are routinely documented in an institutional database. This was retrospectively analyzed using five approximately equal periods: 1=April 2003–March 2005, 2=April 2005–March 2007, 3=April 2007–March 2009, 4= April 2009–March 2011, and 5=April 2011–February 2013. Of 1082 patients, 989 with a pathologic (histologic or cytologic) or clinical diagnosis of early-stage NSCLC (T1-2N0M0) or metastatic lung disease were included in this report. We excluded 8.6% of patients (93 of 1082) for reasons such as more advanced disease, treatment with nonstandard doses (n=5, including those treated with a single fraction), reirradiation for in-field recurrence, a diagnosis of small-cell lung cancer or patients with no recorded stage. Where a patient had undergone more than one course of treatment, data from the first course were used in this report. If more than one lesion was irradiated in this course (this was the case in <7% courses), data from the index lesion in the database were used. As described previously,4 patients were treated by using a risk-adapted strategy in which the prescription dose fractionation was determined by tumor size and proximity to critical structures. In brief, three fractions were typically used for peripheral T1 tumors, five fractions for peripheral T2 tumors or T1-2 tumors in broad contact with the chest wall, and eight fractions for central tumors (e.g., close to mediastinum or central airways, consistent with the definition in Radiation Therapy Oncology Group (RTOG) 0236, or where the target volume was in contact with/overlapping pericardium)9,10 or those considered too large for five fractions. Twelve fractions were introduced more recently for progressively bigger and more central target volumes (e.g., mediastinal extension). Current dose-fractionation schedules are as follows: 3 × 18 Gray (Gy), 5 × 11Gy, 8 × 7.5Gy, and 12 × 5Gy. All routinely prescribed to the 80% isodose, which should cover at least 95% of the planning target volume (PTV), with a maximum dose in the PTV of 140% of the prescribed dose. These schemes have a biological effective dose for tumor effect (using α/β=10) of 151 Gy10, 116 Gy10, 105Gy10, and 90 Gy10, respectively. Patients have routinely undergone four-dimensional computed tomography (CT) scan for treatment planning. Before 2008, patients were treated with eight to 12 fixed non–coplanar conformal beams on the Novalis platform (Brainlab AG, Feldkirchen, Germany) with patient positioning based on stereoscopic spine imaging with ExacTrac (Brainlab AG). This was subsequently replaced by a combination of volumetric modulated arc therapy (VMAT; RapidArc, Varian Medical Systems, Palo Alto, CA) and online cone-beam CT) tumor-based positioning on the Novalis Tx™ (Brainlab and Varian Medical Systems) and TrueBeam™ (Varian Medical Systems) platforms. Since the VMAT treatment planning system involved a change in the dose calculation algorithm (from pencil beam based iPlan® to the Analytic Anisotropic Algorithm in Eclipse™) the dose per fraction was modified and is currently as described above.
The report focuses on patient, tumor and treatment delivery characteristics in order to describe trends in patient care and clinical practice. The purpose was not to describe clinical outcomes, which have recently been reported for a large patient group,4 nor to conduct a longitudinal analysis, both of which are beyond the scope of this brief report. Detailed statistics have not been applied, as the goal was to describe broad changes in clinical practice.
Data from 989 patients treated with lung SBRT between April 2003 and February 2013 forms the basis of this report. Of these, 900 patients had a clinical or pathologic diagnosis of early-stage NSCLC (pathological confirmation in 27% and 42.9% in the first and last periods, respectively) and 89 had metastatic lung disease (pathological confirmation in 75% and 42.9% in the first and last periods, respectively). Computed tomography and fluorodeoxyglucose positron emission tomography evaluation were a routine part of the clinical diagnostic algorithm. In patients with metastatic lung disease the most commonly known primary tumors were colorectal, lung, and sarcoma. The current median follow-up (to last contact or date of death, in years) for all patients, and those considered medically operable, was 2.8 of 5.5, 3.5 of 4.9, 2.9 of 4, 1.7 of 2, and 0.6 of 0.8 years in the periods 1 to 5 respectively. Analyzed over the whole study period, 93.2% of patients had one lesion, 6.3% had two, and 0.5% had more than two treated simultaneously. Table 1 summarizes patient, tumor, and treatment characteristics during the five time periods. There was an almost fivefold increase in the number of patients treated from period 1 to 4. Median patient age fell from 81 years (range, 57–93) in the first period to 71 years (range, 44–93) in the final period. Median age of all patients with metastatic disease was 66 years (range, 41–87) compared with 79 years (range, 46–97) for those with NSCLC. Although there was a trend toward an increase in the proportion of fitter patients (performance status [PS] 0–1) in recent years (59.7% and 65.5% of patients in periods 1 and 2, respectively, compared with 71.4% and 78% in periods 4 and 5 respectively), the proportion of patients considered medically inoperable was relatively stable at 80.6%, 71.1%, 76.9%, 79.1%, and 82% for periods 1 to 5, respectively. Overall, 67.4% of patients had PS 0 to 1 (0.2% missing data); their median age was 77 years; 27.7% were considered medically operable; 11.2% had SBRT for metastatic disease, and 38.5% had pathologic proof of malignancy. For those with PS 2 to 3 (32.6%) the median age was 79 years; 4.6% had metastatic lung disease and 35.6% had a pathologic diagnosis. There were 221 patients (22.3%) classified as medically operable; median values were age = 78.4 years, Charlson Comorbidity Index (CCI)=2 (8.1% missing data), forced expiratory volume in 1 second (FEV1) = 2.07 (8.1% missing), and PS=1. In comparison, there were 768 medically inoperable patients (77.7%) with corresponding median age = 75.8 years, CCI = 3 (10.9% missing), FEV1=1.60 (15.8% missing), and PS=1.
