Ajay Sandhu

SUBSEQUENT MALIGNANCIES IN CHILDREN TREATED FOR HODGKIN'S DISEASE: ASSOCIATIONS WITH GENDER AND RADIATION DOSE

PURPOSE Subsequent malignant neoplasms (SMNs) are a dominant cause of morbidity and mortality in children treated for Hodgkins disease (HD). We evaluated select demographic and therapeutic factors associated with SMNs, specifically gender and radiation dose. METHODS AND MATERIALS A total of 930 children treated for HD at five institutions between 1960 and 1990 were studied. Mean age at diagnosis was 13.6 years, and mean follow-up was 16.8 years (maximum, 39.4 years). Treatment included radiation alone (43%), chemotherapy alone (9%), or both (48%). RESULTS We found that SMNs occurred in 102 (11%) patients, with a 25-year actuarial rate of 19%. With 15,154 patient years of follow-up, only 7.18 cancers were expected (standardized incidence ratio [SIR] = 14.2; absolute excess risk [AER] = 63 cases/10,000 years). The SIR for female subjects, 19.93, was significantly greater than for males, 8.41 (p < 0.0001). After excluding breast cancer, the SIR for female patients was 15.4, still significantly greater than for male patients (p = 0.0012). Increasing radiation dose was associated with an increasing SIR (p = 0.0085). On univariate analysis, an increased risk was associated with female gender, increasing radiation dose, and age at treatment (12-16 years). Using logistic regression, mantle radiation dose increased risk, and this was 2.5-fold for female patients treated with more than 35 Gy primarily because of breast cancer. CONCLUSIONS Survivors of childhood HD are at risk for SMNs, and this risk is greater for female individuals even after accounting for breast cancer. Although SMNs occur in the absence of radiation therapy, the risk increases with RT dose.

Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL⁻¹ (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL⁻¹. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in lung cancer patients.

The diaphragm as an anatomic surrogate for lung tumor motion.

Lung tumor motion due to respiration poses a challenge in the application of modern three-dimensional conformal radiotherapy. Direct tracking of the lung tumor during radiation therapy is very difficult without implanted fiducial markers. Indirect tracking relies on the correlation of the tumors motion and the surrogates motion. The present paper presents an analysis of the correlation between tumor motion and diaphragm motion in order to evaluate the potential use of diaphragm as a surrogate for tumor motion. We have analyzed the correlation between diaphragm motion and superior-inferior lung tumor motion in 32 fluoroscopic image sequences from ten lung cancer patients. A simple linear model and a more complex linear model that accounts for phase delays between the two motions have been used. Results show that the diaphragm is a good surrogate for tumor motion prediction for most patients, resulting in an average correlation factor of 0.94 and 0.98 with each model respectively. The model that accounts for delays leads to an average localization prediction error of 0.8 mm and an error at the 95% confidence level of 2.1 mm. However, for one patient studied, the correlation is much weaker compared to other patients. This indicates that, before using diaphragm for lung tumor prediction, the correlation should be examined on a patient-by-patient basis.

Prostate bed localization with image-guided approach using on-board imaging: Reporting acute toxicity and implications for radiation therapy planning following prostatectomy

OBJECTIVES To report our experience using Image-Guided Radiation Therapy (IGRT) in patients undergoing post-prostatectomy irradiation. METHODS Twenty-six patients were treated with radiotherapy following radical prostatectomy using Intensity Modulated Radiation Therapy (IMRT). Prostate bed localization was done using image guidance to align surgical clips relative to the reference isocenter on the planning digitally reconstructed radiographs. Assuming surgical clips to be surrogate for prostate bed, daily shifts in their position were calculated after aligning with the bony anatomy. Shifts were recorded in three dimensions. The acute toxicity was measured during and after completion of treatment. RESULTS The average (standard deviation) prostate bed motion in anterior-posterior, superior-inferior and left-right directions were: 2.7mm (2.1), 2.4mm (2.1) and 1.0mm (1.7), respectively. The majority of patients experienced only grade 1 symptoms, two patients had grade 2 symptoms and none had grade 3 or higher acute toxicity. CONCLUSIONS Daily IGRT is recommended for accurate target localization during radiation delivery to improve efficacy of treatment and enhance therapeutic ratio. Larger studies with longer follow-up are necessary to make definitive recommendations regarding magnitude of margin reduction around clinical target volume.

