S. Yuan

Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiation Therapy

PURPOSEnTo investigate the plasma dynamics of 5 proinflammatory/fibrogenic cytokines, including interleukin-1beta (IL-1β), IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta1 (TGF-β1) to ascertain their value in predicting radiation-induced lung toxicity (RILT), both individually and in combination with physical dosimetric parameters.nnnMETHODS AND MATERIALSnTreatments of patients receiving definitive conventionally fractionated radiation therapy (RT) on clinical trial for inoperable stages I-III lung cancer were prospectively evaluated. Circulating cytokine levels were measured prior to and at weeks 2 and 4 during RT. The primary endpoint was symptomatic RILT, defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis. Minimum follow-up was 18 months.nnnRESULTSnOf 58 eligible patients, 10 (17.2%) patients developed RILT. Lower pretreatment IL-8 levels were significantly correlated with development of RILT, while radiation-induced elevations of TGF-ß1 were weakly correlated with RILT. Significant correlations were not found for any of the remaining 3 cytokines or for any clinical or dosimetric parameters. Using receiver operator characteristic curves for predictive risk assessment modeling, we found both individual cytokines and dosimetric parameters were poor independent predictors of RILT. However, combining IL-8, TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) compared to either variable alone.nnnCONCLUSIONSnCombining inflammatory cytokines with physical dosimetric factors may provide a more accurate model for RILT prediction. Future study with a larger number of cases and events is needed to validate such findings.

Changes in Global Function and Regional Ventilation and Perfusion on SPECT During the Course of Radiotherapy in Patients With Non-Small-Cell Lung Cancer

PURPOSEnThis study aimed to (1) examine changes in dyspnea, global pulmonary function test (PFT) results, and functional activity on ventilation (V)/perfusion (Q) single-photon emission computerized tomography (SPECT) scans during the course of radiation (RT), and (2) factors associated with the changes in patients with non-small-cell lung cancer (NSCLC).nnnMETHODS AND MATERIALSnFifty-six stage I to III NSCLC patients treated with definitive RT with or without chemotherapy were enrolled prospectively. Dyspnea was graded according to Common Terminology Criteria for Adverse Events version 3.0 prior to and weekly during RT. V/Q SPECT-computed tomography (CT) and PFTs were performed prior to and during RT at approximately 45 Gy. Functions of V and Q activities were assessed using a semiquantitative scoring of SPECT images.nnnRESULTSnBreathing improved significantly at the third week (mean dyspnea grade, 0.8 vs. 0.6; paired t-test p = 0.011) and worsened during the later course of RT (p > 0.05). Global PFT results did not change significantly, while regional lung function on V/Q SPECT improved significantly after ∼45 Gy. The V defect score (DS) was 4.9 pre-RT versus 4.3 during RT (pxa0= 0.01); Q DS was 4.3 pre-RT versus 4.0 during RT (p < 0.01). Improvements in V and Q functions were seen primarily in the ipsilateral lung (V DS, 1.9 pre-RT versus 1.4 during RT, pxa0< 0.01; Q DS, 1.7 pre-RT versus 1.5 during RT, p < 0.01). Baseline primary tumor volume was significantly correlated with pre-RT V/Q DS (p < 0.01). Patients with central lung tumors had greater interval changes in V and Q than those with more peripheral tumors (p <0.05 for both V and Q DS).nnnCONCLUSIONSnRegional ventilation and perfusion improved during RT at 45 Gy. This suggests that adaptive planning based on V/Q SPECT during RT may allow sparing of functionally recoverable lung tissue.

Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity

PURPOSEnPoor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT).nnnMETHODS AND MATERIALSnNSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade ≥2 radiation pneumonitis and fibrosis.nnnRESULTSnThere was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088).nnnCONCLUSIONSnPoor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability.

