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Clinical outcome and predictors of survival and pneumonitis after stereotactic ablative radiotherapy for stage I non-small cell lung cancer

Clinical outcome and predictors of survival and pneumonitis after stereotactic ablative... Background: Stereotactic ablative radiotherapy (SABR) can achieve excellent local control rates in early-stage non- small cell lung cancer (NSCLC) and has emerged as a standard treatment option for patients who cannot undergo surgery or those with isolated recurrences. However, factors that may predict toxicity or survival are largely unknown. We sought here to identify predictors of survival and pneumonitis after SABR for NSCLC in a relatively large single-institution series. Methods: Subjects were 130 patients with stage I NSCLC treated with four-dimensional computed tomography (4D CT) –planned, on-board volumetric image–guided SABR to 50 Gy in 4 fractions. Disease was staged by positron emission tomography/computed tomography (PET/CT) and scans were obtained again at the second follow-up after SABR. Results: At a median follow-up time of 26 months, the 2-year local control rate was 98.5%. The median overall survival (OS) time was 60 months, and OS rates were 93.0% at 1 year, 78.2% at 2 years, and 65.3% at 3 years. No patient experienced grade 4–5 toxicity; 15 had radiation pneumonitis (12 [9.3%] grade 2 and 3 [2.3%] grade 3). Performance status, standardized uptake value (SUV) on staging PET/CT, tumor histology, and disease operability max were associated with OS on univariate analysis, but only staging SUV was independently predictive on max multivariate analysis (P = 0.034). Dosimetric factors were associated with radiation pneumonitis on univariate analysis, but only mean ipsilateral lung dose ≥9.14 Gy was significant on multivariate analysis (P = 0.005). Conclusions: OS and radiation pneumonitis after SABR for stage I NSCLC can be predicted by staging PET SUV max and ipsilateral mean lung dose, respectively. Keywords: Stereotactic body radiotherapy, Stereotactic ablative radiotherapy, Non-small cell lung cancer, F-fluorodeoxyglucose positron emission tomography, Toxicity, Predictive factors * Correspondence: jychang@mdanderson.org Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA Full list of author information is available at the end of the article © 2012 Chang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chang et al. Radiation Oncology 2012, 7:152 Page 2 of 10 http://www.ro-journal.com/content/7/1/152 Background within 2 cm of the bronchial tree or mediastinal struc- Lung cancer is the leading cause of cancer death tures were considered central; all others were considered throughout the world and accounts for 28% of all cancer peripheral. deaths in the United States [1]. Approximately 15%–20% of patients with non-small cell lung cancer (NSCLC) Treatment planning present with early or localized disease that could be trea- Techniques for patient immobilization and treatment ted surgically [2,3]. Stereotactic ablative radiotherapy planning are described elsewhere [6,12]. Briefly, patients (SABR), also known as stereotactic body radiotherapy were immobilized while supine with a customized vac- (SBRT), can achieve local control rates exceeding 90% as uum immobilization bag extending from the head to the well as promising survival rates in such cases when a pelvis. Four-dimensional (4D) CT images were obtained biologically effective dose (BED) of more than 100 Gy is in all cases. Gross tumor volumes (GTVs) were deli- delivered to the planning target volume (PTV) [3-11]. neated by using maximum intensity projection of 4D CT SABR has emerged as a standard treatment option for and modified by visual verification at different breathing stage I disease in patients who cannot undergo surgery phases. The path of movement of the GTV during the for medical reasons [3-7] and for isolated recurrences of respiratory cycle was the internal gross tumor volume NSCLC [6,12,13]. However, the information about fac- (iGTV) [20]. The clinical target volume (CTV) was cre- tors that may predict survival and pneunonitis after ated by expanding the iGTV by 8 mm isotropically, with SABR is limited because of the heterogeneity of the borders edited clinically. A 3-mm margin was added to patients and dose regimens [13-19]. CTV to account for set-up errors, thereby creating the In this report, we reported clinical outcome and used PTV. No additional margins were used between the long-term follow-up data to identify potentially predict- PTV and the block edge. Three-dimensional conformal ive factors for survival and pneumonitis among 130 SABR plans were optimized using 6 to 12 coplanar or patients with stage I NSCLC treated with SABR to non-coplanar 6-MV photon beams. SABR was pre- 50 Gy delivered in 4 fractions over 4 consecutive days scribed to a dose of 50 Gy to the PTV between the 75% (BED 112.5 Gy). and 90% isodose lines, which had been created via Pin- nacle calculation algorithms with heterogeneity correc- Methods tion, and delivered in 4 fractions over 4 consecutive Study design days. Typically, the lower prescription isodose line was We retrospectively analyzed 130 patients who had been chosen when the proximity of critical normal structures prospectively enrolled in either a phase II clinical proto- mandated a compromise to the PTV, and therefore a col on image-guided SABR (n = 46) or in our SABR pro- higher dose to the tumor center and sharper dose gradi- gram (n = 84) according to the same protocol guidelines ents were required. Normal tissue dose-volume con- at The University of Texas MD Anderson Cancer Center straints were based on BED calculations and our between February 2005 and December 2009. Reasons for previous clinical findings of the toxicity of SABR not being enrolled in the phase II protocol included pa- [6,12,21] and are shown in Table 1. Violations to the tient or insurance refusal, not having had the required constraints for the spinal cord, esophagus, and brachial brain magnetic resonance imaging (MRI) or computed plexus were not allowed; constraints on other normal tomography (CT), or not having signed the protocol- tissues were judged on the basis of clinical target cover- specific informed consent forms within the required age. Typically, when the tumor was close to a critical time. All patients provided written informed consent to structure, a compromise in PTV coverage was consid- participate. Eligibility criteria included cytologically or ered acceptable. In any situation, however, the iGTV biopsy-proven stage I NSCLC (T <5 cm, N0, M0) and plus a margin of 5 mm was required to receive at least inability or lack of desire to undergo surgery. Criteria for 95% of the prescribed dose. Patients with lesions very medical inoperability were having a baseline forced ex- close/ abutting to critical structures and whose normal piratory volume in 1 second (FEV1) or lung diffusion tissue dose volume constraints can’t be achieved were capacity <40% of predicted values or severe diabetes treated with different dose regimens. Day-to-day varia- mellitus, cardiovascular disease, cerebral disease, or pul- tions in patient placement were minimized by volumet- monary hypertension. Thirty-four patients whose disease ric imaging of the treatment couch with either a CT-on- was considered borderline operable by thoracic surgeons rails or a cone-beam CT system. had declined surgery. Disease in all patients