Over time, the general trend for all treatments was toward a reduction in median tumor diameter (Table 1). Median size of metastatic and primary tumors was 20 and 27 mm, respectively. Median tumor diameter for three-, five-, eight-, and 12-fraction treatments was 19, 32, 34, and 41 mm, respectively. On average, there were about four times as many peripheral as central tumors throughout the study period (Table 1), with the majority of the latter (57.2%) treated in eight fractions. The proportion of patients with proven malignancy increased between the first and last periods, rising from 29.6% to 40.9% in medically inoperable patients and from 30.8% to 51.7% in those considered medically operable. The ratio of patients with or without a pathologic diagnosis has been steady at about 40:60 over the last 6 years (Table 1). A trend was observed toward an increasing number of metastatic lesions being treated over time (6.0% in the first period, 10% in the fourth period, and 21.7% in last period).
Although the majority of treatments were delivered with three or five fractions throughout the study period, use of eight or 12 fractions increased during the last 4 years (Table 1). A total of 274 of 332 (82.5%) three-fraction treatments were for T1N0M0 tumors, compared with 149 of 402 (37.1%), 77 of 217 (35.5%), and nine of 38 (23.7%) of five, eight, and 12 fractions, respectively. Central tumors accounted for 115 of 217 (53%) and 30 of 38 (78.9%) of eight- and 12-fraction treatments, respectively. Whereas the majority of eight-fraction treatments were initially given for central tumors, the proportion of peripheral tumors treated with eight fractions increased substantially in the last 4 years, to the point where it represented the majority (58% and 65% in periods 4 and 5). Non–coplanar fixed conformal beams with spine-based ExacTrac image guidance were used to treat 51.7% of all patients and VMAT with tumor-based cone-beam CT image guidance was used for 48.3%. VMAT was used for 92.8% and 100% of treatments in periods 4 and 5, respectively.
Although there is a large body of published literature dealing with lung SBRT outcomes, trends in the clinical use of lung SBRT have not been so well described. Although this is a single-center study, the sample size is large, which minimizes the impact of possible inaccuracies in individual data points, and the consistency of the treatment paradigm and decision making facilitates the detection of trends. Despite the increasing number of radiotherapy departments offering lung SBRT in The Netherlands, now approximately two thirds of all centers, a steady increase in patient volume was observed during the first 8 years. This would be in keeping with the introduction and diffusion of this new technique into routine clinical practice, and the tendency to treat patients who might previously have gone untreated.5 Although period 5 was slightly shorter than the others, the reduction in patients treated would be consistent with the widespread national availability of peripheral lung SBRT. The stable percentage of patients with PS of 2 or better is in keeping with the consistent application of institutional selection criteria by the tumor boards. The lower median CCI and higher FEV1 in patients classified as medically operable also support consistency in decision making. The trend toward younger and fitter patients coincides with the increase in patients being treated for metastatic disease.
Despite the proportion of good PS (0 - 1) among patients and the trend toward younger patients, the majority are still considered to be medically inoperable. In addition, the number with pathologic proof of malignancy remains a minority.11 The decision to obtain a pathologic diagnosis will vary among patients. The multidisciplinary tumor board makes an assessment of the risks and benefits of invasive diagnostic procedures and takes into account the high probability of malignancy in patients with a growing, metabolically active lesion in a country with a low incidence of benign fluorodeoxyglucose positron emission tomography positive lung nodules.12 The predominance of peripheral lesions being treated reflects the initial evidence base supporting lung SBRT for such lesions.9 It is therefore noteworthy that the proportion of treatments classified as central has remained relatively stable from the beginning of the program. The concerns about increased toxicity with central lung SBRT were proactively addressed at our center by implementing risk-adapted dose-fractionation schedules and regularly evaluating outcomes.10 With increasing experience, as SBRT was used to treat larger and more central tumors, a 12-fraction scheme was introduced as an extension of the risk-adapted protocol. An appropriate level of caution is needed when treating central, larger, and multiple tumors as normal organ constraints are less well established.13 The results of the prospective multicenter phase I/II RTOG 0813 study for central tumors are currently awaited. The qualitative reduction in median tumor diameter has coincided with a trend to treat more metastatic lesions and with the growing interest in using SBRT to treat patients with low-volume metastatic disease.14 The shift to using VMAT reflects the emergence of new technology that may help increase the efficiency of treatment.15
In summary, we have observed longitudinal trends in patient number, age, performance status, treatment indication, tumor size, dose fractionation, technology, and technique over the last 10 years of lung SBRT in routine clinical practice. With growing numbers of elderly patients with early-stage NSCLC and changing paradigms in the management of metastatic disease, this type of data may be useful for radiotherapy services planning.
The VUmc Department of Radiation Oncology has research collaborations with Varian Medical Systems, and Brainlab.
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