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Reduction in Tumor Volume by Cone Beam Computed Tomography Predicts Overall Survival in Non-Small Cell Lung Cancer Treated With Chemoradiation Therapy
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Reduction in Tumor Volume by Cone Beam Computed Tomography Predicts Overall Survival in Non-Small Cell Lung Cancer Treated With Chemoradiation Therapy Salma K. Jabbour, MD,* Sinae Kim, PhD,y,z Syed A. Haider, MS,* Xiaoting Xu, MD,*,x Alson Wu, MS,* Sujani Surakanti, MD,k Joseph Aisner, MD,k John Langenfeld, MD,{ Ning J. Yue, PhD,* Bruce G. Haffty, MD,* and Wei Zou, PhD* *Department of Radiation Oncology and yDivision of Biometrics, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School; zDepartment of Biostatistics, School of Public Health, Rutgers University; xDepartment of Radiation Oncology, The First Affiliated Hospital of Soochow University, Soochow, China; kDivision of Medical Oncology; {Division of Surgery, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers The State University of New Jersey, New Brunswick, New Jersey Received Oct 7, 2014, and in revised form Jan 10, 2015. Accepted for publication Feb 9, 2015.
Summary We hypothesized that tumor volume response as measured with weekly cone beam computed tomography (CBCT), obtained as part of routine care during chemoradiation therapy, would predict the survival of unresectable non-small cell lung cancer patients. We found that tumor volume reduction, from start to end of treatment, was associated with longer overall survival. Additional prospective study of CBCT is warranted to
Purpose: We sought to evaluate whether tumor response using cone beam computed tomography (CBCT) performed as part of the routine care during chemoradiation therapy (CRT) could forecast the outcome of unresectable, locally advanced, non-small cell lung cancer (NSCLC). Methods and Materials: We manually delineated primary tumor volumes (TV) of patients with NSCLC who were treated with radical CRT on days 1, 8, 15, 22, 29, 36, and 43 on CBCTs obtained as part of the standard radiation treatment course. Percentage reductions in TV were calculated and then correlated to survival and pattern of recurrence using Cox proportional hazard models. Clinical information including histologic subtype was also considered in the study of such associations. Results: We evaluated 38 patients with a median follow-up time of 23.4 months. The median TV reduction was 39.3% (range, 7.3%-69.3%) from day 1 (D1) to day 43 (D43) CBCTs. Overall survival was associated with TV reduction from D1 to D43 (hazard ratio [HR] 0.557, 95% CI 0.39-0.79, PZ.0009). For every 10% decrease in TV from D1 to D43, the risk of death decreased by 44.3%. For patients whose TV decreased 39.3 or <39.3%, log-rank test demonstrated a separation in survival (PZ.02), with median survivals of 31 months versus 10 months, respectively. Neither
Reprint requests to: Salma K. Jabbour, MD, 195 Little Albany St, New Brunswick, NJ 08903. Tel: (732) 253-3939; E-mail: jabbousk@cinj. rutgers.edu Int J Radiation Oncol Biol Phys, Vol. 92, No. 3, pp. 627e633, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.02.017
Presented at the Fifty-Fifth Annual Meeting of the American Society for Radiation Oncology, September 22-25, Atlanta, Georgia. Conflict of interest: none.
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determine whether based on tumor response, treatment could be tailored to aid in improving outcomes.
local recurrence (HR 0.791, 95% CI 0.51-1.23, PZ.29), nor distant recurrence (HR 0.78, 95% CI 0.57-1.08, PZ.137) correlated with TV decrease from D1 to D43. Histologic subtype showed no impact on our findings. Conclusions: TV reduction as determined by CBCT during CRT as part of routine care predicts post-CRT survival. Such knowledge may justify intensification of RT or application of additional therapies. Assessment of genomic characteristics of these tumors may permit a better understanding of behavior or prediction of therapeutic outcomes. Ó 2015 Elsevier Inc. All rights reserved.
Introduction Locally advanced or inoperable non-small cell lung cancer (NSCLC) accounts for approximately 30% of all cases of NSCLC, and today these patients receive a combination of chemotherapy, radiation therapy (RT), and sometimes surgery. Most often, definitive chemoradiation therapy (CRT) is used to offer long-term survival, with expected median survival rates ranging from 14 to 17 months, and 10% to 20% long-term survival (1, 2). The addition of chemotherapy to RT concurrently offers an improvement in survival compared with sequential chemotherapy followed by RT (2-4). Determination of the outcome of CRT for locally advanced NSCLC traditionally relies on follow-up computed tomography (CT) scans, performed at regular intervals after completion of therapy. To date, no imaging method reliably predicts the posttreatment behavior, the individual’s NSCLC response to CRT, or the eventual outcome of this treatment. Modern RT now affords notable advances in the oncologic care of patients with NSCLC. For example, improvements in treatment planning, position verification, and image guidance reduce potential toxicities while improving survival rates (5). As part of standard RT image guidance, kilovoltage (kV) or megavoltage (MV) plain films, orthogonal films, or kV or MV cone beam computed tomography (CBCT) images are now often obtained daily on the linear accelerator (6) to accurately align the patient’s positioning for proper radiation delivery to the tumor. The use of CBCT as part of image-guided RT (IGRT) substantially reduces margin requirements (7) and is thus essential for target localization, especially in the setting of dose escalation (8). CBCT images are registered to the patient’s pretreatment imaging CT simulation planning session to align the geometry of the tumor for accurate radiation delivery. The CBCT permits 3-dimensional alignment of the radiation beams to the primary disease and organs at risk. In contrast, plain films or orthogonal kV or MV views obtained during CRT are nonvolumetric imaging methods that can be aligned primarily to osseous anatomy rather than to soft tissue anatomy in a 2dimensional fashion. A potential additional benefit of CBCT is thus the ability to view the ongoing response of the tumor to CRT.