was staged with chest CT and positron emission tomography (PET)/ Follow-up CT (Discovery ST; GE Healthcare, Milwaukee, WI) Follow-up care consisted of CT imaging and clinical within 3 months before SABR and follow ups. The PET/ examination every 3 months for the first 2 years after CT scan condition was described previously (26). Lesions SABR, every 6 months for the third year, and annually Chang et al. Radiation Oncology 2012, 7:152 Page 3 of 10 http://www.ro-journal.com/content/7/1/152 Table 1 Critical organ dose-volume limits for stereotactic Table 2 Patient characteristics (n = 130) ablative radiotherapy to 50 Gy given in 4 fractions Characteristic Value or No. of patients (%) Organ, Limit, and Volume Maximum dose limits Age, years Esophagus Median 74 D 35 Gy max Range 48–91 ≤ 1cm 30 Gy FEV1, % of predicted ≤ 5cm 20 Gy Median 42 Brachial plexus Range 15–123 D 40 Gy max Staging PET SUV max ≤ 1cm 35 Gy Median 6.20 ≤ 5cm 30 Gy Range 0.5–32.6 Trachea Gross tumor volume, cm D 45 Gy max Median 9.6 ≤ 1cm 35 Gy Range 0.7–51.47 ≤ 5cm 30 Gy Planning target volume, cm Main bronchus and bronchial tree Median 73.2 ≤ 1cm 40 Gy Range 23.36–109.64 ≤ 5cm 35 Gy Sex Heart Men 67 (51.5) ≤ 1cm 40 Gy Women 63 (48.5) ≤ 5cm 35 Gy COPD stage Total lung volume* 0-II 73 (56) V < 20% of total lung volume 20 Gy(RBE) III-IV 57 (44) V < 30% of total lung volume 10 Gy(RBE) History of other types of cancer V < 40% of total lung volume 5 Gy(RBE) Yes 37 (28.5) Major vessels No 93 (71.5) D 45 Gy max ECOG performance status ≤ 1cm 40 Gy 0 or 1 81 (62) ≤ 5cm 35 Gy 2 or 3 49 (38) Skin Lung cancer stage ≤ 1cm 35 Gy IA (T1) 112 (86) ≤ 5cm 30 Gy IB (T2) 18 (14) Chest wall Lung cancer histology ≤ 10 cm 45 Gy Squamous cell carcinoma 36 (28) ≤ 30 cm 35 Gy Adenocarcinoma 58 (45) Spinal cord NSCLC not specified 36 (28) D 25 Gy max Disease status ≤ 5cm 20 Gy Medically inoperable 96 (74) *Defined as right plus left lungs minus the gross tumor volume. Operable 34 (26) Tumor location thereafter. All patients underwent posttreatment fluoro- Peripheral 119 (91.5) deoxyglucose (FDG) PET scans at MD Anderson for dis- Central 11 (8.5) ease staging and at the first or second follow-up visit Abbreviations: FEV1, forced expiratory volume in 1 second; PET, positron (median interval 4.3 months, range 2–7.6 months; the emission toography; SUVmax, maximum standardized uptake value; COPD, wide range reflected unexpectedly interrupted follow-up) chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; and as clinically indicated thereafter. Rates and times of overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), distant metastasis-free Chang et al. Radiation Oncology 2012, 7:152 Page 4 of 10 http://www.ro-journal.com/content/7/1/152 Number of Patients at Risk: OS 130 119 62 28 13 5 PFS 130 100 49 24 11 5 Figure 1 Overall survival (OS) and progression-free survival (PFS) for 130 patients treated with stereotactic ablative radiotherapy (SABR) for stage I NSCLC. survival (DMFS), local failure, regional failure, and dis- then entered in multivariable Cox proportional hazards tant metastasis were calculated from the date of comple- regression analysis. tion of SABR to the last available follow-up. The time of To analyze predictive factors for RP, continuous vari- recurrence was the time at which the first image (PET/ ables such as age, FEV1, GTV, PTV, and dosimetric data CT or CT) showed abnormalities. Local failure was were divided at the medians and analyzed as nominal defined as progressive abnormalities on CT images categorical variables. Total lung volume was defined as corresponding to one or more FDG-avid lesions on right plus left lungs minus the GTV, and ipsilateral lung PET scans; positive biopsy findings within the PTV was defined as the lung containing the lesion to be trea- plus a 1-cm margin; or lesions that appeared in the ted minus the GTV. Comparisons were made with two- same lobe after SABR. Recurrence appearing in differ- sided Pearson’s chi-square tests. P values <0.05 were ent lobes was scored as distant metastasis. Regional considered statistically significant. Characteristics found failure was defined as intrathoracic lymph node relapse to be significant by univariate analysis were then entered outside the PTV. Toxicities, including RP, were scored in a stepwise multiple binary logistic regression analysis according to the National Cancer Institute Common to identify independent predictive factors. Terminology Criteria for Adverse Events v3.0. Results Statistical analyses Patient characteristics, survival, and patterns of failure Data were analyzed with SAS (SAS Institute, Cary, NC) after SABR statistical software, version 9.2. To analyze predictive Characteristics of the 130 patients treated with SABR factors for OS, PFS, LFFS, and DMFS after SABR, con- are listed in Table 2. At a median follow-up time of tinuous variables such as age, FEV1, maximum standar- 26 months (range, 6–78 months), the median OS time dized uptake value (SUV ) on staging PET scans, and for all patients was 60 months (55 months for patients max GTV were discretely divided at the sample median and with medically inoperable disease vs. >60 months [not then analyzed as nominal categorical variables. We used reached] for those with borderline operable disease). the Kaplan-Meier method to estimate survival curves One patient developed local failure concurrent with dis- and the log-rank test to compare the curves. P values < tant metastasis, and one patient developed isolated local 0.05 were considered statistically significant. Character- failure that was salvaged surgically. At 2 years, the istics found to be significant by univariate analysis were local control rate was 98.5%; the regional lymph node Chang et al. Radiation Oncology 2012, 7:152 Page 5 of 10 http://www.ro-journal.com/content/7/1/152 Table 3 Univariate analysis of predictive factors for recurrence rate was 8.5% (11/130), and the isolated overall and progression-free survival regional lymph node recurrence rate was 6.9% (9/130). Overall Survival Progression-Free Survival Thirty patients (23.1%) developed DM, making it the dom- inant pattern of treatment failure. Overall and progression- Characteristic HR (95% CI) P value HR (95% CI) P Value free survival rates for all patients are illustrated in Figure 1. Age, years OS rates were 93.0% at 1 year, 78.2% at 2 years, and 65.3% ≥ 74 1 at 3 years; the corresponding PFS rates were 78.4%, 60.5%, < 74 1.87 (0.93–3.78) 0.080 1.42 (0.83–2.44) 0.196 and 55.0%. With regard to disease control, LFFS rates were Sex 93.7% at 1 year, 88.8% at 2 years, and 88.8% at 3 years; the Male 1 corresponding DMFS rates were 89.1%, 79.4%, and 73.1%. Female 0.93 (0.48–1.82) 0.875 0.86 (0.51–1.47) 0.588 Toxicity associated with SABR COPD stage No patient experienced grade 4 or 5 toxicity, even those 0–II 1 with centrally located lesions. Chest wall pain was experi- III–IV 0.75 (0.37-1.54) 0.413 0.66 (0.37-1.17) 0.594 enced by 12 patients (11 [8.5%] grade 2 and 1 [0.8%] History of other type of cancer grade 3), with median time to onset 8 months after SABR Yes 1 (range 0–27 months). Eight patients (6.2%) had grade 2 or 3 dermatitis (median onset time 2 months, range No 1.55 (0.78–3.09) 0.211 1.29 (0.74–2.24) 0.374 0–10 months). Fifteen patients developed RP (12 [9.2%] ECOG performance status grade 2 and 3 [2.3%] grade 3), with median time to onset 0–11 4 months (range 1–11 months). Only 2 patients (1.5%) 2–3 2.03 (1.04–3.95) 0.037 1.68 (0.99–2.85) 0.050 developed