Danita Kannarunimit

Comparison between target margins derived from 4DCT scans and real‐time tumor motion tracking: Insights from lung tumor patients treated with robotic radiosurgery

PURPOSE A unique capability of the CyberKnife system is dynamic target tracking. However, not all patients are eligible for this approach. Rather, their tumors are tracked statically using the vertebral column for alignment. When using static tracking, the internal target volume (ITV) is delineated on the four-dimensional (4D) CT scan and an additional margin is added to account for setup uncertainty [planning target volume (PTV)]. Treatment margins are difficult to estimate due to unpredictable variations in tumor motion and respiratory pattern during the course of treatment. The inability to track the target and detect changes in respiratory characteristics might result in geographic misses and local tumor recurrences. The purpose of this study is to develop a method to evaluate the adequacy of ITV-to-PTV margins for patients treated in this manner. METHODS Data from 24 patients with lesions in the upper lobe (n = 12), middle lobe (n = 3), and lower lobe (n = 9) were included in this study. Each patient was treated with dynamic tracking and underwent 4DCT scanning at the time of simulation. Data including the 3D coordinates of the target over the course of treatment were extracted from the treatment log files and used to determine actual target motion in the superior-inferior (S-I), anterior-posterior (A-P), and left-right (L-R) directions. Different approaches were used to calculate anisotropic and isotropic margins, assuming that the tumor moves as a rigid body. Anisotropic margins were calculated by separating target motion in the three anatomical directions, and a uniform margin was calculated by shifting the gross tumor volume contours in the 3D space and by computing the percentage of overlap with the PTV. The analysis was validated by means of a theoretical formulation. RESULTS The three methods provided consistent results. A uniform margin of 4.5 mm around the ITV was necessary to assure 95% target coverage for 95% of the fractions included in the analysis. In the case of anisotropic margins, the expansion required in the S-I direction was larger (8.1 mm) than those in the L-R (4.9 mm) and A-P (4.5 mm) directions. This margin accounts for variations of target position within the same treatment fraction. CONCLUSIONS The use of bony alignment for CyberKnife lung stereotactic body radiation therapy requires careful considerations, in terms of the potential for increased toxicity or local miss. Our method could be used by other centers to determine the adequacy of ITV-to-PTV margins for their patients.

Analysis of Dose Distribution and Risk of Pneumonitis in Stereotactic Body Radiation Therapy for Centrally Located Lung Tumors A Comparison of Robotic Radiosurgery, Helical Tomotherapy and Volumetric Modulated Arc Therapy

Stereotactic body radiation therapy (SBRT) to central lung tumors is associated with normal -tissue toxicity. Highly conformal technologies may reduce the risk of complications. This study compares physical dose characteristics and anticipated risks of radiation pneumonitis (RP) among three SBRT modalities: robotic radiosurgery (RR), helical tomotherapy (HT) and volumetric modulated arc therapy (VMAT). Nine patients with central lung tumors ≤5 cm were compared. RR, HT and VMAT plans were developed per RTOG 0831. Dosimetric comparisons included target coverage, conformity index, heterogeneity index, gradient index, maximal dose at 2 cm from target (D2 cm), and dose-volume parameters for organs at risk (OARs). Efficiency endpoints included total beam-on time and monitor units. RP risk was derived from Lyman-Kutcher-Burman modeling on in-house software. The average GTV and PTV were 11.6 ± 7.86 cm3 and 36.8 ± 18.1 cm3. All techniques resulted in similar target coverage (p = 0.64) and dose conformity (p = 0.88). While RR had sharper fall-off gradient (p = 0.002) and lower D2 cm (p = 0.02), HT and VMAT produced greater homogeneity (p < 0.001) and delivery efficiency (p = 0.001). RP risk predicted from whole or contralateral lung volumes was less than 10%, but was 2-3 times higher using ipsilateral volumes. Using whole (p = 0.04, p = 0.02) or ipsilateral (p = 0.004, p = 0.0008) volumes, RR and VMAT had a lower risk of RP than HT. Using contralateral volumes, RR had the lowest RP risk (p = 0.0002, p = 0.0003 versus HT, VMAT). RR, HT and VMAT were able to provide clinically acceptable plans following the guidelines provided by RTOG 0813. All techniques provided similar coverage and conformity. RR seemed to produce a lower RP risk for a scenario of small PTV-OAR overlap and small PTV. VMAT and HT produced greater homogeneity, potentially desirable for a large PTV-OAR overlap. VMAT probably yields the lowest RP risk for a large PTV. Understanding subtle differences among these technologies may assist in situations where multiple choices of modality are available.