We hypothesized that the use of weekly CBCTs would provide an understanding of the response to CRT and that this response would predict patients’ survival and tumor biology.
Methods and Materials Thirty-eight patients with locally advanced, biopsy-proven, unresectable, stage II-III NSCLC whom we treated with CRT, and whom we also followed up with CBCTs performed as part of their standard RT course, were eligible for inclusion in this Institutional Review Boarddapproved study. All patients were staged with chest CT scan, positron emission tomography (PET)/CT scan, brain magnetic resonance imaging, and mediastinal lymph node biopsy. Data collection included age, performance status, pathology reports, clinical stage of lung cancer, treatment information, and follow-up data including first site of recurrence, time to recurrence, and survival. Patients received definitive concurrent CRT over 6 to 7 weeks in daily (5 days/week) fractions of 180 to 200 cGy for a median total dose of 6210 cGy (range, 52007400 cGy) targeted to the primary tumor. Table 1 indicates the patient demographics.
Chemoradiation therapy Patients were placed in a supine position with arms up on the CIVCO Body Pro-Lok System (Kalona, IA). A motion study using fluoroscopy allowed limitation of TV motion to 1 cm. Then the patient was transferred to the CT simulator (General Electric LightSpeed 16), where a 4dimensional CT scan with intravenous contrast medium, breathing coaching, and retrospective gating (Varian RPM System, Varian Medical Systems, Palo Alto, CA) were performed. The 4-dimensional CT scan with 10-phase CT scans through the breathing cycle permitted the delineation of an internal target volume on the CT average scan. RT was planned as per Radiation Therapy Oncology Group (RTOG) 0617. The chemotherapy regimens consisted of intravenous weekly paclitaxel (45 mg/m2/week) with carboplatin (AUC Z 2/week) or cisplatin 50 mg/m2/day on days 1, 8, 29, 36 and etoposide, 50 mg/m2/d on days 1 to 5 and 29 to 33.
Volume 92 Number 3 2015 Table 1
CBCT in unresectable lung cancer
Patient demographics and treatment details Characteristic
Age (y) Mean (SD)/median (range) Gender Female Male Stage II IIIA IIIB Histology Squamous cell carcinoma Adenocarcinoma Poorly differentiated carcinoma Concurrent chemotherapy Carboplatin þ paclitaxel Cisplatin þ etoposide Cisplatin Cisplatin þ pemetrexed Carboplatin Paclitaxel Initial TV (at day 1) Mean (SD) Median (range) Patterns of failure Local recurrence Distant recurrence Local þ distant recurrence
n (%) 67.3 (8.85)/68 (52-81) 15 (39.5) 23 (60.5) 3 (7.9) 17 (44.7) 18 (47.4) 18 (47.4) 14 (36.8) 6 (15.8) 19 15 1 1 1 1
(50) (39.5) (2.6) (2.6) (2.6) (2.6)
133.6 (168.8) 76.5 (6.99-765.7) 10 (26.3) 21 (55.3) 4 (10.5)
Abbreviations: SD Z standard deviation; TV Z tumor volume.
CBCT imaging Before RT was begun, kV CBCT images of the tumor area were acquired immediately before delivery of each radiation fraction to align the TV, as part of the standard course of RT. Of these, we used weekly CBCT images (days 1, 8, 15, 22, 29, 36, and 43 of treatment) for this study to evaluate changes in primary TV during the course of CRT. We obtained follow-up chest CT scans 6 to 8 weeks after the completion of CRT and then every 3 months for the first year, every 6 months for 2 years, and yearly thereafter. The CT scans were evaluated by thoracic radiologists and further reviewed by medical and radiation oncologists. The CBCT contours were generated manually for this study; to maintain consistency, lung window settings were used for all images, and contours were reviewed by 2 or more of the study authors. Figure 1 depicts an example of a contoured slice of a CBCT image. By contouring a given tumor mass on successive slices (along the z axis) of a single CBCT image set, we obtained a 3-dimensional representation of the primary tumor that allowed us to calculate the TV. This procedure was repeated for each weekly CBCT image set for each patient, resulting in TV values over the course of treatment. The follow-up diagnostic imaging was imported into the treatment planning system
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and fused with the CT simulation scan, and the diagnostic scan was contoured. We did not encounter significant difficulty in differentiating TVs from radiation changes when fused to the original treatment plan, given that radiation changes were generally mild at an early time point, without significant consolidation.
Statistical analysis We used a linear mixed model with random intercepts to study the changes of TV values over the treatment and follow-up duration. The TV values were transformed to a natural logarithm scale for normality. Time was treated as a continuous variable, and natural log-transformed TV measurements at day 1 (D1) as a baseline covariate. Reduction of TV from baseline to the last day of treatment was calculated as follows: 100*(TV from CBCT D1 e TV from CBCT D43)/(TV from CBCT D1). Missing TV measurements at D43 were imputed using multiple imputations with 100 repetitions. To investigate the association between TV reduction and time-to-event outcome (overall survival [OS] and time to local recurrence [LR], distant recurrence [DR], or any recurrence), we used a univariate Cox proportional hazard regression model with reduction as a covariate. Hazard ratios (HR) with 95% confidence interval (CI) were estimated using the model. Because of the limited sample size, model selection was not performed. Clinical predictors considered in the multivariate model included histologic subtype, type of chemotherapy, or stage. We included these predictors in the multivariate setting based on their univariate results. Cox proportional hazard model was in the multivariate setting also. Proportionality assumptions were evaluated and held true. Differences in OS and time to DR and LR were assessed by log-rank test, stratified according to TV reduction (median of TV reduction vs < median of TV reduction). Kaplan-Meier curves were also provided. Pearson correlation coefficients were calculated to study linear association in natural log-transformed TVs between the 2 time points (D1 vs D43 and also D43 vs follow-up CT scans) and were tested for statistical significance. A paired t test was performed to compare means of natural transformed TV at D43 and at follow-up. All hypothesis-testing procedures were done in 2-sided fashion at a significance level of 5%, and P<.05 was considered statistically significant. Analyses were performed using SAS 9.2 (Cary, NC) and R 3.1.0.
