Daniel C. Fernandez

Stability of endoscopic ultrasound-guided fiducial marker placement for esophageal cancer target delineation and image-guided radiation therapy

PURPOSE Fiducial markers have been integrated into the management of multiple malignancies to guide more precise delivery of radiation therapy (RT). Fiducials placed at the margins of esophageal tumors are potentially useful to facilitate both RT target delineation and image-guided RT (IGRT). In this study, we report on the stability of endoscopic ultrasound (EUS)-guided fiducial placement for esophageal cancers and utilization for radiation treatment planning and IGRT. METHODS An institutional review board-approved database was queried for patients treated for esophageal cancer with chemoradiotherapy (CRT). Patients included in the analysis had a diagnosis of esophageal cancer, were referred for treatment with CRT, and had fiducials placed under EUS guidance. Images acquired at time of radiation treatment planning, daily IGRT imaging, post-treatment restaging, and surveillance scans were analyzed to determine the stability of implanted markers. RESULTS We identified 60 patients who underwent EUS-guided fiducial marker placement near the margins of their esophageal tumors in preparation for RT treatment planning. A total of 105 fiducial markers were placed. At time of CT simulation, 99 markers were visualized. Fifty-seven patients had post-treatment imaging available for review. Of the 100 implanted fiducials in these 57 patients, 94 (94%) were visible at time of RT simulation. Eighty-eight (88%) fiducials were still present post-treatment imaging at a median of 107 days (range, 33-471 days) after implantation. CONCLUSIONS EUS-guided fiducial marker placement for esophageal cancer aids in target delineation for radiation planning and daily IGRT. Fiducial stability is reproducible and facilitates conformal treatment with image-guided RT techniques.

Primary bladder preservation treatment for urothelial bladder cancer.

BACKGROUND Significant advancements have occurred in surgical procedures and chemoradiation therapy for bladder preservation. METHODS This review addresses primary treatment options for bladder cancer, including an overview of bladder-sparing strategies. RESULTS Surgical series demonstrate that highly selected patients with cT2N0M0 urothelial bladder cancers can be managed with partial cystectomy and bilateral pelvic lymphadenectomy. For patients with cT2N0M0 to cT4aN0M0 urothelial bladder cancers, neoadjuvant chemotherapy followed by radical cystectomy or maximal transurethral resection of the bladder tumor (TURBT) followed by chemoradiation therapy results in equivalent survival rates. However, each treatment option has a different impact on quality of life. Current chemoradiation therapy trials are evaluating novel approaches to improve outcomes. CONCLUSIONS Maximal TURBT followed by chemoradiation therapy demonstrated equivalent survival with radical cystectomy while preserving bladder function in the majority of patients. Future efforts will be directed toward improving survival and quality of life.

A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy ± intensity modulated radiation therapy

BACKGROUND AND PURPOSE We sought to analyze the effect of polyethylene glycol (PEG) hydrogel on rectal doses in prostate cancer patients undergoing radiotherapy. MATERIALS AND METHODS Between July 2009 and April 2013, we treated 200 clinically localized prostate cancer patients with high-dose rate (HDR) brachytherapy±intensity modulated radiation therapy. Half of the patients received a transrectal ultrasound (TRUS)-guided transperineal injection of 10mL PEG hydrogel (DuraSeal™ Spinal Sealant System; Covidien, Mansfield, MA) in their anterior perirectal fat immediately prior to the first HDR brachytherapy treatment and 5mL PEG hydrogel prior to the second HDR brachytherapy treatment. Prostate, rectal, and bladder doses and prostate-rectal distances were calculated based upon treatment planning CT scans. RESULTS There was a success rate of 100% (100/100) with PEG hydrogel implantation. PEG hydrogel significantly increased the prostate-rectal separation (mean±SD, 12±4mm with gel vs. 4±2mm without gel, p<0.001) and significantly decreased the mean rectal D2 mL (47±9% with gel vs. 60±8% without gel, p<0.001). Gel decreased rectal doses regardless of body mass index (BMI). CONCLUSIONS PEG hydrogel temporarily displaced the rectum away from the prostate by an average of 12mm and led to a significant reduction in rectal radiation doses, regardless of BMI.

A dosimetric comparison of volumetric modulated arc therapy with step-and-shoot intensity modulated radiation therapy for prostate cancer

PURPOSE To compare variable dose-rate volumetric modulated arc therapy (VMAT) with 7-field, step-and-shoot intensity modulated radiation therapy (IMRT) in prostate cancer patients treated with a consistent planning target volume (PTV) to a uniform total radiation therapy dose. METHODS AND MATERIALS We studied 32 patients who received 8100 cGy in 45 daily fractions to their prostate and proximal 1 cm of the seminal vesicles using variable dose rate VMAT (n = 22) or 7-field, step-and-shoot IMRT (n = 10) for intermediate-risk or high-risk prostate cancer between July 2010 and April 2013. In 90% of patients, VMAT was delivered with 2 arcs. To have an unbiased comparison of plan quality, patients who were treated with VMAT were also planned with IMRT and vice versa. Each patient served as his own control for the comparison. RESULTS VMAT reduced median radiation beam-on time from 4.3 to 3.4 minutes (P = .03). There was no statistically significant difference in PTV volumes between the VMAT and step-and-shoot IMRT groups (P = .76). VMAT dose distributions were more homogeneous (P = .003). There was no difference between groups with regard to rectal V60, V65, V70, V75, bladder V65, V70, V75, V80, or femoral heads V33. CONCLUSIONS Two-arc VMAT resulted in shorter beam-on times and more homogenous dose distributions than 7-field, step-and-shoot IMRT for prostate cancer. With decreased beam-on time, the intrafraction motion during irradiation is reduced, thus improving confidence that the delivered dose distribution agrees with the plan.