Efficacy of intensity-modulated radiotherapy with concurrent carboplatin in nasopharyngeal carcinoma

Abstract Background. The aim of the prospective phase II study was to evaluate the efficacy and toxicities of concurrent carboplatin with intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma (NPC). Patients and methods. Between October 2005 and November 2011, 73 stage II‒IVB NPC patients received IMRT 70 Gy concurrently with three cycles of carboplatin (AUC 5) every three weeks, followed by three cycles of adjuvant carboplatin (AUC 5) and 5-FU (1,000 mg/m2/day for four days) every four weeks. All patients were evaluated for tumour response using response evaluation criteria in solid tumour (RECIST) criteria, survival analysis using Kaplan-Meier methods, and toxicities according to common terminology criteria for adverse events (CTCAE) version 4.0. Results. At three months after chemoradiation, 82.2% and 17.8% of patients achieved complete and partial response, respectively. With a median follow-up of 48.1 months (1.3‒97.8 months), 9.6% and 17.8% had local recurrence and distant metastasis, respectively. The median survival was not reached. A three-year overall survival was 83.6% and a progression-free survival was 65.3%. Regarding treatment compliance, 97.2%, 68.5% and 69.8% completed radiation treatment, concurrent carboplatin and adjuvant chemotherapy, respectively. Grade 3‒4 acute toxicities were oral mucositis (16.4%), dysphagia (16.4%), xerostomia (15.1%) and haematotoxicity (6.8%). Conclusions. Carboplatin concurrently with IMRT provided excellent tumour response, manageable toxicities and good compliance. This should be considered as an alternative treatment for NPC patients.

Prevalence and significance of plasma Epstein-Barr Virus DNA level in nasopharyngeal carcinoma

Abstract Epstein-Barr virus (EBV) DNA has been recognized as a promising tumor marker for nasopharyngeal carcinoma (NPC). This study aims to demonstrate the prevalence of plasma EBV DNA and its temporal correlation with treatment outcomes in the modern era. A total of 204 patients with Stage I–IVB NPC treated with intensity-modulated radiotherapy (IMRT) were enrolled. Quantitative plasma EBV DNA measurement was performed before treatment (pre-IMRT), on the fifth week of radiation (mid-IMRT), at 3 months after radiation (post-IMRT), then every 6 months until disease relapse. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method. Plasma EBV DNA was detected in 110 patients (53.9%), with a median pre-IMRT EBV DNA level of 8005 copies/ml. Significant correlation was noted between pre-IMRT EBV DNA level and disease stage, but not between pre-IMRT EBV DNA level and World Health Organization classification. With a median follow-up time of 35.1 months, the 3-year PFS and OS rates were higher in the group with undetectable pre-IMRT EBV DNA level compared with in the group in which it was detectable. When classified according to disease stage and pre-IMRT EBV DNA, patients with early disease and detectable pre-IMRT EBV DNA experienced poorer survival than those with locally advanced disease and undetectable pre-IMRT EBV DNA. According to the dynamic changes in EBV DNA level between pre-IMRT and mid/post IMRT, survival was significantly higher in patients who achieved an undetectable level following treatment. On multivariate analysis, post-IMRT EBV DNA level was the strongest predictor of all treatment outcomes (P < 0.001). Our study demonstrated the clinical significance of the plasma EBV DNA level at specific time points, as well as of the dynamic changes in the EBV DNA level. Disappearance of plasma EBV DNA after treatment was associated with better survival.

Prognostic value of plasma EBV DNA for nasopharyngeal cancer patients during treatment with intensity-modulated radiation therapy and concurrent chemotherapy