Results Thirty-eight patients with NSCLC treated with definitive CRT were included. The median follow-up time was 23.4 months. Patients with stage II disease were treated with definitive CRT when they were considered inoperable because of medical comorbidities or if they required a pneumonectomy that would not have been tolerated
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Fig. 1. Example of tumor volume (TV) contouring. (a) Computed tomographic (CT) image before treatment course showing primary TV. (b) Cone beam CT (CBCT) of patient on day 1 of treatment, with TV contoured. (c) CBCT of patient on day 43 of treatment; contour indicates TV shrinkage. because of underlying lung dysfunction. Ninety-two percent of patients received platinum-doublet therapy concurrently with RT. Single-agent chemotherapy was administered if the patient could not tolerate platinumdoublet therapy concurrently with radiation. There was no difference in survival for patients (nZ4) who discontinued treatment prematurely having received <60 Gy compared with those who completed 60 Gy (PZ.74).
TV reduction over treatment period From D1 to D43, median TV shrinkage was 39.3% (range, 7.3%-69.3%), with the TVs decreasing consistently over the treatment periods (Fig. 2) rather than at a particular time point during CRT. TV reduction occurred in all cases during CRT. Weekly natural log-transformed TV values decreased by an average of 0.091 (95% CI Z 0.102 to 0.081; P<.0001) adjusted for natural log-transformed TV measured at D1. TV reduction was slightly more considerable from D1 to D8 and D29 to D36, with log-transformed TV reductions of 0.114 (PZ.008) and 0.118 (PZ.004), respectively.
TV reduction and overall survival The median OS was 17 months. The OS was significantly associated with a reduction in primary TV from D1 to D43 (PZ.0009; HR 0.6; 95% CI 0.39-0.79). For every 10%
decrease in primary TV from D1 to D43, the risk of death decreased by 44.3% (Fig. 3). Patients were grouped based on TV reduction median of TV reduction versus
Distant and local recurrences Local recurrence was experienced by 26.3% of patients as the first site of failure. The median time to LR was 12.3 months (mean, 16.1 months; standard equivalent, 2.0 months). We found no statistically significant association between TV reduction from D1 to D43 and risk for development of LR (PZ.29; HR 0.79, CI 0.51 to 1.23). Approximately 14% of patients with adenocarcinoma (ACA) demonstrated LR, whereas 44.4% of patients with squamous cell carcinoma (SCC) experienced LR, and no patients with poorly differentiated carcinomas (PDC) experienced LR. Fifty-five percent of patients experienced DR as the first site of failure. The median time to DR was 18.9 months
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Fig. 2. Spaghetti plot of tumor volume against treatment cycle (day 1 to day 43) for all patients. Patients who received 30 fractions of radiation therapy had cone beam computed tomography (CBCT) only on day 36. Day 43 CBCTs were obtained for patients who received a seventh week of chemoradiation therapy. TV Z tumor volume. (mean 21.3, standard equivalent 2.8 months). We found no statistically significant association between TV reductions from D1 to D43 and risk for the development of DR. Seventy-one percent of ACA patients experienced DR as the first site of treatment failure, in contrast to 33% in patients with PDC and 50% of patients with SCC.
Histologic subtype outcomes Histologic subtype (SCC, ACA, PDC) did not demonstrate any association with survival (PZ.74) or progression-free survival (log-rank test; PZ.74). We found no significant
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Fig. 4. Kaplan-Meier curves for overall survival associated with median tumor volume reduction 39.3% or <39.3% from day 1 to day 43. GTV Z gross tumor volume. association between histology and TV reduction from D1 to D43 (PZ.88). Likewise, we found no statistically significant association between TV reduction (from D1 to D43) and progression-free survival (PZ.24). There was no difference among the histologic subtypes in terms of rate of TV reduction (PZ.56).
Chemotherapy type On univariate analysis, there was no impact of chemotherapy type on TV reduction from D1 to D43 (PZ.33). OS and time to LR or DR with either cisplatin-based or carboplatin-based therapies were not different (PZ.60, .19, .16, respectively). However, the carboplatin group had an improved time to recurrence of 11.5 months versus 5.8 months in the cisplatin group (PZ.04). There was no association between chemotherapy type and histology on OS (PZ.27). Multivariate analysis results showed no association between OS, DR, or any recurrence (PZ.25, 045, 0.91, respectively), and TV reduction did not change depending on type of chemotherapy. By contrast, LR and TV reduction did vary with type of chemotherapy (PZ.02); specifically, the HR for TV reduction from D1 to D43 in the cisplatin group was 0.46 (95% CI 0.26-0.83). Therefore, for every 10% increase in TV reduction from D1 to D43, the risk of LR decreased by 53.8% in the cisplatin group. Such an effect for the carboplatin cohort was not significant (HR 1.6, 95% CI 0.72-3.52).
Correlation to follow-up CT scans after CRT
Fig. 3. Kaplan-Meier overall survival curve with 95% confidence limits for this cohort.
We identified 27 patients with available follow-up CT scan data for TV measurements. We found a significant correlation of 0.86 between log-transformed TVs at D43 and TV
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(P<.0001). The means of the log-transformed TV at D43 and at follow-up were statistically different (P<.001; mean at D43 is 0.48 higher than at follow-up), consistent with continued tumor shrinkage after completion of CRT.
