Lucullus H.T. Leung

Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: A prospective study on disease control and preservation of salivary function

Xerostomia is a uniform complication after radiotherapy (RT) for nasopharyngeal carcinoma (NPC). Dosimetric studies suggested that intensity‐modulated RT (IMRT) can spare part of the parotid glands from high‐dose radiation. Disease control and salivary function after IMRT for early‐stage NPC was studied prospectively.

White Matter Anisotropy in Post-Treatment Childhood Cancer Survivors: Preliminary Evidence of Association With Neurocognitive Function

PURPOSE We aim to determine if the loss of white matter fractional anisotropy (FA), measured by diffusion tensor magnetic resonance imaging (DTI), in post-treatment childhood medulloblastoma (MED) and acute lymphoblastic leukemia (ALL) survivors correlate with intelligence quotient (IQ) scores. MATERIALS AND METHODS MED and ALL survivors (n = 30; 20 male, 10 female; age range, 6.0 to 22.1 years; mean, 13.1 years) were recruited for DTI and IQ tests. In this cross-sectional study, age-matched normal control (n = 55; 32 male, 23 female; age range, 6.0 to 23 years; mean, 12.1 years) DTI was obtained to compute percentage difference in white matter FA (DeltaFA%) for each patient compared with the age-matched control group. Multivariate regression analysis was performed to determine the relationships between DeltaFA%, age at treatment, irradiation dose, time interval from treatment, and full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ). Receiver operating characteristics curves were used to determine the best DeltaFA% cutoffs for predicting FSIQ, VIQ, and PIQ of less than 85. RESULTS DeltaFA% had a significant effect on FSIQ (adjusted r2 = 0.439; P < .001), VIQ (adjusted r(2) = 0.237; P = .028), and PIQ (adjusted r(2) = 0.491; P < .001) after adjusting for the effects of age at treatment, irradiation dose, and time interval from treatment. The best DeltaFA% value to predict less than 85 scores in FSIQ, VIQ, and PIQ was -3.3% with specificities of 100% and sensitivities ranging from 77.8% to 87.5%. CONCLUSION Our preliminary findings suggest that white matter FA may be a clinically useful biomarker for the assessment of treatment-related neurotoxicity in post-treatment childhood cancer survivors.

Linear accelerator-based stereotactic radiosurgery for limited, locally persistent, and recurrent nasopharyngeal carcinoma: Efficacy and complications

PURPOSE To evaluate the efficacy and complication of linear accelerator-based stereotactic radiosurgery (SRS) when used as salvage treatment for early-stage persistent and recurrent nasopharyngeal carcinoma (NPC) after primary radiotherapy (RT). MATERIALS AND METHODS Between March 1998 and June 2001, 18 patients (15 men and 3 women; median age 46 years, range 32-84) with locally persistent or recurrent NPC confined to the nasopharynx (rT1) or with limited extension to the nasal fossa or parapharyngeal space (rT2) were treated by SRS. Thirteen patients had rT1 disease and 5 had rT2 disease. Most patients had disease not amenable to surgery or brachytherapy. All patients had undergone previous radical RT. Persistent disease was defined as tumor relapse within 4 months of completion of primary RT, and recurrence as tumor relapse beyond 4 months. Seven patients were treated for persistent disease, eight for a first recurrence, and three for a second recurrence. SRS was performed using multiple noncoplanar arcs of photons delivered to the target volume, which was defined by axial CT at a 3 mm thickness, supplemented by MRI in selected patients (67%). The median target volume was 5.3 cm(3) (range 2.2-16.9). The median SRS dose was 12.5 Gy (range 11-14) delivered to the 80% isodose line. All patients underwent serial nasopharyngoscopy and imaging after SRS. The median follow-up was 26 months (range 11-48). RESULTS After SRS, 16 (89%) of 18 patients had complete regression of tumor as assessed by nasopharyngoscopy and biopsy. Four patients with an initial complete response to SRS subsequently developed local relapse again, with one recurrence developing outside the target volume 8 months after SRS and three within the target volume at 6-26 months after SRS. Two patients with local disease controlled by SRS developed relapse in other sites (neck node and liver metastases). The actuarial 2-year local control rate after SRS was 72%. Patients treated for persistent disease had a better local control rate (100%; 7 of 7) than those treated for recurrent disease (46%; 5 of 11). Patients with rT1 disease also had a better outcome after SRS compared with those with rT2 disease, with a control rate of 77% (10 of 13) for rT1 disease and 40% (2 of 5) for rT2 disease. Treatments were well tolerated, with no acute side effects. One patient had radiologic evidence of temporal lobe necrosis, although the right temporal lobe had already received a high dose during prior RT. That patient also developed additional local recurrence and liver metastases and died. The actuarial 2-year survival rate was 86%. CONCLUSIONS Our preliminary results indicate that SRS is an effective treatment modality for persistent and recurrent early-stage NPC, with early control rates comparable to other salvage treatments such as brachytherapy and nasopharyngectomy. A modest SRS dose at 12.5 Gy also appears to be effective and is associated with minimal morbidities. More clinical experience and longer follow-up are needed to validate our results and to address fully the role of SRS in salvaging local failures of NPC.