Liver motion during cone beam computed tomography guided stereotactic body radiation therapy

PURPOSE Understanding motion characteristics of liver such as, interfractional and intrafractional motion variability, difference in motion within different locations in the organ, and their complex relationship with the breathing cycles are particularly important for image-guided liver SBRT. The purpose of this study was to investigate such motion characteristics based on fiducial markers tracked with the x-ray projections of the CBCT scans, taken immediately prior to the treatments. METHODS Twenty liver SBRT patients were analyzed. Each patient had three fiducial markers (2 × 5-mm gold) percutaneously implanted around the gross tumor. The prescription ranged from 2 to 8 fractions per patient. The CBCT projections data for each fraction (∼650 projections∕scan), for each patient, were analyzed and the 2D positions of the markers were extracted using an in-house algorithm. In total, >55 000 x-ray projections were analyzed from 85 CBCT scans. From the 2D extracted positions, a 3D motion trajectory of the markers was constructed, from each CBCT scans, resulting in left-right (LR), anterior-posterior (AP), and cranio-caudal (CC) location information of the markers with >55 000 data points. The authors then analyzed the interfraction and intrafraction liver motion variability, within different locations in the organ, and as a function of the breathing cycle. The authors also compared the motion characteristics against the planning 4DCT and the RPM™ (Varian Medical Systems, Palo Alto, CA) breathing traces. Variations in the appropriate gating window (defined as the percent of the maximum range at which 50% of the marker positions are contained), between fractions were calculated as well. RESULTS The range of motion for the 20 patients were 3.0 ± 2.0 mm, 5.1 ± 3.1 mm, and 17.9 ± 5.1 mm in the planning 4DCT, and 2.8 ± 1.6 mm, 5.3 ± 3.1 mm, and 16.5 ± 5.7 mm in the treatment CBCT, for LR, AP, and CC directions, respectively. The range of respiratory period was 3.9 ± 0.7 and 4.2 ± 0.8 s during the 4DCT simulation and the CBCT scans, respectively. The authors found that breathing-induced AP and CC motions are highly correlated. That is, all markers moved cranially also moved posteriorly and vice versa, irrespective of the location. The LR motion had a more variable relationship with the AP∕CC motions, and appeared random with respect to the location. That is, when the markers moved toward cranial-posterior direction, 58% of the markers moved to the patient-right, 22% of the markers moved to the patient-left, and 20% of the markers had minimal∕none motion. The absolute difference in the motion magnitude between the markers, in different locations within the liver, had a positive correlation with the absolute distance between the markers (R(2) = 0.69, linear-fit). The interfractional gating window varied significantly for some patients, with the largest having 29.4%-56.4% range between fractions. CONCLUSIONS This study analyzed the liver motion characteristics of 20 patients undergoing SBRT. A large variation in motion was observed, interfractionally and intrafractionally, and that as the distance between the markers increased, the difference in the absolute range of motion also increased. This suggests that marker(s) in closest proximity to the target be used.

Patient-specific motion artifacts in 4DCT

PURPOSE Four-dimensional computed tomography (4DCT) has enhanced images of the thorax and upper abdomen during respiration, but intraphase residual motion artifacts will persist in cine-mode scanning. In this study, the source and magnitude of projection artifacts due to intraphase target motion is investigated. METHODS A theoretical model of geometric uncertainty due to partial projection artifacts in cine-mode 4DCT was derived based on ideal periodic motion. Predicted artifacts were compared to measured errors with a rigid lung phantom attached to a programmable motion platform. Ideal periodic motion and actual patient breathing patterns were used as input for phantom motion. Reconstructed target dimensions were measured along the direction of motion and compared to the actual, known dimensions. RESULTS Artifacts due to intraphase residual motion in cine-mode 4DCT range from a few mm up to a few cm on a given scanner, and can be predicted based on target motion and CT gantry rotation time. Errors in ITV and GTV dimensions were accurately characterized by the theoretical uncertainty at all phases when sinusoidal motion was considered, and in 96% of 300 measurements when patient breathing patterns were used as motion input. When peak-to-peak motion of 1.5 cm is combined with a breathing period of 4 s and gantry rotation time of 1 s, errors due to partial projection artifacts can be greater than 1 cm near midventilation and are a few mm in the inhale and exhale phases. Incorporation of such uncertainty into margin design should be considered in addition to other uncertainties. CONCLUSIONS Artifacts due to intraphase residual motion exist in 4DCT, even for ideal breathing motions (e.g., sine waves). It was determined that these motion artifacts depend on patient-specific tumor motion and CT gantry rotation speed. Thus, if the patient-specific motion parameters are known (i.e., amplitude and period), a patient-specific margin can and should be designed to compensate for this uncertainty.

Stereotactic body radiation therapy in octogenarians with stage I lung cancer.