Discussion We herein demonstrate that CBCTs, performed as part of routine care for locally advanced NSCLC patients receiving definitive CRT, may predict patient survival outcomes using IGRT. NSCLCs also continued to reduce in volume after the last day of CRT. CBCT technology contributes negligible doses of radiation above a standard course of radiation and may provide invaluable information about a patient’s treatment course and prognosis. These results appear very enticing when placed in the context of the available literature. First, there is no currently accepted method to detect an early response to CRT for NSCLC. Currently, most rely on a restaging chest CT scan performed 6 to 8 weeks after the completion of therapy to determine the status of disease. Some investigators use PET scanning as a modality to assess tumor response after radiation-based therapy for NSCLC. PET scanning is feasible in posttreatment response assessment, and it can often differentiate tumor response from inflammatory response in the lung (9-11). In the ACRIN 6668/ RTOG 0235 clinical trial, PET scanning before and after treatment for NSCLC treated with CRT demonstrated that pretreatment standardized uptake value (SUV) peak and SUVmax were not associated with survival, whereas higher posttreatment SUVpeak and SUVmax were associated with worse survival in stage III NSCLC. SUVs did not differ greatly between the institutional versus central readings, but there were some cases with significant discrepancies, highlighting some level of operator dependency (12). Our study indicates that early imaging with CBCT as part of routine care during CRT could predict the outcome of CRT at a much earlier time point (ie, during CRT for unresectable NSCLC). Second, these results, which demonstrate the predictive value of an early response assessment, may provide the rationale for changing the treatment paradigm, including modifying treatment with intensification of RT or incorporating additional therapies. Conversely, patients with substantial early responses to CRT may be more likely to achieve pathologic complete response, which is known to occur in approximately 15% of patients treated with preoperative CRT (13), and perhaps these patients could also benefit from more intense therapy or additional agents, or could achieve comparable results with lower total RT doses. Knowledge of early responses could thus possibly permit better individualization of therapy. Other studies also assessed tumor regression during RT for NSCLC. Fox et al (14) evaluated TV changes using repeated CT during RT in 22 patients, 15 of whom received concurrent chemotherapy. This study indicated a median
International Journal of Radiation Oncology Biology Physics
parenchymal tumor reduction of 24.7% at 30 Gy and 44.3% at 50 Gy, similar to our median reduction of 39.5%. Standard CT scans during and after RT using a deformable registration model revealed progressive tumor shrinkage after RT (15), similar to our findings. Brink et al (16) used an automated model to assess TV regression using kV CBCT and showed that pronounced TV regression correlated with worse survival. However, about 30% of patients did not receive concurrent chemotherapy. In addition, only 9% of cases were manually delineated; therefore, most of the analyses relied on a nonvalidated automated model. Furthermore, this study did not correlate final TV at followup with tumor regression during RT as a final confirmation of tumor response after therapy (16). By contrast, Bral et al (17) evaluated MVCT-based assessment of NSCLC treated with 2 different radiation schemas, including a hypofractionated regimen, and in which about half of the patients received RT alone. This amount of heterogeneity makes these results difficult to interpret. Their results demonstrated superior long-term local progression-free survival for concurrent chemotherapy in patients with better treatment response (17), but there was no correlation to OS with a short median follow-up time of 18 months. In our study, there was no correlation between LR and TV reduction. In modern oncology, tumor genetics have been shown to predict a tumor’s failure pattern and longterm disease outcome (18). Our finding of TV reduction during CRT as seen on CBCTs is likely predictive of disease biology. Although LR is important in locally advanced NSCLC treated with CRT and is a major concern, the primary initial pattern of failure is distant failure in the majority of patients (19). Also, it is unclear why there was greater TV shrinkage and fewer LRs in cisplatin-treated patients but improved time to recurrence in those treated with carboplatin. A complete literature search did not elucidate any specific patterns of failure related to chemotherapy type. It is important to consider that this proposal of CBCT use is indicative of overall tumor biology and may inform clinical decision making for additional or alternative regimens depending on tumor response or lack thereof. The relatively small sample size of our study constitutes a weakness for conclusions. Nevertheless, our population represents a relatively homogeneous cohort, with similar CRT regimens (ie, standard platinum doublets and curative dose RT) and reasonable, uniform follow-up. Although our analysis was retrospective, the data were collected prospectively. Our survival rates appear very comparable with those of historical controls, and the median TV shrinkage of 39.3% in our study also appears similar to those in other series, suggesting that our data generally represent the population, but we also recognize that further study is needed. Our data support the important concept that TV reduction through the use of CRT contributes to improving OS for locally advanced NSCLC, a well-proven tenet (4, 20-22). Our study demonstrates the ability of CBCT to quantify TV reduction, and it strongly suggests that this predicts survival earlier than other means.
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A paradigm, such as ours, of early assessment of the efficacy of CRT for locally advanced NSCLC using CBCT warrants additional study in a prospective fashion with consideration of therapy assignments based on early response. Coupling such an approach with the burgeoning knowledge of biomarkers such as genomics may help determine the biological and physiologic patterns that correlate with response to CRT.
References 1. Curran WJ Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011;103:14521460. 2. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III nonsmall-cell lung cancer. J Clin Oncol 1999;17:2692-2699. 3. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-smallcell lung cancer: A randomized phase II locally advanced multimodality protocol. J Clin Oncol 2005;23:5883-5891. 4. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992;326:524-530. 5. Liao ZX, Komaki RR, Thames HD Jr., et al. Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010;76:775-781. 6. Dawson LA, Jaffray DA. Advances in image-guided radiation therapy. J Clin Oncol 2007;25:938-946. 7. Grills IS, Hugo G, Kestin LL, et al. Image-guided radiotherapy via daily online cone-beam CT substantially reduces margin requirements for stereotactic lung radiotherapy. Int J Radiat Oncol Biol Phys 2008; 70:1045-1056. 8. Purdie TG, Bissonnette JP, Franks K, et al. Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: Localization, verification, and intrafraction tumor position. Int J Radiat Oncol Biol Phys 2007;68:243-252. 9. Kong FM, Frey KA, Quint LE, et al. A pilot study of [18F]fluorodeoxyglucose positron emission tomography scans during and after radiation-based therapy in patients with non small-cell lung cancer. J Clin Oncol 2007;25:3116-3123.