esophagitis (both grade 1) with the esophageal Lung cancer stage dose-volume constraints used here. No definitive radiation- IA (T1) 1 induced cardiovascular toxicity was noted. IB (T2) 1.28 (0.53–3.08) 0.586 1.11 (0.54–2.27) 0.776 Predictors of OS and PFS after SABR Lung cancer histology Next we explored whether SUV or other variables max Non-squamous 1 could predict clinical outcomes after SABR for stage I Squamous 1.16 (1.01–1.34) 0.043 1.09 (0.97–1.22) 0.173 disease. Univariate analysis revealed that staging PET Staging PET SUV max SUV (dichotomized at the median 6.2, P = 0.028), max < 6.2 1 Eastern Cooperative Oncology Group (ECOG) perform- ance status (P = 0.037), tumor histology (P = 0.043), and ≥ 6.2 2.10 (1.01-4.33) 0.028 1.81 (1.05–3.10) 0.032 whether the disease was considered medically operable Gross tumor volume, cm or not (P = 0.036) were significantly associated with OS < 9.6 1 (Table 3); performance status and staging PET SUV max ≥ 9.6 1.55 (0.79–3.05) 0.204 1.42 (0.84–2.42) 0.195 were also associated with PFS after SABR. Multivariate Disease status Cox regression analysis showed that staging PET SUV- Medically inoperable 1 was the only independent significant predictor of OS max (hazard ratio [HR] 2.15; 95% confidence interval [CI] Operable 0.36 (0.14–0.94) 0.036 0.51 (0.26–1.02) 0.055 1.06–4.34; P = 0.034): patients whose PET SUV at sta- max Tumor location ging was less than the median 6.2 had higher rates of Peripheral 1 long-term OS than did those with staging PET SUV max Central 0.97 (0.34–2.76) 0.954 0.89 (0.35–2.25) 0.809 ≥6.2 (Figure 2, P = 0.034). No significant predictors were Radiation pneumonitis identified for LFFS and DMFS. No 1 Risk factors for grade 2–3RP Yes 1.19 (0.65–2.16) 0.571 0.92 (0.43–1.94) 0.819 Univariate analysis of patient characteristics and dosi- Abbreviations: HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; metric factors dichotomized at the medians (Table 4) PET, positron emission tomography; SUVmax, maximum standardized uptake revealed that many dosimetric variables (lung volumes value. receiving anywhere from 5 Gy to 40 Gy and mean lung doses [MLDs]) were associated with the incidence of analysis with stepwise selection of variables found to be grade 2–3RP(P < 0.05) but that other patient character- significant in univariate analysis showed that only an MLD istics (e.g., FEV1, tumor location, performance status, and to the ipsilateral lung ≥9.14 Gy (the median value) was GTV) were not. Multivariate binary logistic regression associated with grade 2–3 RP (odds ratio [OR] 18.86; 95% Chang et al. Radiation Oncology 2012, 7:152 Page 6 of 10 http://www.ro-journal.com/content/7/1/152 Number of Patients at Risk: SUV<6.2 62 59 31 14 6 3 SUV 6.2 68 53 28 11 4 1 Figure 2 Overall survival according to maximum standardized uptake value (SUV ) on staging PET/CT scans. max CI 2.398–148.27; P = 0.005). Interestingly, when we used Having other predictive tools in addition to traditional Cox regression analysis to take onset time of pneumonitis factors such as age, disease stage, performance status, into consideration, ipsilateral lung V40 become the most tumor histology, and comorbidities to predict outcome be- significant predictor for grade 2–3 RP, indicating high dose fore therapy is begun would be valuable both for the (40 Gy) may be correlated with grade 2–3 RP developed choice of initial treatment and for identifying which within certain time after SABR. patients might benefit from additional systemic therapy. Several surgical series [22-25] showed that pretreatment Discussion SUV had predictive value in stage I NSCLC treated max We found that SABR to a dose of 50 Gy delivered in 4 surgically; one of these studies, an analysis of 136 patients, fractions (BED 112.5 Gy) produced a 2-year local con- found that a pretreatment SUV >5.5 predicted worse max trol rate of 98.5%, a median OS time of 60 months, recurrence and survival [23]. However, information on and minimal toxicity (minimal grade 3 and no grade 4 SUV and SABR remains very limited at this time or 5). SUV on the staging PET/CT scan was the [14-16,26]. Hoopes et al. [14] retrospectively evaluated max only predictor of OS, with SUV less than the me- the predictive value of PET SUV in a prospective phase max max dian 6.2 being associated with better survival. The I/II dose escalation clinical trial in which SABR was given MLD to the ipsilateral lung (i.e., the lung containing to 58 patients at doses of 24 to 72 Gy in 3 fractions. Local the lesion to be treated, minus the GTV) was the only control rates in that trial ranged from <70% to >95% for significant predictor of grade 2 or 3 RP. Among 130 the various dose groups, and pretreatment PET SUV max patients, only two (<2%) experienced LF, one of which was not found to predict local control or survival. Another occurred simultaneously with DM. The thoracic lymph retrospective study by Burdick and colleagues [16] showed node recurrence rate of 8.5% was consistent with most that pretreatment SUV did not predict regional failure, max reported findings [3-11], and DM remained the dom- distant failure, or survival; however, the 72 patients in that inant pattern of failure. This finding, common in other study had also been treated with a wide range of radiation studies as well [3-7,9], underscores the need for novel doses (60 Gy in 3 fractions, 50 Gy in 5 fractions, or 50 Gy systemic treatments to reduce the incidence of distant in 10 fractions), and only 68.1% of patients had had failure. Molecular markers may also be helpful for biopsy-proven NSCLC. identifying patients who may benefit from adjuvant The relative strengths of our study were our relatively chemotherapy. large population (n = 130) and our inclusion of only Chang et al. Radiation Oncology 2012, 7:152 Page 7 of 10 http://www.ro-journal.com/content/7/1/152 Table 4 Univariate analysis of patient and dosimetric characteristics and risk of radiation pneumonitis (n = 130) Characteristic Grade 0–1 RP Grade 2–3RP P Value No. of Patients (%) No. of Patients (%) Sex 0.882 Male 59 (51.3) 8 (53.3) Female 56 (48.7) 7 (46.7) Age 0.310 ≥74 years 62 (53.9) 6 (40.0) <74 years 53 (46.1) 9 (60.0) COPD stage 0.154 0–II 62 (53.9) 11 (73.3) III–IV 53 (46.1) 4 (26.7) History of other type of cancer 0.440 Yes 34 (29.6) 3 (20.0) No 81 (70.4) 12 (80.0) ECOG score before SABR 0.711 0–1 71 (61.7) 10 (66.7) 2–3 44 (38.3) 5 (33.3) Gross tumor volume, cm 0.375 ≥9.6 55 (47.8) 9 (60.0) <9.6 60 (52.2) 6 (40.0) Planning target volume, cm 0.151 ≥73.2 54 (47.0) 10 (66.7) <73.2 61 (53.0) 5 (33.3) Tumor location 0.471 Peripheral 106 (92.2) 13 (86.7) Central 9 (7.8) 2 (13.3) Total lung volume* V < 0.001 ≥ 20.2% 51 (44.3) 14 (93.3) < 20.2% 64 (55.7) 1 (6.7) V < 0.001 ≥ 14.3% 51 (44.3) 14 (93.3) < 14.3% 64 (55.7) 1 (6.7) V 0.003 ≥ 11.0% 52 (45.2) 13 (86.7) < 11.0% 63 (54.8) 2 (13.3) V 0.055 ≥ 8.5% 54 (47.0) 11 (73.3) < 8.5% 61 (53.0) 4 (26.7) V 0.055 ≥ 6.4% 54 (47.0) 11 (73.3) < 6.4% 61 (53.0) 4 (26.7) V 0.003 ≥ 5.0% 52 (45.2) 13 (86.7) < 5.0% 63 (54.8) 2 (13.3) Chang et al. Radiation Oncology 2012, 7:152 Page 8 of 10 http://www.ro-journal.com/content/7/1/152 Table 4 Univariate analysis of patient and dosimetric characteristics and risk of radiation pneumonitis (n = 130) (Continued) V 0.003 ≥ 3.9% 52 (45.2) 13 (86.7) < 3.9% 63 (54.8) 2 (13.3) V 0.013 ≥ 3.1% 53 (46.1) 12 (80.0) < 3.1% 62 (53.9) 3 (20.0) Mean dose to total lung volume 0.013 ≥ 5.05 Gy 53 (46.1) 12 (80.0) < 5.05 Gy 62 (53.9) 3 (20.0) Ipsilateral lung