Metabolic Tumor Volume on PET Reduced More than Gross Tumor Volume on CT during Radiotherapy in Patients with Non-Small Cell Lung Cancer Treated with 3DCRT or SBRT

ObjectiveWe have previously demonstrated that tumor reduces in activity and size during the course of radiotherapy (RT) in a limited number of patients with non-small cell lung cancer (NSCLC). This study aimed to quantify the metabolic tumor volume (MTV) on positron emission tomography (PET) and compare its changes with those of gross tumor volume (GTV) on computed tomography (CT) during-RT for 3D conformal radiotherapy (3DCRT) and stereotactic body radiotherapy (SBRT).MethodsPatients with stage I–III NSCLC treated with a definitive course of RT ± chemotherapy were eligible for this prospective study. FDG-PET/CT scans were acquired within 2xa0weeks before RT (pre-RT) and at about two thirds of total dose during-RT. PET metabolic tumor volumes (PET-MTVs) were delineated using a method combining the tumor/aorta ratio autosegmentation and CT anatomy-based manual editing. Data are presented as mean (95xa0% confident interval).ResultsThe MTV delineation methodology was first confirmed to be highly reproducible by comparing volumes defined by different physicians and using different systems (coefficiencyu2009>u20090.98). Fifty patients with 88 primary and nodal lesions were evaluated. The mean ratios of MTV/GTV were 0.70 (−0.07u2009∼u20091.47) and 0.33 (−0.30u2009∼u20090.95) for pre-RT and during-RT, respectively. PET-MTV reduced by 70xa0% (62–77xa0%), while CT-GTV by 41xa0% (33–49xa0%) (pu2009<u20090.001) during-RT. MTV reduction was 72.9xa0% and 15.4xa0% for 3DCRT and SBRT, respectively (pu2009<u20090.001).ConclusionPET-MTV reduced more than CT-GTV during-RT, while patients treated with 3DCRT reduced more than SBRT. RTOG1106 is using during-RT PET-MTV to adapt radiation therapy in 3DCRT.

Semiquantification and Classification of Local Pulmonary Function by V/Q Single Photon Emission Computed Tomography in Patients with Non-small Cell Lung Cancer: Potential Indication for Radiotherapy Planning

Introduction: Perfusion (Q) single photon emission computed tomography (SPECT) has been used to divert dose away from higher-functioning lung during radiation therapy (RT) planning. This study aimed to (1) study regional lung function through coregistered pulmonary ventilation/perfusion (V/Q)-SPECT-CT and (2) classify these defects for its potential value in radiation planning in patients with non-small cell lung cancer (NSCLC). Methods: Patients with stages I to III NSCLC requiring radiation-based therapy were eligible for this prospective study. V/Q-SPECT performed within 2 weeks before the start of radiation was interpreted by nuclear medicine physicians and then measured by a semiquantitative score. The potential mechanism of V and Q defects was analyzed; the potential impact of V/Q-SPECT over Q-SPECT alone was completed through classified applications (high-dose RT versus RT avoidance) during planning. Results: Images of 51 consecutive patients were analyzed. The V and Q defects were matched, reverse mismatched (V defect > Q defect), and mismatched (Q defect > V defect) in 61, 31, and 8% of patients, respectively. Tumor was the leading cause of the defects of ipsilateral lung in 73% of patients. The defect scores of the ipsilateral lung were greater in patients with central primaries than those with peripheral primaries for both V-SPECT (2.3 ± 1.1 versus 1.5 ± 0.8, p = 0.017) and Q-SPECT (2.2 ± 0.8 versus 1.4 ± 0.6, p = 0.000). The patients with chronic obstructive pulmonary disease had greater defect scores in contralateral lung for both V-SPECT (1.5 ± 0.7 versus 1.0 ± 0.8, p = 0.006) and Q-SPECT (1.4 ± 0.6 versus 1.0 ± 0.4, p = 0.010). On assessing the potential value of SPECT on RT plan, 39% of patients could have their RT plan when applying V/Q-SPECT rather than Q-SPECT alone. Conclusions: V/Q-SPECT provides a more comprehensive functional assessment, may provide additional value over Q-SPECT alone in assessing local pulmonary function, and guide RT plan decisions in patients with NSCLC.

Genetic variations in TGFβ1, tPA, and ACE and radiation-induced thoracic toxicities in patients with non-small-cell lung cancer.