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10. Pottgen C, Levegrun S, Theegarten D, et al. Value of 18F-fluoro-2deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 2006;12:97-106. 11. Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl J Med 2006;354:496-507. 12. Machtay M, Duan F, Siegel BA, et al. Prediction of survival by [18F] fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: Results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 2013;31:3823-3830. 13. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: A phase III randomised controlled trial. Lancet 2009;374: 379-386. 14. Fox J, Ford E, Redmond K, et al. Quantification of tumor volume changes during radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2009;74:341-348. 15. Guckenberger M, Baier K, Richter A, et al. Evolution of surface-based deformable image registration for adaptive radiotherapy of non-small cell lung cancer (NSCLC). Radiat Oncol 2009;4:68. 16. Brink C, Bernchou U, Bertelsen A, et al. Locoregional control of nonsmall cell lung cancer in relation to automated early assessment of tumor regression on cone beam computed tomography. Int J Radiat Oncol Biol Phys 2014;89:916-923. 17. Bral S, De Ridder M, Duchateau M, et al. Daily megavoltage computed tomography in lung cancer radiotherapy: Correlation between volumetric changes and local outcome. Int J Radiat Oncol Biol Phys 2011;80:1338-1342. 18. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-1813. 19. Garg S, Gielda BT, Kiel K, et al. Patterns of locoregional failure in stage III non-small cell lung cancer treated with definitive chemoradiation therapy. Pract Radiat Oncol 2014;4:342-348. 20. Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986;12:539-547. 21. Saunders M, Dische S, Barrett A, et al. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: Mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999; 52:137-148. 22. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-2190.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Reduction in Tumor Volume by Cone Beam Computed Tomography Predicts Overall Survival in Non-Small Cell Lung Cancer Treated With Chemoradiation Therapy Salma K. Jabbour, MD,* Sinae Kim, PhD,y,z Syed A. Haider, MS,* Xiaoting Xu, MD,*,x Alson Wu, MS,* Sujani Surakanti, MD,k Joseph Aisner, MD,k John Langenfeld, MD,{ Ning J. Yue, PhD,* Bruce G. Haffty, MD,* and Wei Zou, PhD* *Department of Radiation Oncology and yDivision of Biometrics, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School; zDepartment of Biostatistics, School of Public Health, Rutgers University; xDepartment of Radiation Oncology, The First Affiliated Hospital of Soochow University, Soochow, China; kDivision of Medical Oncology; {Division of Surgery, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers The State University of New Jersey, New Brunswick, New Jersey Received Oct 7, 2014, and in revised form Jan 10, 2015. Accepted for publication Feb 9, 2015.
Summary We hypothesized that tumor volume response as measured with weekly cone beam computed tomography (CBCT), obtained as part of routine care during chemoradiation therapy, would predict the survival of unresectable non-small cell lung cancer patients. We found that tumor volume reduction, from start to end of treatment, was associated with longer overall survival. Additional prospective study of CBCT is warranted to
Purpose: We sought to evaluate whether tumor response using cone beam computed tomography (CBCT) performed as part of the routine care during chemoradiation therapy (CRT) could forecast the outcome of unresectable, locally advanced, non-small cell lung cancer (NSCLC). Methods and Materials: We manually delineated primary tumor volumes (TV) of patients with NSCLC who were treated with radical CRT on days 1, 8, 15, 22, 29, 36, and 43 on CBCTs obtained as part of the standard radiation treatment course. Percentage reductions in TV were calculated and then correlated to survival and pattern of recurrence using Cox proportional hazard models. Clinical information including histologic subtype was also considered in the study of such associations. Results: We evaluated 38 patients with a median follow-up time of 23.4 months. The median TV reduction was 39.3% (range, 7.3%-69.3%) from day 1 (D1) to day 43 (D43) CBCTs. Overall survival was associated with TV reduction from D1 to D43 (hazard ratio [HR] 0.557, 95% CI 0.39-0.79, PZ.0009). For every 10% decrease in TV from D1 to D43, the risk of death decreased by 44.3%. For patients whose TV decreased 39.3 or <39.3%, log-rank test demonstrated a separation in survival (PZ.02), with median survivals of 31 months versus 10 months, respectively. Neither
Reprint requests to: Salma K. Jabbour, MD, 195 Little Albany St, New Brunswick, NJ 08903. Tel: (732) 253-3939; E-mail: jabbousk@cinj. rutgers.edu Int J Radiation Oncol Biol Phys, Vol. 92, No. 3, pp. 627e633, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.02.017
Presented at the Fifty-Fifth Annual Meeting of the American Society for Radiation Oncology, September 22-25, Atlanta, Georgia. Conflict of interest: none.
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determine whether based on tumor response, treatment could be tailored to aid in improving outcomes.
local recurrence (HR 0.791, 95% CI 0.51-1.23, PZ.29), nor distant recurrence (HR 0.78, 95% CI 0.57-1.08, PZ.137) correlated with TV decrease from D1 to D43. Histologic subtype showed no impact on our findings. Conclusions: TV reduction as determined by CBCT during CRT as part of routine care predicts post-CRT survival. Such knowledge may justify intensification of RT or application of additional therapies. Assessment of genomic characteristics of these tumors may permit a better understanding of behavior or prediction of therapeutic outcomes. Ó 2015 Elsevier Inc. All rights reserved.