Longitudinal diffusion tensor magnetic resonance imaging study of radiation induced white matter damage in a rat model

Radiation-induced white matter (WM) damage is a major side effect of whole brain irradiation among childhood cancer survivors. We evaluate longitudinally the diffusion characteristics of the late radiation-induced WM damage in a rat model after 25 and 30 Gy irradiation to the hemibrain at 8 time points from 2 to 48 weeks postradiation. We hypothesize that diffusion tensor magnetic resonance imaging (DTI) indices including fractional anisotropy (FA), trace, axial diffusivity (lambda(//)), and radial diffusivity (lambda( perpendicular)) can accurately detect and monitor the histopathologic changes of radiation-induced WM damage, measured at the EC, and that these changes are dose and time dependent. Results showed a progressive reduction of FA, which was driven by reduction in lambda(//) from 4 to 40 weeks postradiation, and an increase in lambda( perpendicular) with return to baseline in lambda(//) at 48 weeks postradiation. Histologic evaluation of irradiated WM showed reactive astrogliosis from 4 weeks postradiation with reversal at 36 weeks, and demyelination, axonal degeneration, and necrosis at 48 weeks postradiation. Moreover, changes in lambda(//) correlated with reactive astrogliosis (P < 0.01) and lambda( perpendicular) correlated with demyelination (P < 0.01). Higher radiation dose (30 Gy) induced earlier and more severe histologic changes than lower radiation dose (25 Gy), and these differences were reflected by the magnitude of changes in lambda(//) and lambda( perpendicular). DTI indices reflected the histopathologic changes of WM damage and our results support the use of DTI as a biomarker to noninvasively monitor radiation-induced WM damage.

Preservation of quality of life after intensity‐modulated radiotherapy for early‐stage nasopharyngeal carcinoma: Results of a prospective longitudinal study

Xerostomia is a ubiquitous complication after conventional radiotherapy for nasopharyngeal carcinoma (NPC) that seriously impairs patient quality of life (QOL). The effect on QOL of parotid‐sparing intensity‐modulated radiotherapy (IMRT) for early‐stage NPC was assessed prospectively.

Stereotactic radiosurgery as a salvage treatment for locally persistent and recurrent nasopharyngeal carcinoma

The purpose of this work was to study the efficacy of stereotactic radiosurgery as a salvage treatment in patients with locally persistent and recurrent nasopharyngeal carcinoma (NPC).