volume† V < 0.001 ≥ 37.7% 51 (44.3) 14 (93.3) < 37.7% 64 (55.7) 1 (6.7) V < 0.001 ≥ 28.5% 51 (44.3) 14 (93.3) < 28.5% 64 (55.7) 1 (6.7) V < 0.001 ≥ 21.9% 51 (44.3) 14 (93.3) < 21.9% 64 (55.7) 1 (6.7) V < 0.001 ≥ 16.9% 51 (44.3) 14 (93.3) < 16.9% 64 (55.7) 1 (6.7) V 0.003 ≥ 13.1% 52 (45.2) 13 (86.7) < 13.1% 63 (54.8) 2 (13.3) V 0.013 ≥ 10.4% 53 (46.1) 12 (80.0) < 10.4% 62 (53.9) 3 (20.0) V 0.003 ≥ 8.1% 52 (45.2) 13 (86.7) < 8.1% 63 (54.8) 2 (13.3) V 0.013 ≥ 6.3% 53 (46.1) 12 (80.0) < 6.3% 62 (53.9) 3 (20.0) Mean dose to ipsilateral lung volume < 0.001 ≥9.14 Gy 51 (44.3) 14 (93.3) <9.14 Gy 64 (55.7) 1 (6.7) * Defined as right plus left lungs minus the gross tumor volume. † Defined as the lung containing the lesion to be treated, minus the gross tumor volume. Abbreviations: RP, radiation pneumonitis; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; SABR, stereotactic ablative radiotherapy; Vx, volume of lung receiving ≥x Gy; GTV, gross tumor volume; MLD, mean lung dose. patients with biopsy-proven, PET/CT-determined stage I both before and after treatment at the same institution. (T1N0M0, T <5 cm) NSCLC who had all been treated Our multivariate analyses indicated that having a staging with the same dose and who all underwent PET/CT PET SUV level >6.2 predicted worse OS, and patients max Chang et al. Radiation Oncology 2012, 7:152 Page 9 of 10 http://www.ro-journal.com/content/7/1/152 with this feature may benefit from systemic therapy to re- <9.14 Gy, only 1 (1.5%) had grade 2–3RP (P < 0.001). duce the likelihood of distant failure, which still remains This finding is consistent with those of Guckenberger problematic. The predictive value of PET SUV may well and colleagues, who also reported a correlation between depend on the dose regimen used and perhaps some pa- irradiated ipsilateral lung volume and SABR-induced RP tient characteristics that we did not consider. Additional [30]. In addition, ipsilateral V40 appears to be correlated studies are needed to validate our observations. with grade 2–3 RP when the onset times of RP were As we and others reported before, PET SUVs mea- considered. The specific dose cutoffs may be different sured after SABR may be useful for detecting recurrence using different dose regimens. Our cutoffs should be (19, 26). In the current study, the staging PET SUV considered only when the same or similar SABR dose max levels for the 2 patients who developed local recurrence regimens are used. To minimize the MLD to the ipsilat- were 1.8 and 6.5 but had increased to 9.8 and 7.2, re- eral lung, one should consider using optimal image guid- spectively, by 1 year after SABR. However, among the ance to reduce the set-up margin; prescribing the dose other 128 patients who did not experience local recur- to the lower isodose line rather than the higher one; and rence in this study, 32 patients had a SUV >3 and 8 not using an additional margin between the PTV to the max patients had a SUV >5 within 6 months after SABR. block edge. max Thus it seems likely that PET images obtained within Abbreviations 6 months after SABR may have a high false-positive rate. 4D: Four-dimensional; BED: Biologically equivalent dose; CI: Confidence Indeed, we and others have noted that PET images with interval; CT: Computed tomography; DMFS: Distant metastasis-free survival; ECOG: Eastern cooperative oncology group; FDG: Fluorodeoxyglucose; SUV >5 more than 6–12 months after SABR could indi- FEV1: Forced expiratory volume in 1 second; GTV: Gross tumor volume; cate possible local recurrence, but biopsy is still recom- HR: Hazard ratio; iGTV: Internal gross tumor volume; LFFS: Local facilure-free mended for confirmation [−25, 26], particularly when survival; MLD: Mean lung dose; MRI: Magnetic resonance imaging; NSCLC: Non-small cell lung cancer; OR: Odds ratio; OS: Overall survival; salvage surgery is planned [27]. PET: Positron emission tomography; PFS: Progression-free survival; The most common side effect of SABR in our study was PTV: Planning target volume; RP: Radiation pneumonitis; SABR: Stereotactic chest-wall pain (12 patients, or 9.3%). A previous study ablative radiotherapy; SUV : Maximum standardized uptake value. max from our group showed that limiting the chest-wall V Competing interests to < 30 cm reduced the incidence of chest-wall pain to 5% The authors declare that they have no competing interests. [21]. However, for lesions next to the chest wall, we rec- ommend that >95% of the GTV plus a 5-mm margin re- Authors’ contributions JYC conceived the study, oversaw the study design and data collection, and ceive at least the full prescribed dose, even if the chest- 3 wrote the manuscript; HL helped to conceive and coordinate the study, to wall dose exceeds 35 Gy to 30 cm . In our practice, 35 Gy collect data, and to write the manuscript; JYC and PB designed the to 50 cm is allowed for lesions close to the chest wall. treatment plans and supervised their delivery; JYC and HL carried out the data and statistical analysis; and RK, ZL, JW, RJM, JAR, and SGS provided data RP can be a severe or even fatal side effect of irradi- and participated in the coordination and design of the study. All authors ation for lesions within 2 cm of the bronchial tree trea- read and approved the final manuscript. ted with 54 Gy delivered in 3 fractions [4]. Reports of dose-volume analyses in SABR-induced RP have been Funding Dr. Chang received a Research Scholar Award from the Radiological Society limited [13,17,18,28-30]. Barriger and others reported of North America and a Career Development Award from MD Anderson correlations between total lung MLD (<4 Gy vs. >4 Gy), Cancer Center’s Specialized Programs of Research Excellence in Lung Cancer lung V (<4% vs. >4%) and grade 2–4 RP among from the National Cancer Institute (P50 CA70907). This research was also supported by Cancer Center Support Grant CA016672 to MD Anderson. patients treated with SABR to total doses of 42–60 Gy given in 8- to 20-Gy fractions [31]. Matsuo found the as- Acknowledgments sociation between V25 and symptomatic RP after SABR We thank the members of the Thoracic Radiation Oncology section in the Division of Radiation Oncology for their support of this clinical study and Ms. (17) . With our dose regimen (50 Gy in 4 fractions), our Christine Wogan of the Division of Radiation Oncology for editorial normal-tissue dose-volume constraints (Table 1), and assistance. our use of 4D CT-based treatment planning and volu- Author details metric on-board image-guided SABR delivery, we did Departments of Radiation Oncology, The University of Texas MD Anderson not observe any grade 4–5 RP. We saw no difference in Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA. Department of RP between central versus peripheral lesions when nor- Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Thoracic and Cardiovascular Surgery, The mal tissue dose volume constraints were respected and University of Texas MD Anderson Cancer Center, Houston, TX, USA. inappropriate cases were excluded, and only 3 patients (2.3%) experienced grade 3 RP. 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Matsuo Y, Shibuya K, Nakamura M, Narabayashi M, Sakanaka K, Ueki N, Miyagi K, Norihisa Y, Mizowaki T, Nagata Y, Hiraoka M: Dose-volume metrics associated with radiation pneumonitis after stereotactic body radiation therapy for lung cancer. Int J Radiat Oncol Biol Phys 2012, 15(4): e545–e549. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Clinical outcome and predictors of survival and pneumonitis after stereotactic ablative radiotherapy for stage I non-small cell lung cancer