Introduction Locally advanced or inoperable non-small cell lung cancer (NSCLC) accounts for approximately 30% of all cases of NSCLC, and today these patients receive a combination of chemotherapy, radiation therapy (RT), and sometimes surgery. Most often, definitive chemoradiation therapy (CRT) is used to offer long-term survival, with expected median survival rates ranging from 14 to 17 months, and 10% to 20% long-term survival (1, 2). The addition of chemotherapy to RT concurrently offers an improvement in survival compared with sequential chemotherapy followed by RT (2-4). Determination of the outcome of CRT for locally advanced NSCLC traditionally relies on follow-up computed tomography (CT) scans, performed at regular intervals after completion of therapy. To date, no imaging method reliably predicts the posttreatment behavior, the individual’s NSCLC response to CRT, or the eventual outcome of this treatment. Modern RT now affords notable advances in the oncologic care of patients with NSCLC. For example, improvements in treatment planning, position verification, and image guidance reduce potential toxicities while improving survival rates (5). As part of standard RT image guidance, kilovoltage (kV) or megavoltage (MV) plain films, orthogonal films, or kV or MV cone beam computed tomography (CBCT) images are now often obtained daily on the linear accelerator (6) to accurately align the patient’s positioning for proper radiation delivery to the tumor. The use of CBCT as part of image-guided RT (IGRT) substantially reduces margin requirements (7) and is thus essential for target localization, especially in the setting of dose escalation (8). CBCT images are registered to the patient’s pretreatment imaging CT simulation planning session to align the geometry of the tumor for accurate radiation delivery. The CBCT permits 3-dimensional alignment of the radiation beams to the primary disease and organs at risk. In contrast, plain films or orthogonal kV or MV views obtained during CRT are nonvolumetric imaging methods that can be aligned primarily to osseous anatomy rather than to soft tissue anatomy in a 2dimensional fashion. A potential additional benefit of CBCT is thus the ability to view the ongoing response of the tumor to CRT.
We hypothesized that the use of weekly CBCTs would provide an understanding of the response to CRT and that this response would predict patients’ survival and tumor biology.
Methods and Materials Thirty-eight patients with locally advanced, biopsy-proven, unresectable, stage II-III NSCLC whom we treated with CRT, and whom we also followed up with CBCTs performed as part of their standard RT course, were eligible for inclusion in this Institutional Review Boarddapproved study. All patients were staged with chest CT scan, positron emission tomography (PET)/CT scan, brain magnetic resonance imaging, and mediastinal lymph node biopsy. Data collection included age, performance status, pathology reports, clinical stage of lung cancer, treatment information, and follow-up data including first site of recurrence, time to recurrence, and survival. Patients received definitive concurrent CRT over 6 to 7 weeks in daily (5 days/week) fractions of 180 to 200 cGy for a median total dose of 6210 cGy (range, 52007400 cGy) targeted to the primary tumor. Table 1 indicates the patient demographics.
Chemoradiation therapy Patients were placed in a supine position with arms up on the CIVCO Body Pro-Lok System (Kalona, IA). A motion study using fluoroscopy allowed limitation of TV motion to 1 cm. Then the patient was transferred to the CT simulator (General Electric LightSpeed 16), where a 4dimensional CT scan with intravenous contrast medium, breathing coaching, and retrospective gating (Varian RPM System, Varian Medical Systems, Palo Alto, CA) were performed. The 4-dimensional CT scan with 10-phase CT scans through the breathing cycle permitted the delineation of an internal target volume on the CT average scan. RT was planned as per Radiation Therapy Oncology Group (RTOG) 0617. The chemotherapy regimens consisted of intravenous weekly paclitaxel (45 mg/m2/week) with carboplatin (AUC Z 2/week) or cisplatin 50 mg/m2/day on days 1, 8, 29, 36 and etoposide, 50 mg/m2/d on days 1 to 5 and 29 to 33.
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Patient demographics and treatment details Characteristic
Age (y) Mean (SD)/median (range) Gender Female Male Stage II IIIA IIIB Histology Squamous cell carcinoma Adenocarcinoma Poorly differentiated carcinoma Concurrent chemotherapy Carboplatin þ paclitaxel Cisplatin þ etoposide Cisplatin Cisplatin þ pemetrexed Carboplatin Paclitaxel Initial TV (at day 1) Mean (SD) Median (range) Patterns of failure Local recurrence Distant recurrence Local þ distant recurrence
n (%) 67.3 (8.85)/68 (52-81) 15 (39.5) 23 (60.5) 3 (7.9) 17 (44.7) 18 (47.4) 18 (47.4) 14 (36.8) 6 (15.8) 19 15 1 1 1 1
(50) (39.5) (2.6) (2.6) (2.6) (2.6)
133.6 (168.8) 76.5 (6.99-765.7) 10 (26.3) 21 (55.3) 4 (10.5)
Abbreviations: SD Z standard deviation; TV Z tumor volume.
CBCT imaging Before RT was begun, kV CBCT images of the tumor area were acquired immediately before delivery of each radiation fraction to align the TV, as part of the standard course of RT. Of these, we used weekly CBCT images (days 1, 8, 15, 22, 29, 36, and 43 of treatment) for this study to evaluate changes in primary TV during the course of CRT. We obtained follow-up chest CT scans 6 to 8 weeks after the completion of CRT and then every 3 months for the first year, every 6 months for 2 years, and yearly thereafter. The CT scans were evaluated by thoracic radiologists and further reviewed by medical and radiation oncologists. The CBCT contours were generated manually for this study; to maintain consistency, lung window settings were used for all images, and contours were reviewed by 2 or more of the study authors. Figure 1 depicts an example of a contoured slice of a CBCT image. By contouring a given tumor mass on successive slices (along the z axis) of a single CBCT image set, we obtained a 3-dimensional representation of the primary tumor that allowed us to calculate the TV. This procedure was repeated for each weekly CBCT image set for each patient, resulting in TV values over the course of treatment. The follow-up diagnostic imaging was imported into the treatment planning system
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and fused with the CT simulation scan, and the diagnostic scan was contoured. We did not encounter significant difficulty in differentiating TVs from radiation changes when fused to the original treatment plan, given that radiation changes were generally mild at an early time point, without significant consolidation.