Experimental verification of the Acuros XB and AAA dose calculation adjacent to heterogeneous media for IMRT and RapidArc of nasopharygeal carcinoma

PURPOSE To compare the doses calculated by the Acuros XB (AXB) algorithm and analytical anisotropic algorithm (AAA) with experimentally measured data adjacent to and within heterogeneous medium using intensity modulated radiation therapy (IMRT) and RapidArc(®) (RA) volumetric arc therapy plans for nasopharygeal carcinoma (NPC). METHODS Two-dimensional dose distribution immediately adjacent to both air and bone inserts of a rectangular tissue equivalent phantom irradiated using IMRT and RA plans for NPC cases were measured with GafChromic(®) EBT3 films. Doses near and within the nasopharygeal (NP) region of an anthropomorphic phantom containing heterogeneous medium were also measured with thermoluminescent dosimeters (TLD) and EBT3 films. The measured data were then compared with the data calculated by AAA and AXB. For AXB, dose calculations were performed using both dose-to-medium (AXB_Dm) and dose-to-water (AXB_Dw) options. Furthermore, target dose differences between AAA and AXB were analyzed for the corresponding real patients. The comparison of real patient plans was performed by stratifying the targets into components of different densities, including tissue, bone, and air. RESULTS For the verification of planar dose distribution adjacent to air and bone using the rectangular phantom, the percentages of pixels that passed the gamma analysis with the ± 3%/3mm criteria were 98.7%, 99.5%, and 97.7% on the axial plane for AAA, AXB_Dm, and AXB_Dw, respectively, averaged over all IMRT and RA plans, while they were 97.6%, 98.2%, and 97.7%, respectively, on the coronal plane. For the verification of planar dose distribution within the NP region of the anthropomorphic phantom, the percentages of pixels that passed the gamma analysis with the ± 3%/3mm criteria were 95.1%, 91.3%, and 99.0% for AAA, AXB_Dm, and AXB_Dw, respectively, averaged over all IMRT and RA plans. Within the NP region where air and bone were present, the film measurements represented the dose close to unit density water in a heterogeneous medium, produced the best agreement with the AXB_Dw. For the verification of point doses within the target using TLD in the anthropomorphic phantom, the absolute percentage deviations between the calculated and measured data when averaged over all IMRT and RA plans were 1.8%, 1.7%, and 1.8% for AAA, AXB_Dm and AXB_Dw, respectively. From all the verification results, no significant difference was found between the IMRT and RA plans. The target dose analysis of the real patient plans showed that the discrepancies in mean doses to the PTV component in tissue among the three dose calculation options were within 2%, but up to about 4% in the bone content, with AXB_Dm giving the lowest values and AXB_Dw giving the highest values. CONCLUSIONS In general, the verification measurements demonstrated that both algorithms produced acceptable accuracy when compared to the measured data. GafChromic(®) film results indicated that AXB produced slightly better accuracy compared to AAA for dose calculation adjacent to and within the heterogeneous media. Users should be aware of the differences in calculated target doses between options AXB_Dm and AXB_Dw, especially in bone, for IMRT and RA in NPC cases.

Verification and dosimetric impact of Acuros XB algorithm on intensity modulated stereotactic radiotherapy for locally persistent nasopharyngeal carcinoma

PURPOSE The main aim of the current study was to assess the dosimetric impact on intensity modulated stereotactic radiotherapy (IMSRT) for locally persistent nasopharyngeal carcinoma (NPC) due to the recalculation from the Anisotropic Analytical Algorithm (AAA) to the recently released Acuros XB (AXB) algorithm. The dosimetric accuracy of using AXB in predicting air∕tissue interface doses from an open single small field in a simple geometric phantom and intensity modulated small fields in an anthropomorphic phantom was also investigated. METHODS The central axis percentage depth doses (PDD) of a rectangular phantom containing an air cavity were calculated by both AAA and AXB from 6 MV beam with small field sizes (2 × 2 to 5 × 5 cm(2)). These data were compared to PDD measured by thin thermoluminescent dosimeters (TLDs) and Monte Carlo simulations. The doses predicted by AAA and AXB near air∕tissue interfaces from five different IMSRT plans were compared to the TLD measured doses in an anthropomorphic phantom. The PTV coverage, conformity and doses to organs at risk (OARs) calculated by AAA and AXB were compared for 12 patients, using identical beam setup, leaves movement and monitor units. RESULTS Testing using the simple rectangular phantom demonstrated that AAA and AXB overestimated the PDD at the air∕tissue interfaces by up to 41% and 6%, respectively, from a 2 × 2 cm(2) field. The secondary build-up curves predicted by AXB caught up well with the measured data at around 2 mm beyond the air cavity. Testing using the anthropomorphic phantom showed that AAA overestimated the doses by up to 10%, while the measured doses matched those of the AXB to within 3%. Using AAA, the planning target coverage represented by 100% of the reference dose was estimated to be 4% higher than using AXB. The averaged minimum dose to the PTV predicted by AAA was about 4% higher and OARs doses 3% to 6% higher compared to AXB. CONCLUSIONS AXB should be used whenever possible as the standard reference for IMSRT boost of NPC cases. The more accurate AXB indicating lower target coverage and lower minimum target dose compared to AAA should be noted.