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Springer Journals
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Copyright © 2012 by Chang et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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10.1186/1748-717X-7-152
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22963661
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Abstract

Background: Stereotactic ablative radiotherapy (SABR) can achieve excellent local control rates in early-stage non- small cell lung cancer (NSCLC) and has emerged as a standard treatment option for patients who cannot undergo surgery or those with isolated recurrences. However, factors that may predict toxicity or survival are largely unknown. We sought here to identify predictors of survival and pneumonitis after SABR for NSCLC in a relatively large single-institution series. Methods: Subjects were 130 patients with stage I NSCLC treated with four-dimensional computed tomography (4D CT) –planned, on-board volumetric image–guided SABR to 50 Gy in 4 fractions. Disease was staged by positron emission tomography/computed tomography (PET/CT) and scans were obtained again at the second follow-up after SABR. Results: At a median follow-up time of 26 months, the 2-year local control rate was 98.5%. The median overall survival (OS) time was 60 months, and OS rates were 93.0% at 1 year, 78.2% at 2 years, and 65.3% at 3 years. No patient experienced grade 4–5 toxicity; 15 had radiation pneumonitis (12 [9.3%] grade 2 and 3 [2.3%] grade 3). Performance status, standardized uptake value (SUV) on staging PET/CT, tumor histology, and disease operability max were associated with OS on univariate analysis, but only staging SUV was independently predictive on max multivariate analysis (P = 0.034). Dosimetric factors were associated with radiation pneumonitis on univariate analysis, but only mean ipsilateral lung dose ≥9.14 Gy was significant on multivariate analysis (P = 0.005). Conclusions: OS and radiation pneumonitis after SABR for stage I NSCLC can be predicted by staging PET SUV max and ipsilateral mean lung dose, respectively. Keywords: Stereotactic body radiotherapy, Stereotactic ablative radiotherapy, Non-small cell lung cancer, F-fluorodeoxyglucose positron emission tomography, Toxicity, Predictive factors * Correspondence: jychang@mdanderson.org Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA Full list of author information is available at the end of the article © 2012 Chang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chang et al. Radiation Oncology 2012, 7:152 Page 2 of 10 http://www.ro-journal.com/content/7/1/152 Background within 2 cm of the bronchial tree or mediastinal struc- Lung cancer is the leading cause of cancer death tures were considered central; all others were considered throughout the world and accounts for 28% of all cancer peripheral. deaths in the United States [1]. Approximately 15%–20% of patients with non-small cell lung cancer (NSCLC) Treatment planning present with early or localized disease that could be trea- Techniques for patient immobilization and treatment ted surgically [2,3]. Stereotactic ablative radiotherapy planning are described elsewhere [6,12]. Briefly, patients (SABR), also known as stereotactic body radiotherapy were immobilized while supine with a customized vac- (SBRT), can achieve local control rates exceeding 90% as uum immobilization bag extending from the head to the well as promising survival rates in such cases when a pelvis. Four-dimensional (4D) CT images were obtained biologically effective dose (BED) of more than 100 Gy is in all cases. Gross tumor volumes (GTVs) were deli- delivered to the planning target volume (PTV) [3-11]. neated by using maximum intensity projection of 4D CT SABR has emerged as a standard treatment option for and modified by visual verification at different breathing stage I disease in patients who cannot undergo surgery phases. The path of movement of the GTV during the for medical reasons [3-7] and for isolated recurrences of respiratory cycle was the internal gross tumor volume NSCLC [6,12,13]. However, the information about fac- (iGTV) [20]. The clinical target volume (CTV) was cre- tors that may predict survival and pneunonitis after ated by expanding the iGTV by 8 mm isotropically, with SABR is limited because of the heterogeneity of the borders edited clinically. A 3-mm margin was added to patients and dose regimens [13-19]. CTV to account for set-up errors, thereby creating the In this report, we reported clinical outcome and used PTV. No additional margins were used between the long-term follow-up data to identify potentially predict- PTV and the block edge. Three-dimensional conformal ive factors for survival and pneumonitis among 130 SABR plans were optimized using 6 to 12 coplanar or patients with stage I NSCLC treated with SABR to non-coplanar 6-MV photon beams. SABR was pre- 50 Gy delivered in 4 fractions over 4 consecutive days scribed to a dose of 50 Gy to the PTV between the 75% (BED 112.5 Gy). and 90% isodose lines, which had been created via Pin- nacle calculation algorithms with heterogeneity correc- Methods tion, and delivered in 4 fractions over 4 consecutive Study design days. Typically, the lower prescription isodose line was We retrospectively analyzed 130 patients who had been chosen when the proximity of critical normal structures prospectively enrolled in either a phase II clinical proto- mandated a compromise to the PTV, and therefore a col on image-guided SABR (n = 46) or in our SABR pro- higher dose to the tumor center and sharper dose gradi- gram (n = 84) according to the same protocol guidelines ents were required. Normal tissue dose-volume con- at The University of Texas MD Anderson Cancer Center straints were based on BED calculations and our between February 2005 and December 2009. Reasons for previous clinical findings of the toxicity of SABR not being enrolled in the phase II protocol included pa- [6,12,21] and are shown in Table 1. Violations to the tient or insurance refusal, not having had the required constraints for the spinal cord, esophagus, and brachial brain magnetic resonance imaging (MRI) or computed plexus were not allowed; constraints on other normal tomography (CT), or not having signed the protocol- tissues were judged on the basis of clinical target cover- specific informed consent forms within the required age. Typically, when the tumor was close to a critical time. All patients provided written informed consent to structure, a compromise in PTV coverage was consid- participate. Eligibility criteria included cytologically or ered acceptable. In any situation, however, the iGTV biopsy-proven stage I NSCLC (T <5 cm, N0, M0) and plus a margin of 5 mm was required to receive at least inability or lack of desire to undergo surgery. Criteria for 95% of the prescribed dose. Patients with lesions very medical inoperability were having a baseline forced ex- close/ abutting to critical structures and whose normal piratory volume in 1 second (FEV1) or lung diffusion tissue dose volume constraints can’t be achieved were capacity <40% of predicted values or severe diabetes treated with different dose regimens. Day-to-day varia- mellitus, cardiovascular disease, cerebral disease, or pul- tions in patient placement were minimized by volumet- monary