Statistical analysis We used a linear mixed model with random intercepts to study the changes of TV values over the treatment and follow-up duration. The TV values were transformed to a natural logarithm scale for normality. Time was treated as a continuous variable, and natural log-transformed TV measurements at day 1 (D1) as a baseline covariate. Reduction of TV from baseline to the last day of treatment was calculated as follows: 100*(TV from CBCT D1 e TV from CBCT D43)/(TV from CBCT D1). Missing TV measurements at D43 were imputed using multiple imputations with 100 repetitions. To investigate the association between TV reduction and time-to-event outcome (overall survival [OS] and time to local recurrence [LR], distant recurrence [DR], or any recurrence), we used a univariate Cox proportional hazard regression model with reduction as a covariate. Hazard ratios (HR) with 95% confidence interval (CI) were estimated using the model. Because of the limited sample size, model selection was not performed. Clinical predictors considered in the multivariate model included histologic subtype, type of chemotherapy, or stage. We included these predictors in the multivariate setting based on their univariate results. Cox proportional hazard model was in the multivariate setting also. Proportionality assumptions were evaluated and held true. Differences in OS and time to DR and LR were assessed by log-rank test, stratified according to TV reduction (median of TV reduction vs < median of TV reduction). Kaplan-Meier curves were also provided. Pearson correlation coefficients were calculated to study linear association in natural log-transformed TVs between the 2 time points (D1 vs D43 and also D43 vs follow-up CT scans) and were tested for statistical significance. A paired t test was performed to compare means of natural transformed TV at D43 and at follow-up. All hypothesis-testing procedures were done in 2-sided fashion at a significance level of 5%, and P<.05 was considered statistically significant. Analyses were performed using SAS 9.2 (Cary, NC) and R 3.1.0.
Results Thirty-eight patients with NSCLC treated with definitive CRT were included. The median follow-up time was 23.4 months. Patients with stage II disease were treated with definitive CRT when they were considered inoperable because of medical comorbidities or if they required a pneumonectomy that would not have been tolerated
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Fig. 1. Example of tumor volume (TV) contouring. (a) Computed tomographic (CT) image before treatment course showing primary TV. (b) Cone beam CT (CBCT) of patient on day 1 of treatment, with TV contoured. (c) CBCT of patient on day 43 of treatment; contour indicates TV shrinkage. because of underlying lung dysfunction. Ninety-two percent of patients received platinum-doublet therapy concurrently with RT. Single-agent chemotherapy was administered if the patient could not tolerate platinumdoublet therapy concurrently with radiation. There was no difference in survival for patients (nZ4) who discontinued treatment prematurely having received <60 Gy compared with those who completed 60 Gy (PZ.74).
TV reduction over treatment period From D1 to D43, median TV shrinkage was 39.3% (range, 7.3%-69.3%), with the TVs decreasing consistently over the treatment periods (Fig. 2) rather than at a particular time point during CRT. TV reduction occurred in all cases during CRT. Weekly natural log-transformed TV values decreased by an average of 0.091 (95% CI Z 0.102 to 0.081; P<.0001) adjusted for natural log-transformed TV measured at D1. TV reduction was slightly more considerable from D1 to D8 and D29 to D36, with log-transformed TV reductions of 0.114 (PZ.008) and 0.118 (PZ.004), respectively.
TV reduction and overall survival The median OS was 17 months. The OS was significantly associated with a reduction in primary TV from D1 to D43 (PZ.0009; HR 0.6; 95% CI 0.39-0.79). For every 10%
decrease in primary TV from D1 to D43, the risk of death decreased by 44.3% (Fig. 3). Patients were grouped based on TV reduction median of TV reduction versus
Distant and local recurrences Local recurrence was experienced by 26.3% of patients as the first site of failure. The median time to LR was 12.3 months (mean, 16.1 months; standard equivalent, 2.0 months). We found no statistically significant association between TV reduction from D1 to D43 and risk for development of LR (PZ.29; HR 0.79, CI 0.51 to 1.23). Approximately 14% of patients with adenocarcinoma (ACA) demonstrated LR, whereas 44.4% of patients with squamous cell carcinoma (SCC) experienced LR, and no patients with poorly differentiated carcinomas (PDC) experienced LR. Fifty-five percent of patients experienced DR as the first site of failure. The median time to DR was 18.9 months
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Fig. 2. Spaghetti plot of tumor volume against treatment cycle (day 1 to day 43) for all patients. Patients who received 30 fractions of radiation therapy had cone beam computed tomography (CBCT) only on day 36. Day 43 CBCTs were obtained for patients who received a seventh week of chemoradiation therapy. TV Z tumor volume. (mean 21.3, standard equivalent 2.8 months). We found no statistically significant association between TV reductions from D1 to D43 and risk for the development of DR. Seventy-one percent of ACA patients experienced DR as the first site of treatment failure, in contrast to 33% in patients with PDC and 50% of patients with SCC.
Histologic subtype outcomes Histologic subtype (SCC, ACA, PDC) did not demonstrate any association with survival (PZ.74) or progression-free survival (log-rank test; PZ.74). We found no significant
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Fig. 4. Kaplan-Meier curves for overall survival associated with median tumor volume reduction 39.3% or <39.3% from day 1 to day 43. GTV Z gross tumor volume. association between histology and TV reduction from D1 to D43 (PZ.88). Likewise, we found no statistically significant association between TV reduction (from D1 to D43) and progression-free survival (PZ.24). There was no difference among the histologic subtypes in terms of rate of TV reduction (PZ.56).
Chemotherapy type On univariate analysis, there was no impact of chemotherapy type on TV reduction from D1 to D43 (PZ.33). OS and time to LR or DR with either cisplatin-based or carboplatin-based therapies were not different (PZ.60, .19, .16, respectively). However, the carboplatin group had an improved time to recurrence of 11.5 months versus 5.8 months in the cisplatin group (PZ.04). There was no association between chemotherapy type and histology on OS (PZ.27). Multivariate analysis results showed no association between OS, DR, or any recurrence (PZ.25, 045, 0.91, respectively), and TV reduction did not change depending on type of chemotherapy. By contrast, LR and TV reduction did vary with type of chemotherapy (PZ.02); specifically, the HR for TV reduction from D1 to D43 in the cisplatin group was 0.46 (95% CI 0.26-0.83). Therefore, for every 10% increase in TV reduction from D1 to D43, the risk of LR decreased by 53.8% in the cisplatin group. Such an effect for the carboplatin cohort was not significant (HR 1.6, 95% CI 0.72-3.52).