Introduction: We hypothesized that radiation-induced thoracic toxicity (RITT) of the lung, esophagus and pericardium share a similar mechanism, and aimed to examine whether genetic variation of transforming growth factor–beta1 (TGF&bgr;1), tissue plasminogen activator (tPA) and angiotensin converting enzyme (ACE), are associated with RITT in patients with non–small-cell lung cancer (NSCLC). Methods: Patients with stage I–III NSCLC were enrolled and received radiotherapy (RT). Blood samples were obtained pre-RT and at 4 to 5 weeks during RT, and plasma TGF-&bgr;1 was measured using an enzyme-linked immunosorbent assay. The DNA samples extracted from blood pre-RT were analyzed for the following frequent genetic variations: TGF&bgr;1 509C/T, tPA -7351 C/T, and ACE I/D. RITT score was defined as the sum of radiation-induced toxicity grades in esophagus, lung, and pericardium. Results: Seventy-six NSCLC patients receiving definitive RT were enrolled. Patients with TGF&bgr;1 509CC had higher mean grade of esophagitis (1.4 ± 0.2 versus 0.8 ± 0.2, p = 0.019) and RITT score (2.6 ± 0.3 versus 1.6 ± 0.3, p = 0.009) than T allele carriers. Although no significant relationship was observed between RITT and the tPA or ACE variants individually, patients with any high-risk alleles (tPA CC or ACE D or TGF&bgr;1 509CC) had significantly higher grade of developing combined RITT (p < 0.001). Patients with TGF&bgr;1 509CC had greater increase of plasma TGF &bgr;1 levels at 4 to 5 weeks during RT than T allele carriers did (CC 1.2 ± 0.2 versus T 0.7 ± 0.1, p = 0.047). Conclusion: This exploratory study demonstrated that sensitivity of radiation toxicity may be determined by genomic factors associated with TGF&bgr;1 and genes involved in TGF&bgr;1 pathway.

Use of increase in esophageal FDG SUV during radiotherapy to predict radiation esophagitis.

e17509 Background: Esophageal uptake of FDG is commonly seen in patients with non-small cell lung cancer (NSCLC), but the relationship of the uptake to radiation esophagitis has not been delineated. Since esophageal mucosa is sensitive to the effect of radiation, we hypothesized that: (1) esophageal FDG activity changes during fractionated radiotherapy (RT), (2) these changes are associated with radiation esophagitis. Methods: Patients with stage I-III NSCLC were prospectively enrolled and received >60 Gy RT. FDG-PET/CT scans were acquired prior to and during RT after the delivery of 45 Gy. Normalized standardized uptake values (NSUV), defined by the esophageal maximum SUV relative to intravascular background within the aortic arch, were measured at the levels of the primary tumor, sternal notch, aortic arch, carina, and gastro-esophageal junction. Grade ≥2 radiation esophagitis was defined as an event. Results: 16 of 50 patients had radiation esophagitis event. Clinical stage, concurrent chemotherapy, ma...

SU‐FF‐J‐19: V‐Q SPECT to Individualize Adaptive Radiation Plan in Patients with Non‐Small Cell Lung Cancer (NSCLC)

Purposes: This study aimed to assess the changes of lung ventilation (V) and perfusion (Q) function by single photon emission tomography (V/Q SPECT) at 45 Gy during radiation therapy (RT), and determine if V/Q SPECT during‐RT can be used to decrease dose to the functioning lung.Methods: V/Q SPECT‐CT and FDG‐PET‐CT were performed prior and during‐RT (@45Gy) for patients enrolled in prospective clinical trials for stage I–III NSCLC. The V and Q functions were assessed using a semi‐quantitative system. An adaptive plan was generated after RT of 45 Gy to the target based on the during‐RT FDG‐PET‐CT. The during‐RT SPECT was used to optimize the plan to minimize dose to the functioning lung.Results: Of 45 patients analyzed, 100% had lung functional defects at or around the primary tumor and the majority of them have defects in the remaining lung. The V/Q defects were mismatched in 40% and 50% patients for pre‐ and during‐RT SPECT, respectively. After 45 Gy, the global and local lung function improved in one third patients. Specifically, there was a significant improvement in V scores in ipsilateral lung (P=0.002), while there was no significant changes in V scores of the contralateral lung and Q scores of the ipsilateral lung at or around the tumor at 45 Gy during‐RT. Using V/Q SPECT at 45 Gy for voxel based optimization, the mean dose to the functioning lung decreased remarkably while maintaining the physical dose to the target and the physical dose based lung normal tissue complication probability. Conclusion: V/Q SPECT‐CT acquired during the course of treatment has a potential to escalate the tumordose and or decrease the dose to the functioning lung. Clinical trials are ongoing to assess if the therapeutic ratio (long‐term survival over lung toxicity) will improve in patients with NSCLC.