Dosimetric Impact of Using the Acuros XB Algorithm for Intensity Modulated Radiation Therapy and RapidArc Planning in Nasopharyngeal Carcinomas

PURPOSE To assess the dosimetric implications for the intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy with RapidArc (RA) of nasopharyngeal carcinomas (NPC) due to the use of the Acuros XB (AXB) algorithm versus the anisotropic analytical algorithm (AAA). METHODS AND MATERIALS Nine-field sliding window IMRT and triple-arc RA plans produced for 12 patients with NPC using AAA were recalculated using AXB. The dose distributions to multiple planning target volumes (PTVs) with different prescribed doses and critical organs were compared. The PTVs were separated into components in bone, air, and tissue. The change of doses by AXB due to air and bone, and the variation of the amount of dose changes with number of fields was also studied using simple geometric phantoms. RESULTS Using AXB instead of AAA, the averaged mean dose to PTV70 (70 Gy was prescribed to PTV70) was found to be 0.9% and 1.2% lower for IMRT and RA, respectively. It was approximately 1% lower in tissue, 2% lower in bone, and 1% higher in air. The averaged minimum dose to PTV70 in bone was approximately 4% lower for both IMRT and RA, whereas it was approximately 1.5% lower for PTV70 in tissue. The decrease in target doses estimated by AXB was mostly contributed from the presence of bone, less from tissue, and none from air. A similar trend was observed for PTV60 (60 Gy was prescribed to PTV60). The doses to most serial organs were found to be 1% to 3% lower and to other organs 4% to 10% lower for both techniques. CONCLUSIONS The use of the AXB algorithm is highly recommended for IMRT and RapidArc planning for NPC cases.

Mapping radiation dose distribution on the fractional anisotropy map: Applications in the assessment of treatment-induced white matter injury

We describe a method to map whole brain radiation dose distribution on to diffusion tensor MR (DT-MR) fractional anisotropy (FA) images and illustrate its applications for studying dose-effect relationships and regional susceptibility in two childhood medulloblastoma survivors. To determine the FA changes voxel-by-voxel in white matter, the post-treatment follow-up FA maps were coregistered to baseline pre-treatment FA maps and automatic segmentation for white matter was carried out. DeltaFA maps representing relative FA change in white matter were hence generated for visual inspection and quantitative analysis. The radiation dose distribution, calculated from radiotherapy plan and exported as images, was coregistered to baseline FA images. DT-MR imaging and processing noise was small with root mean square value of 1.49% for mean DeltaFA. We evaluated the mean DeltaFA changes of regions-of-interest according to radiation dose regions to provide an estimate of the dose-response and found increasing reduction in mean DeltaFA with increasing radiation dose up to 45 Gy after which there was a reversal in the mean FA trend and mean FA approached baseline value. We also found more severe mean FA reduction in the frontal lobes compared to the parietal lobes despite the same radiation dose, suggesting regional susceptibility in the frontal lobe, and mean FA increase in the brainstem after radiation in both patients. We conclude that the method described may be useful in estimating dose-effect relationships and studying regional susceptibility of the brain to radiation in medulloblastoma survivors.