Abstract Background Plasma EBV DNA concentrations at the time of diagnosis (pre-EBV) and post treatment (post-EBV) have significant value for predicting the clinical outcome of nasopharyngeal cancer (NPC) patients. However, the prognostic value of the EBV concentration during radiation therapy (mid-EBV) has not been vigorously studied. Patients and methods This was a post hoc analysis of 105 detectable pre-EBV NPC patients from a phase II/III study comparing sequential (SEQ) versus simultaneous integrated boost (SIB) intensity-modulated radiation therapy (IMRT). Plasma EBV DNA concentrations were measured by PCR before commencement of IMRT, at the 5th week of radiation therapy and 3 months after the completion of IMRT. The objective was to identify the prognostic value of mid-EBV to predict overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). Results A median pre-EBV was 6880 copies/ml. Mid-EBV and post-EBV were detectable in 14.3% and 6.7% of the patients, respectively. The median follow-up time was 45.3 months. The 3-year OS, PFS and DMFS rates were 86.0% vs. 66.7% (p = 0.043), 81.5% vs. 52.5% (p = 0.006), 86.1% vs. 76.6% (p = 0.150), respectively, for those with undetectable mid-EBV vs. persistently detectable mid-EBV. However, in the multivariate analysis, only persistently detectable post-EBV was significantly associated with a worse OS (hazard ratio (HR) = 6.881, 95% confident interval (CI) 1.699-27.867, p = 0.007), PFS (HR = 5.117, 95% CI 1.562–16.768, p = 0.007) and DMFS (HR = 129.071, 95%CI 19.031–875.364, p < 0.001). Conclusions Detectable post-EBV was the most powerful adverse prognostic factor for OS, PFS and DMFS; however, detectable mid-EBV was associated with worse OS, PFS especially Local-PFS (LPFS) and may facilitate adaptive treatment during the radiation treatment period.

Validation of previously reported predictors for radiation-induced hypothyroidism in nasopharyngeal cancer patients treated with intensity-modulated radiation therapy, a post hoc analysis from a Phase III randomized trial

Abstract This study aimed to validate previously reported dosimetric parameters, including thyroid volume, mean dose, and percentage thyroid volume, receiving at least 40, 45 and 50 Gy (V40, V45 and V50), absolute thyroid volume spared (VS) from 45, 50 and 60 Gy (VS45, VS50 and VS60), and clinical factors affecting the development of radiation-induced hypothyroidism (RHT). A post hoc analysis was performed in 178 euthyroid nasopharyngeal cancer (NPC) patients from a Phase III study comparing sequential versus simultaneous-integrated boost intensity-modulated radiation therapy. RHT was determined by increased thyroid-stimulating hormone (TSH) with or without reduced free thyroxin, regardless of symptoms. The median follow-up time was 42.5 months. The 1-, 2- and 3-year freedom from RHT rates were 78.4%, 56.4% and 43.4%, respectively. The median latency period was 21 months. The thyroid gland received a median mean dose of 53.5 Gy. Female gender, smaller thyroid volume, higher pretreatment TSH level (≥1.55 μU/ml) and VS60 < 10 cm3 were significantly associated with RHT in univariate analyses. Only pretreatment TSH ≥ 1.55 μU/ml and VS60 < 10 cm3 were significant predictors in multivariate analysis. Our results suggested that patients with pretreatment TSH ≥ 1.55 μU/ml should be cautious about the risk of RHT. The VS60 ≥ 10 cm3 is recommended for treatment planning.

Optimal plasma pretreatment EBV DNA cut-off point for nasopharyngeal cancer patients treated with intensity modulated radiation therapy

Objective Plasma Epstein-Barr virus (EBV) DNA concentration at the time of diagnosis (pre-EBV) can be used to stratify risk for nasopharyngeal cancer (NPC) patients. However, pre-EBV cut-off values vary among studies. Methods This was a post hoc analysis of 208 NPC patients from a phase II/III study comparing sequential (SEQ) vs. simultaneous integrated boost (SIB) intensity modulated radiation therapy. The objective was to identify the optimal pre-EBV cut-off value to predict overall survival (OS), progression free survival (PFS) and distant metastatic free survival (DMFS) rates. Results The pre-EBV and post-treatment EBV DNA (post-EBV) were detectable in 59.1% and 3.8% of the patients, respectively. A new pre-EBV cut-off value of 2300 copies/ml was identified by the receiver operating characteristics analysis. This cut-off value showed 82% sensitivity, 59% specificity and 31.7% positive and 93.5% negative predictive values in predicting OS. The 3-year OS, PFS and DMFS were 95.6 vs. 73.8%, 89.8 vs. 55.3% and 93 vs. 70.1% for pre-EBV < vs. ≥2300 copies/ml, respectively. Older age group (≥45 years), high pre-EBV and detectable post-EBV concentration were independent predictors for OS, PFS and DMFS in a multivariate analysis. When the stage grouping and pre-EBV value were combined, a subgroup of patients with stage II-III and pre-EBV values <2300 copies/ml. had the best survival outcomes, while the worst survival subgroup was the patients with stage III-IVb with pre-EBV values ≥2300 copies/ml. Conclusions Pre-EBV cut-off of 2300 copies/ml is an optimal value predicting OS, PFS and DMFS.