Correlation to follow-up CT scans after CRT
Fig. 3. Kaplan-Meier overall survival curve with 95% confidence limits for this cohort.
We identified 27 patients with available follow-up CT scan data for TV measurements. We found a significant correlation of 0.86 between log-transformed TVs at D43 and TV
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(P<.0001). The means of the log-transformed TV at D43 and at follow-up were statistically different (P<.001; mean at D43 is 0.48 higher than at follow-up), consistent with continued tumor shrinkage after completion of CRT.
Discussion We herein demonstrate that CBCTs, performed as part of routine care for locally advanced NSCLC patients receiving definitive CRT, may predict patient survival outcomes using IGRT. NSCLCs also continued to reduce in volume after the last day of CRT. CBCT technology contributes negligible doses of radiation above a standard course of radiation and may provide invaluable information about a patient’s treatment course and prognosis. These results appear very enticing when placed in the context of the available literature. First, there is no currently accepted method to detect an early response to CRT for NSCLC. Currently, most rely on a restaging chest CT scan performed 6 to 8 weeks after the completion of therapy to determine the status of disease. Some investigators use PET scanning as a modality to assess tumor response after radiation-based therapy for NSCLC. PET scanning is feasible in posttreatment response assessment, and it can often differentiate tumor response from inflammatory response in the lung (9-11). In the ACRIN 6668/ RTOG 0235 clinical trial, PET scanning before and after treatment for NSCLC treated with CRT demonstrated that pretreatment standardized uptake value (SUV) peak and SUVmax were not associated with survival, whereas higher posttreatment SUVpeak and SUVmax were associated with worse survival in stage III NSCLC. SUVs did not differ greatly between the institutional versus central readings, but there were some cases with significant discrepancies, highlighting some level of operator dependency (12). Our study indicates that early imaging with CBCT as part of routine care during CRT could predict the outcome of CRT at a much earlier time point (ie, during CRT for unresectable NSCLC). Second, these results, which demonstrate the predictive value of an early response assessment, may provide the rationale for changing the treatment paradigm, including modifying treatment with intensification of RT or incorporating additional therapies. Conversely, patients with substantial early responses to CRT may be more likely to achieve pathologic complete response, which is known to occur in approximately 15% of patients treated with preoperative CRT (13), and perhaps these patients could also benefit from more intense therapy or additional agents, or could achieve comparable results with lower total RT doses. Knowledge of early responses could thus possibly permit better individualization of therapy. Other studies also assessed tumor regression during RT for NSCLC. Fox et al (14) evaluated TV changes using repeated CT during RT in 22 patients, 15 of whom received concurrent chemotherapy. This study indicated a median
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parenchymal tumor reduction of 24.7% at 30 Gy and 44.3% at 50 Gy, similar to our median reduction of 39.5%. Standard CT scans during and after RT using a deformable registration model revealed progressive tumor shrinkage after RT (15), similar to our findings. Brink et al (16) used an automated model to assess TV regression using kV CBCT and showed that pronounced TV regression correlated with worse survival. However, about 30% of patients did not receive concurrent chemotherapy. In addition, only 9% of cases were manually delineated; therefore, most of the analyses relied on a nonvalidated automated model. Furthermore, this study did not correlate final TV at followup with tumor regression during RT as a final confirmation of tumor response after therapy (16). By contrast, Bral et al (17) evaluated MVCT-based assessment of NSCLC treated with 2 different radiation schemas, including a hypofractionated regimen, and in which about half of the patients received RT alone. This amount of heterogeneity makes these results difficult to interpret. Their results demonstrated superior long-term local progression-free survival for concurrent chemotherapy in patients with better treatment response (17), but there was no correlation to OS with a short median follow-up time of 18 months. In our study, there was no correlation between LR and TV reduction. In modern oncology, tumor genetics have been shown to predict a tumor’s failure pattern and longterm disease outcome (18). Our finding of TV reduction during CRT as seen on CBCTs is likely predictive of disease biology. Although LR is important in locally advanced NSCLC treated with CRT and is a major concern, the primary initial pattern of failure is distant failure in the majority of patients (19). Also, it is unclear why there was greater TV shrinkage and fewer LRs in cisplatin-treated patients but improved time to recurrence in those treated with carboplatin. A complete literature search did not elucidate any specific patterns of failure related to chemotherapy type. It is important to consider that this proposal of CBCT use is indicative of overall tumor biology and may inform clinical decision making for additional or alternative regimens depending on tumor response or lack thereof. The relatively small sample size of our study constitutes a weakness for conclusions. Nevertheless, our population represents a relatively homogeneous cohort, with similar CRT regimens (ie, standard platinum doublets and curative dose RT) and reasonable, uniform follow-up. Although our analysis was retrospective, the data were collected prospectively. Our survival rates appear very comparable with those of historical controls, and the median TV shrinkage of 39.3% in our study also appears similar to those in other series, suggesting that our data generally represent the population, but we also recognize that further study is needed. Our data support the important concept that TV reduction through the use of CRT contributes to improving OS for locally advanced NSCLC, a well-proven tenet (4, 20-22). Our study demonstrates the ability of CBCT to quantify TV reduction, and it strongly suggests that this predicts survival earlier than other means.
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A paradigm, such as ours, of early assessment of the efficacy of CRT for locally advanced NSCLC using CBCT warrants additional study in a prospective fashion with consideration of therapy assignments based on early response. Coupling such an approach with the burgeoning knowledge of biomarkers such as genomics may help determine the biological and physiologic patterns that correlate with response to CRT.
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