BACKGROUND The purpose of this study was to describe our clinical experience using stereotactic body radiation therapy (SBRT) to treat medically inoperable stage I non-small-cell lung cancer (NSCLC) in very elderly patients. PATIENTS AND METHODS Twenty-four consecutive octogenarians with stage I NSCLC were treated with SBRT between 2007 and 2011 at a single center. Median prescription dose was 48 Gy (range, 48-56). Follow-up clinical examination and computed tomography (CT) were performed every 2 to 3 months. RESULTS Median age was 85 years (range, 80-89). Twenty-three (96%) patients had peripheral tumors, and median tumor size was 22 mm (range, 11-49). Tissue diagnosis was obtained in 16 (67%) patients. Median follow-up for all patients was 27.6 months (range, 4.3-61.2). The 24-month disease-free survival was 77% (95% confidence interval [CI], 61%-97%). The 24-month overall survival (OS) was 74% (95% CI, 57%-94%). No local failure (LF) was observed during the period of observation. Nodal failure (NF) and distant failure (DF) occurred in 2 and 4 patients, respectively. The cumulative incidence of competing mortality at 24 months was estimated at 13% (95% CI, 3%-30%). No difference in outcomes with or without tissue diagnosis was observed. No grade ≥ 3 early or late treatment-related toxicities were observed. CONCLUSION Octogenarians tolerate SBRT well, which makes it an attractive treatment option.

Evaluation of patient setup uncertainty of optical guided frameless system for intracranial stereotactic radiosurgery

The optically‐guided frameless system (OFLS) has been used in our clinic for intracranial stereotactic radiosurgery (SRS) since 2006, as it is especially effective in IMRT‐based radiosurgery (IMRS), which allows treating multiple brain lesions simultaneously using single isocenter approach. This study reports our retrospective analysis of patient setup accuracy using this system. The OFLS consists of a bite block with fiducial markers and an infra‐red camera system. To test reproducibility, patients are taken for reseat verification after bite block construction. Upon the completion of radiosurgery planning, the isocenter position(s) and images are sent to the optical guidance computer where fiducials are manually registered from the CT scan. During treatment, patient setup is monitored and guided by the camera readings on the fiducials. In addition, two orthogonal kV images are acquired and used as an isocenter verification tool. In addition, we have analyzed the reseat and fiducial digitization data of 56 patients. Retrospective comparison of kV images with reference images has been carried out for all the patients to evaluate actual patient setup accuracy at the time of treatment. The histogram of the findings shows that 82.2% of patients had 3D isodisplacement (E≤1mm; 5.2% had 1<E≤2mm). Hence, for 87.5 % of the patients in the study, treatments were finished under the optical guidance with a maximum setup error of 2 mm and the median setup error of 0 mm. For the remaining 12.5% of patients in the study, the isodisplacements were greater than 2 mm and the treatment records showed that those patients were repositioned, guided by the orthogonal kV‐images. It is found that the OFLS in the SRS treatment has acceptable accuracy when used in conjunction with orthogonal kV images, and the use of orthogonal kV images as a verification tool ensures the efficacy of frameless localization in the radiosurgery treatment. PACS numbers: 87.53.Ly, 87.61.Tg, 87.55.Qr, 87.56.‐v, 29.20.Ej

Intensity-modulated radiosurgery with rapidarc for multiple brain metastases and comparison with static approach

Rotational RapidArc (RA) and static intensity-modulated radiosurgery (IMRS) have been used for brain radiosurgery. This study compares the 2 techniques from beam delivery parameters and dosimetry aspects for multiple brain metastases. Twelve patients with 2-12 brain lesions treated with IMRS were replanned using RA. For each patient, an optimal 2-arc RA plan from several trials was chosen for comparison with IMRS. Homogeneity, conformity, and gradient indexes have been calculated. The mean dose to normal brain and maximal dose to other critical organs were evaluated. It was found that monitor unit (MU) reduction by RA is more pronounced for cases with larger number of brain lesions. The MU-ratio of RA and IMRS is reduced from 104% to 39% when lesions increase from 2 to 12. The dose homogeneities are comparable in both techniques and the conformity and gradient indexes and critical organ doses are higher in RA. Treatment time is greatly reduced by RA in intracranial radiosurgery, because RA uses fewer MUs, fewer beams, and fewer couch angles.

Tumor motion prediction with the diaphragm as a surrogate: a feasibility study

We have previously assessed the use of the diaphragm as a surrogate for predicting real-time tumor position with linear models built with training data extracted from the same treatment fraction (Cerviño et al 2009 Phys. Med. Biol. 54 3529-41). However, practical use in the clinical setting requires the capability of predicting tumor position throughout the treatment course using a model built at the beginning of the course. We evaluate the inter-fraction applicability of linear models to predict superior-inferior tumor position based on diaphragm position using 21 fluoroscopic sequences from five lung cancer patients. Tumor position is predicted with models built during the first fluoroscopic sequence of each patient. Other fluoroscopic sets are registered to the first set with five different methods. The mean localization prediction error and maximum error at a 95% confidence level averaged over all patients are found to be 1.2 mm and 2.9 mm, respectively, for bony registration and 1.2 mm and 2.8 mm, respectively, for registration based on the mean position of the tumor in the first two breathing cycles. Other registration methods produce larger prediction errors. In the clinical setting, this prediction error could be added as a margin to the target volume. We therefore conclude that it is feasible to predict lung tumor motion with diaphragm with sufficient accuracy in the clinical setting.