Health-related quality-of-life changes due to high-dose-rate brachytherapy, low-dose-rate brachytherapy, or intensity-modulated radiation therapy for prostate cancer.

PURPOSE To compare urinary, bowel, and sexual health-related quality-of-life (HRQOL) changes due to high-dose-rate (HDR) brachytherapy, low-dose-rate (LDR) brachytherapy, or intensity-modulated radiation therapy (IMRT) monotherapy for prostate cancer. METHODS AND MATERIALS Between January 2002 and September 2013, 413 low-risk or favorable intermediate-risk prostate cancer patients were treated with HDR brachytherapy monotherapy to 2700-2800 cGy in two fractions (n = 85), iodine-125 LDR brachytherapy monotherapy to 14,500 cGy in one fraction (n = 249), or IMRT monotherapy to 7400-8100 cGy in 37-45 fractions (n = 79) without pelvic lymph node irradiation. No androgen deprivation therapy was given. Patients used an international prostate symptoms score questionnaire, an expanded prostate cancer index composite-26 bowel questionnaire, and a sexual health inventory for men questionnaire to assess their urinary, bowel, and sexual HRQOL, respectively, pretreatment and at 1, 3, 6, 9, 12, and 18 months posttreatment. RESULTS Median follow-up was 32 months. HDR brachytherapy and IMRT patients had significantly less deterioration in their urinary HRQOL than LDR brachytherapy patients at 1 and 3 months after irradiation. The only significant decrease in bowel HRQOL between the groups was seen 18 months after treatment, at which point IMRT patients had a slight, but significant, deterioration in their bowel HRQOL compared with HDR and LDR brachytherapy patients. HDR brachytherapy patients had worse sexual HRQOL than both LDR brachytherapy and IMRT patients after treatment. CONCLUSIONS IMRT and HDR brachytherapy cause less severe acute worsening of urinary HRQOL than LDR brachytherapy. However, IMRT causes a slight, but significant, worsening of bowel HRQOL compared with HDR and LDR brachytherapy.

Reproducibility of F18‐FDG PET radiomic features for different cervical tumor segmentation methods, gray‐level discretization, and reconstruction algorithms

Abstract Site‐specific investigations of the role of radiomics in cancer diagnosis and therapy are emerging. We evaluated the reproducibility of radiomic features extracted from 18Flourine–fluorodeoxyglucose (18F‐FDG) PET images for three parameters: manual versus computer‐aided segmentation methods, gray‐level discretization, and PET image reconstruction algorithms. Our cohort consisted of pretreatment PET/CT scans from 88 cervical cancer patients. Two board‐certified radiation oncologists manually segmented the metabolic tumor volume (MTV1 and MTV2) for each patient. For comparison, we used a graphical‐based method to generate semiautomated segmented volumes (GBSV). To address any perturbations in radiomic feature values, we down‐sampled the tumor volumes into three gray‐levels: 32, 64, and 128 from the original gray‐level of 256. Finally, we analyzed the effect on radiomic features on PET images of eight patients due to four PET 3D‐reconstruction algorithms: maximum likelihood‐ordered subset expectation maximization (OSEM) iterative reconstruction (IR) method, fourier rebinning‐ML‐OSEM (FOREIR), FORE‐filtered back projection (FOREFBP), and 3D‐Reprojection (3DRP) analytical method. We extracted 79 features from all segmentation method, gray‐levels of down‐sampled volumes, and PET reconstruction algorithms. The features were extracted using gray‐level co‐occurrence matrices (GLCM), gray‐level size zone matrices (GLSZM), gray‐level run‐length matrices (GLRLM), neighborhood gray‐tone difference matrices (NGTDM), shape‐based features (SF), and intensity histogram features (IHF). We computed the Dice coefficient between each MTV and GBSV to measure segmentation accuracy. Coefficient values close to one indicate high agreement, and values close to zero indicate low agreement. We evaluated the effect on radiomic features by calculating the mean percentage differences (d¯) between feature values measured from each pair of parameter elements (i.e. segmentation methods: MTV1‐MTV2, MTV1‐GBSV, MTV2‐GBSV; gray‐levels: 64‐32, 64‐128, and 64‐256; reconstruction algorithms: OSEM‐FORE‐OSEM, OSEM‐FOREFBP, and OSEM‐3DRP). We used |d¯| as a measure of radiomic feature reproducibility level, where any feature scored |d¯| ±SD ≤ |25|% ± 35% was considered reproducible. We used Bland–Altman analysis to evaluate the mean, standard deviation (SD), and upper/lower reproducibility limits (U/LRL) for radiomic features in response to variation in each testing parameter. Furthermore, we proposed U/LRL as a method to classify the level of reproducibility: High— ±1% ≤ U/LRL ≤ ±30%; Intermediate— ±30% < U/LRL ≤ ±45%; Low— ±45 < U/LRL ≤ ±50%. We considered any feature below the low level as nonreproducible (NR). Finally, we calculated the interclass correlation coefficient (ICC) to evaluate the reliability of radiomic feature measurements for each parameter. The segmented volumes of 65 patients (81.3%) scored Dice coefficient >0.75 for all three volumes. The result outcomes revealed a tendency of higher radiomic feature reproducibility among segmentation pair MTV1‐GBSV than MTV2‐GBSV, gray‐level pairs of 64‐32 and 64‐128 than 64‐256, and reconstruction algorithm pairs of OSEM‐FOREIR and OSEM‐FOREFBP than OSEM‐3DRP. Although the choice of cervical tumor segmentation method, gray‐level value, and reconstruction algorithm may affect radiomic features, some features were characterized by high reproducibility through all testing parameters. The number of radiomic features that showed insensitivity to variations in segmentation methods, gray‐level discretization, and reconstruction algorithms was 10 (13%), 4 (5%), and 1 (1%), respectively. These results suggest that a careful analysis of the effects of these parameters is essential prior to any radiomics clinical application.