hypertension. Thirty-four patients whose disease ric imaging of the treatment couch with either a CT-on- was considered borderline operable by thoracic surgeons rails or a cone-beam CT system. had declined surgery. Disease in all patients was staged with chest CT and positron emission tomography (PET)/ Follow-up CT (Discovery ST; GE Healthcare, Milwaukee, WI) Follow-up care consisted of CT imaging and clinical within 3 months before SABR and follow ups. The PET/ examination every 3 months for the first 2 years after CT scan condition was described previously (26). Lesions SABR, every 6 months for the third year, and annually Chang et al. Radiation Oncology 2012, 7:152 Page 3 of 10 http://www.ro-journal.com/content/7/1/152 Table 1 Critical organ dose-volume limits for stereotactic Table 2 Patient characteristics (n = 130) ablative radiotherapy to 50 Gy given in 4 fractions Characteristic Value or No. of patients (%) Organ, Limit, and Volume Maximum dose limits Age, years Esophagus Median 74 D 35 Gy max Range 48–91 ≤ 1cm 30 Gy FEV1, % of predicted ≤ 5cm 20 Gy Median 42 Brachial plexus Range 15–123 D 40 Gy max Staging PET SUV max ≤ 1cm 35 Gy Median 6.20 ≤ 5cm 30 Gy Range 0.5–32.6 Trachea Gross tumor volume, cm D 45 Gy max Median 9.6 ≤ 1cm 35 Gy Range 0.7–51.47 ≤ 5cm 30 Gy Planning target volume, cm Main bronchus and bronchial tree Median 73.2 ≤ 1cm 40 Gy Range 23.36–109.64 ≤ 5cm 35 Gy Sex Heart Men 67 (51.5) ≤ 1cm 40 Gy Women 63 (48.5) ≤ 5cm 35 Gy COPD stage Total lung volume* 0-II 73 (56) V < 20% of total lung volume 20 Gy(RBE) III-IV 57 (44) V < 30% of total lung volume 10 Gy(RBE) History of other types of cancer V < 40% of total lung volume 5 Gy(RBE) Yes 37 (28.5) Major vessels No 93 (71.5) D 45 Gy max ECOG performance status ≤ 1cm 40 Gy 0 or 1 81 (62) ≤ 5cm 35 Gy 2 or 3 49 (38) Skin Lung cancer stage ≤ 1cm 35 Gy IA (T1) 112 (86) ≤ 5cm 30 Gy IB (T2) 18 (14) Chest wall Lung cancer histology ≤ 10 cm 45 Gy Squamous cell carcinoma 36 (28) ≤ 30 cm 35 Gy Adenocarcinoma 58 (45) Spinal cord NSCLC not specified 36 (28) D 25 Gy max Disease status ≤ 5cm 20 Gy Medically inoperable 96 (74) *Defined as right plus left lungs minus the gross tumor volume. Operable 34 (26) Tumor location thereafter. All patients underwent posttreatment fluoro- Peripheral 119 (91.5) deoxyglucose (FDG) PET scans at MD Anderson for dis- Central 11 (8.5) ease staging and at the first or second follow-up visit Abbreviations: FEV1, forced expiratory volume in 1 second; PET, positron (median interval 4.3 months, range 2–7.6 months; the emission toography; SUVmax, maximum standardized uptake value; COPD, wide range reflected unexpectedly interrupted follow-up) chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; and as clinically indicated thereafter. Rates and times of overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), distant metastasis-free Chang et al. Radiation Oncology 2012, 7:152 Page 4 of 10 http://www.ro-journal.com/content/7/1/152 Number of Patients at Risk: OS 130 119 62 28 13 5 PFS 130 100 49 24 11 5 Figure 1 Overall survival (OS) and progression-free survival (PFS) for 130 patients treated with stereotactic ablative radiotherapy (SABR) for stage I NSCLC. survival (DMFS), local failure, regional failure, and dis- then entered in multivariable Cox proportional hazards tant metastasis were calculated from the date of comple- regression analysis. tion of SABR to the last available follow-up. The time of To analyze predictive factors for RP, continuous vari- recurrence was the time at which the first image (PET/ ables such as age, FEV1, GTV, PTV, and dosimetric data CT or CT) showed abnormalities. Local failure was were divided at the medians and analyzed as nominal defined as progressive abnormalities on CT images categorical variables. Total lung volume was defined as corresponding to one or more FDG-avid lesions on right plus left lungs minus the GTV, and ipsilateral lung PET scans; positive biopsy findings within the PTV was defined as the lung containing the lesion to be trea- plus a 1-cm margin; or lesions that appeared in the ted minus the GTV. Comparisons were made with two- same lobe after SABR. Recurrence appearing in differ- sided Pearson’s chi-square tests. P values <0.05 were ent lobes was scored as distant metastasis. Regional considered statistically significant. Characteristics found failure was defined as intrathoracic lymph node relapse to be significant by univariate analysis were then entered outside the PTV. Toxicities, including RP, were scored in a stepwise multiple binary logistic regression analysis according to the National Cancer Institute Common to identify independent predictive factors. Terminology Criteria for Adverse Events v3.0. Results Statistical analyses Patient characteristics, survival, and patterns of failure Data were analyzed with SAS (SAS Institute, Cary, NC) after SABR statistical software, version 9.2. To analyze predictive Characteristics of the 130 patients treated with SABR factors for OS, PFS, LFFS, and DMFS after SABR, con- are listed in Table 2. At a median follow-up time of tinuous variables such as age, FEV1, maximum standar- 26 months (range, 6–78 months), the median OS time dized uptake value (SUV ) on staging PET scans, and for all patients was 60 months (55 months for patients max GTV were discretely divided at the sample median and with medically inoperable disease vs. >60 months [not then analyzed as nominal categorical variables. We used reached] for those with borderline operable disease). the Kaplan-Meier method to estimate survival curves One patient developed local failure concurrent with dis- and the log-rank test to compare the curves. P values < tant metastasis, and one patient developed isolated local 0.05 were considered statistically significant. Character- failure that was salvaged surgically. At 2 years, the istics found to be significant by univariate analysis were local control rate was 98.5%; the regional lymph node Chang et al. Radiation Oncology 2012, 7:152 Page 5 of 10 http://www.ro-journal.com/content/7/1/152 Table 3 Univariate analysis of predictive factors for recurrence rate was 8.5% (11/130), and the isolated overall and progression-free survival regional lymph node recurrence rate was 6.9% (9/130). Overall Survival Progression-Free Survival Thirty patients (23.1%) developed DM, making it the dom- inant pattern of treatment failure. Overall and progression- Characteristic HR (95% CI) P value HR (95% CI) P Value free survival rates for all patients are illustrated in Figure 1. Age, years OS rates were 93.0% at 1 year, 78.2% at 2 years, and 65.3% ≥ 74 1 at 3 years; the corresponding PFS rates were 78.4%, 60.5%, < 74 1.87 (0.93–3.78) 0.080 1.42 (0.83–2.44) 0.196 and 55.0%. With regard to disease control, LFFS rates were Sex 93.7% at 1 year, 88.8% at 2 years, and 88.8% at 3 years; the Male 1 corresponding DMFS rates were 89.1%, 79.4%, and 73.1%. Female 0.93 (0.48–1.82) 0.875 0.86 (0.51–1.47) 0.588 Toxicity associated with SABR COPD stage No patient experienced grade 4 or 5 toxicity, even those 0–II 1 with centrally located lesions. Chest wall pain was experi- III–IV 0.75 (0.37-1.54) 0.413 0.66 (0.37-1.17) 0.594 enced by 12 patients (11 [8.5%] grade 2 and 1 [0.8%] History of other type of cancer grade 3), with median time to onset 8 months after SABR Yes 1 (range 0–27 months). Eight patients (6.2%) had grade 2 or 3 dermatitis (median onset time 2 months, range No 1.55 (0.78–3.09) 0.211 1.29 (0.74–2.24) 0.374 0–10 months). Fifteen patients developed RP (12 [9.2%] ECOG performance status grade 2 and 3 [2.3%] grade 3), with median time to onset 0–11 4 months (range 1–11 months). Only 2 patients (1.5%) 2–3 2.03 (1.04–3.95) 0.037 1.68 (0.99–2.85) 0.050 developed esophagitis (both grade 1) with the esophageal Lung cancer stage dose-volume constraints used here. No definitive radiation- IA (T1) 1 induced cardiovascular toxicity was noted. IB (T2) 1.28 (0.53–3.08) 0.586 1.11 (0.54–2.27) 0.776 Predictors of OS and PFS after SABR Lung cancer histology Next we explored whether SUV or other variables max Non-squamous 1 could predict clinical outcomes after SABR for stage I Squamous 1.16 (1.01–1.34) 0.043 1.09 (0.97–1.22) 0.173 disease. Univariate analysis revealed that staging PET Staging PET SUV max SUV (dichotomized at the median 6.2, P = 0.028), max < 6.2 1 Eastern Cooperative Oncology Group (ECOG) perform- ance status (P = 0.037), tumor histology (P = 0.043), and ≥ 6.2 2.10 (1.01-4.33) 0.028 1.81 (1.05–3.10) 0.032 whether the disease was considered medically operable Gross tumor volume, cm or not (P = 0.036) were significantly associated with OS < 9.6 1 (Table 3); performance status and staging PET SUV max ≥ 9.6 1.55 (0.79–3.05) 0.204 1.42 (0.84–2.42) 0.195 were also associated with PFS after SABR. Multivariate Disease status Cox regression analysis showed that staging PET SUV- Medically inoperable 1 was the only independent significant predictor of OS max (hazard ratio [HR] 2.15; 95% confidence interval [CI] Operable 0.36 (0.14–0.94) 0.036 0.51 (0.26–1.02) 0.055 1.06–4.34; P = 0.034): patients whose PET SUV at sta- max Tumor location ging was less than the median 6.2 had higher rates of Peripheral 1 long-term OS than did those with staging PET SUV max Central 0.97 (0.34–2.76) 0.954 0.89 (0.35–2.25) 0.809 ≥6.2 (Figure 2, P = 0.034). No significant predictors were Radiation pneumonitis identified for LFFS and DMFS. No 1 Risk factors for grade 2–3RP Yes 1.19 (0.65–2.16) 0.571 0.92 (0.43–1.94) 0.819 Univariate analysis of patient characteristics and dosi- Abbreviations: HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; metric factors dichotomized at the medians (Table 4) PET, positron emission tomography; SUVmax, maximum standardized uptake revealed that many dosimetric variables (lung volumes value. receiving anywhere from 5 Gy to 40 Gy and mean lung doses [MLDs]) were associated with the incidence of analysis with stepwise selection of variables found to be grade 2–3RP(P < 0.05) but that other patient character- significant in univariate analysis showed that only an MLD istics (e.g., FEV1, tumor location, performance status, and to the ipsilateral lung ≥9.14 Gy (the median value) was GTV) were not. Multivariate binary logistic regression associated with grade 2–3 RP (odds ratio [OR] 18.86; 95% Chang et al. Radiation Oncology 2012, 7:152 Page 6 of 10 http://www.ro-journal.com/content/7/1/152 Number of Patients at Risk: SUV<6.2 62 59 31 14 6 3 SUV 6.2 68 53 28 11 4 1 Figure 2 Overall survival according to maximum standardized uptake value (SUV ) on staging PET/CT scans. max CI 2.398–148.27; P = 0.005). Interestingly, when we used Having other predictive tools in addition to traditional Cox regression analysis to take onset time of pneumonitis factors such as age, disease stage, performance status, into consideration, ipsilateral lung V40 become the most tumor histology, and comorbidities to predict outcome be- significant predictor for grade 2–3 RP, indicating high dose fore therapy is begun would be valuable both for the (40 Gy) may be correlated with grade 2–3 RP developed choice of initial treatment and for identifying which within certain time after SABR. patients might benefit from additional systemic therapy. Several surgical series [22-25] showed that pretreatment Discussion SUV had predictive value in stage I NSCLC treated max We found that SABR to a dose of 50 Gy delivered in 4 surgically; one of these studies, an analysis of 136 patients, fractions (BED 112.5 Gy) produced a 2-year local con- found that a pretreatment SUV >5.5 predicted worse max trol rate of 98.5%, a median OS time of 60 months, recurrence and survival [23]. However, information on and minimal toxicity (minimal grade 3 and no grade 4 SUV and SABR remains very limited at this time or 5). SUV on the staging PET/CT scan was the [14-16,26]. Hoopes et al. [14] retrospectively evaluated max only predictor of OS, with SUV less than the me- the predictive value of PET SUV in a prospective phase max max dian 6.2 being associated with better survival. The I/II dose escalation clinical trial in which SABR was given MLD to the ipsilateral lung (i.e., the lung containing to 58 patients at doses of 24 to 72 Gy in 3 fractions. Local the lesion to be treated, minus the GTV) was the only control rates in that trial ranged from <70% to >95% for significant predictor of grade 2 or 3 RP. Among 130 the various dose groups, and pretreatment PET SUV max patients, only two (<2%) experienced LF, one of which was not found to predict local control or survival. Another occurred simultaneously with DM. The thoracic lymph retrospective study by Burdick and colleagues [16] showed node recurrence rate of 8.5% was consistent with most that pretreatment SUV did not predict regional failure, max reported findings [3-11], and DM remained the dom- distant failure, or survival; however, the 72 patients in that inant pattern of failure. This finding, common in other study had also been treated with a wide range of radiation studies as well [3-7,9], underscores the need for novel doses (60 Gy in 3 fractions, 50 Gy in 5 fractions, or 50 Gy systemic treatments to reduce the incidence of distant in 10 fractions), and only 68.1% of patients had had failure. Molecular markers may also be helpful for biopsy-proven NSCLC. identifying patients who may benefit from adjuvant The relative strengths of our study were our relatively chemotherapy. large population (n = 130) and our inclusion of only Chang et al. Radiation Oncology 2012, 7:152 Page 7 of 10 http://www.ro-journal.com/content/7/1/152 Table 4 Univariate analysis of patient and dosimetric characteristics and risk of radiation pneumonitis (n = 130) Characteristic Grade 0–1 RP Grade 2–3RP P Value No. of Patients (%) No. of Patients (%) Sex 0.882 Male 59 (51.3) 8 (53.3) Female 56 (48.7) 7 (46.7) Age 0.310 ≥74 years 62 (53.9) 6 (40.0) <74 years 53 (46.1) 9 (60.0) COPD stage 0.154 0–II 62 (53.9) 11 (73.3) III–IV 53 (46.1) 4 (26.7) History of other type of cancer 0.440 Yes 34 (29.6) 3 (20.0) No 81 (70.4) 12 (80.0) ECOG score before SABR 0.711 0–1 71 (61.7) 10 (66.7) 2–3 44 (38.3) 5 (33.3) Gross tumor volume, cm 0.375 ≥9.6 55 (47.8) 9 (60.0) <9.6 60 (52.2) 6 (40.0) Planning target volume, cm 0.151 ≥73.2 54 (47.0) 10 (66.7) <73.2 61 (53.0) 5 (33.3) Tumor location 0.471 Peripheral 106 (92.2) 13 (86.7) Central 9 (7.8) 2 (13.3) Total lung volume* V < 0.001 ≥ 20.2% 51 (44.3) 14 (93.3) < 20.2% 64 (55.7) 1 (6.7) V < 0.001 ≥ 14.3% 51 (44.3) 14 (93.3) < 14.3% 64 (55.7) 1 (6.7) V 0.003 ≥ 11.0% 52 (45.2) 13 (86.7) < 11.0% 63 (54.8) 2 (13.3) V 0.055 ≥ 8.5% 54 (47.0) 11 (73.3) < 8.5% 61 (53.0) 4 (26.7) V 0.055 ≥ 6.4% 54 (47.0) 11 (73.3) < 6.4% 61 (53.0) 4 (26.7) V 0.003 ≥ 5.0% 52 (45.2) 13 (86.7) < 5.0% 63 (54.8) 2 (13.3) Chang et al. Radiation Oncology 2012, 7:152 Page 8 of 10 http://www.ro-journal.com/content/7/1/152 Table 4 Univariate analysis of patient and dosimetric characteristics and risk of radiation pneumonitis (n = 130) (Continued) V 0.003 ≥ 3.9% 52 (45.2) 13 (86.7) < 3.9% 63 (54.8) 2 (13.3) V 0.013 ≥ 3.1% 53 (46.1) 12 (80.0) < 3.1% 62 (53.9) 3 (20.0) Mean dose to total lung volume 0.013 ≥ 5.05 Gy 53 (46.1) 12 (80.0) < 5.05 Gy 62 (53.9) 3 (20.0) Ipsilateral lung volume† V < 0.001 ≥ 37.7% 51 (44.3) 14 (93.3) < 37.7% 64 (55.7) 1 (6.7) V < 0.001 ≥ 28.5% 51 (44.3) 14 (93.3) < 28.5% 64 (55.7) 1 (6.7) V < 0.001 ≥ 21.9% 51 (44.3) 14 (93.3) < 21.9% 64 (55.7) 1 (6.7) V < 0.001 ≥ 16.9% 51 (44.3) 14 (93.3) < 16.9% 64 (55.7) 1 (6.7) V 0.003 ≥ 13.1% 52 (45.2) 13 (86.7) < 13.1% 63 (54.8) 2 (13.3) V 0.013 ≥ 10.4% 53 (46.1) 12 (80.0) < 10.4% 62 (53.9) 3 (20.0) V 0.003 ≥ 8.1% 52 (45.2) 13 (86.7) < 8.1% 63 (54.8) 2 (13.3) V 0.013 ≥ 6.3% 53 (46.1) 12 (80.0) < 6.3% 62 (53.9) 3 (20.0) Mean dose to ipsilateral lung volume < 0.001 ≥9.14 Gy 51 (44.3) 14 (93.3) <9.14 Gy 64 (55.7) 1 (6.7) * Defined as right plus left lungs minus the gross tumor volume. † Defined as the lung containing the lesion to be treated, minus the gross tumor volume. Abbreviations: RP, radiation pneumonitis; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; SABR, stereotactic ablative radiotherapy; Vx, volume of lung receiving ≥x Gy; GTV, gross tumor volume; MLD, mean lung dose. patients with biopsy-proven, PET/CT-determined stage I both before and after treatment at the same institution. (T1N0M0, T <5 cm) NSCLC who had all been treated Our multivariate analyses indicated that having a staging with the same dose and who all underwent PET/CT PET SUV level >6.2 predicted worse OS, and patients max Chang et al. Radiation Oncology 2012, 7:152 Page 9 of 10 http://www.ro-journal.com/content/7/1/152 with this feature may benefit from systemic therapy to re- <9.14 Gy, only 1 (1.5%) had grade 2–3RP (P < 0.001). duce the likelihood of distant failure, which still remains This finding is consistent with those of Guckenberger problematic. The predictive value of PET SUV may well and colleagues, who also reported a correlation between depend on the dose regimen used and perhaps some pa- irradiated ipsilateral lung volume and SABR-induced RP tient characteristics that we did not consider. Additional [30]. In addition, ipsilateral V40 appears to be correlated studies are needed to validate our observations. with grade 2–3 RP when the onset times of RP were As we and others reported before, PET SUVs mea- considered. The specific dose cutoffs may be different sured after SABR may be useful for detecting recurrence using different dose regimens. Our cutoffs should be (19, 26). In the current study, the staging PET SUV considered only when the same or similar SABR dose max levels for the 2 patients who developed local recurrence regimens are used. To minimize the MLD to the ipsilat- were 1.8 and 6.5 but had increased to 9.8 and 7.2, re- eral lung, one should consider using optimal image guid- spectively, by 1 year after SABR. However, among the ance to reduce the set-up margin; prescribing the dose other 128 patients who did not experience local recur- to the lower isodose line rather than the higher one; and rence in this study, 32 patients had a SUV >3 and 8 not using an additional margin between the PTV to the max patients had a SUV >5 within 6 months after SABR. block edge. max Thus it seems likely that PET images obtained within Abbreviations 6 months after SABR may have a high false-positive rate. 4D: Four-dimensional; BED: Biologically equivalent dose; CI: Confidence Indeed, we and others have noted that PET images with interval; CT: Computed tomography; DMFS: Distant metastasis-free survival; ECOG: Eastern cooperative oncology group; FDG: Fluorodeoxyglucose; SUV >5 more than 6–12 months after SABR could indi- FEV1: Forced expiratory volume in 1 second; GTV: Gross tumor volume; cate possible local recurrence, but biopsy is still recom- HR: Hazard ratio; iGTV: Internal gross tumor volume; LFFS: Local facilure-free mended for confirmation [−25, 26], particularly when survival; MLD: Mean lung dose; MRI: Magnetic resonance imaging; NSCLC: Non-small cell lung cancer; OR: Odds ratio; OS: Overall survival; salvage surgery is planned [27]. PET: Positron emission tomography; PFS: Progression-free survival; The most common side effect of SABR in our study was PTV: Planning target volume; RP: Radiation pneumonitis; SABR: Stereotactic chest-wall pain (12 patients, or 9.3%). A previous study ablative radiotherapy; SUV : Maximum standardized uptake value. max from our group showed that limiting the chest-wall V Competing interests to < 30 cm reduced the incidence of chest-wall pain to 5% The authors declare that they have no competing interests. [21]. However, for lesions next to the chest wall, we rec- ommend that >95% of the GTV plus a 5-mm margin re- Authors’ contributions JYC conceived the study, oversaw the study design and data collection, and ceive at least the full prescribed dose, even if the chest- 3 wrote the manuscript; HL helped to conceive and coordinate the study, to wall dose exceeds 35 Gy to 30 cm . In our practice, 35 Gy collect data, and to write the manuscript; JYC and PB designed the to 50 cm is allowed for lesions close to the chest wall. treatment plans and supervised their delivery; JYC and HL carried out the data and statistical analysis; and RK, ZL, JW, RJM, JAR, and SGS provided data RP can be a severe or even fatal side effect of irradi- and participated in the coordination and design of the study. All authors ation for lesions within 2 cm of the bronchial tree trea- read and approved the final manuscript. ted with 54 Gy delivered in 3 fractions [4]. Reports of dose-volume analyses in SABR-induced RP have been Funding Dr. Chang received a Research Scholar Award from the Radiological Society limited [13,17,18,28-30]. Barriger and others reported of North America and a Career Development Award from MD Anderson correlations between total lung MLD (<4 Gy vs. >4 Gy), Cancer Center’s Specialized Programs of Research Excellence in Lung Cancer lung V (<4% vs. >4%) and grade 2–4 RP among from the National Cancer Institute (P50 CA70907). This research was also supported by Cancer Center Support Grant CA016672 to MD Anderson. patients treated with SABR to total doses of 42–60 Gy given in 8- to 20-Gy fractions [31]. Matsuo found the as- Acknowledgments sociation between V25 and symptomatic RP after SABR We thank the members of the Thoracic Radiation Oncology section in the Division of Radiation Oncology for their support of this clinical study and Ms. (17) . With our dose regimen (50 Gy in 4 fractions), our Christine Wogan of the Division of Radiation Oncology for editorial normal-tissue dose-volume constraints (Table 1), and assistance. our use of 4D CT-based treatment planning and volu- Author details metric on-board image-guided SABR delivery, we did Departments of Radiation Oncology, The University of Texas MD Anderson not observe any grade 4–5 RP. We saw no difference in Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA. Department of RP between central versus peripheral lesions when nor- Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Thoracic and Cardiovascular Surgery, The mal tissue dose volume constraints were respected and University of Texas MD Anderson Cancer Center, Houston, TX, USA. inappropriate cases were excluded, and only 3 patients (2.3%) experienced grade 3 RP. 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Radiation Oncology – Springer Journals

Published: Sep 10, 2012

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