High-dose-rate endorectal brachytherapy for locally advanced rectal cancer in previously irradiated patients

PURPOSE Preoperative high-dose-rate (HDR) endorectal brachytherapy is well tolerated among patients with locally advanced rectal cancer. However, these studies excluded patients who previously received pelvic radiation therapy (RT). Because a favorable toxicity profile has been published for HDR endorectal brachytherapy, we evaluated this technique in patients who have previously received pelvic irradiation. METHODS AND MATERIALS We included patients who had received pelvic irradiation for a previous pelvic malignancy and later received preoperative HDR endorectal brachytherapy for rectal cancer. Brachytherapy was delivered to a total dose of 26 Gy in 4 consecutive daily 6.5 Gy fractions. RESULTS We evaluated 10 patients who previously received pelvic external beam radiation therapy (EBRT) alone (n=6), EBRT and brachytherapy (n=2), or brachytherapy alone (n=2). The median interval between the initial course of RT and endorectal brachytherapy was approximately 11 years (range, 1-19 years). Two patients experienced a complete pathologic response while 1 patient had a near complete pathologic response. No acute grade ≥3 toxicity was observed. No intraoperative or postoperative surgical complications were observed. CONCLUSIONS Preoperative HDR endorectal brachytherapy is an alternative to EBRT for patients with locally advanced rectal cancer who have previously received pelvic RT.

Lipiodol as a Fiducial Marker for Image-Guided Radiation Therapy for Bladder Cancer

PURPOSE To evaluate Lipiodol as a liquid, radio-opaque fiducial marker for image-guided radiation therapy (IGRT) for bladder cancer. MATERIALS AND METHODS Between 2011 and 2012, 5 clinical T2a-T3b N0 M0 stage II-III bladder cancer patients were treated with maximal transurethral resection of a bladder tumor (TURBT) and image-guided radiation therapy (IGRT) to 64.8 Gy in 36 fractions ± concurrent weekly cisplatin-based or gemcitabine chemotherapy. Ten to 15mL Lipiodol, using 0.5mL per injection, was injected into bladder submucosa circumferentially around the entire periphery of the tumor bed immediately following maximal TURBT. The authors looked at inter-observer variability regarding the size and location of the tumor bed (CTVboost) on computed tomography scans with versus without Lipiodol. RESULTS Median follow-up was 18 months. Lipiodol was visible on every orthogonal two-dimensional kV portal image throughout the entire, 7-week course of IGRT. There was a trend towards improved inter-observer agreement on the CTVboost with Lipiodol (p = 0.06). In 2 of 5 patients, the tumor bed based upon Lipiodol extended outside a planning target volume that would have been treated with a radiation boost based upon a cystoscopy report and an enhanced computed tomography (CT) scan for staging. There was no toxicity attributable to Lipiodol. CONCLUSIONS Lipiodol constitutes a safe and effective fiducial marker that an urologist can use to demarcate a tumor bed immediately following maximal TURBT. Lipiodol decreases inter-observer variability in the definition of the extent and location of a tumor bed on a treatment planning CT scan for a radiation boost.

External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

PURPOSE To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. MATERIALS AND METHODS From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. RESULTS Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, therewas no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. CONCLUSIONS There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine- 125 provide similar bDFS, DMFS, and OS.

Quality of life after high-dose-rate brachytherapy monotherapy for prostate cancer

Purpose There is little information in the literature on health-related quality of life (HRQOL) changes due to high-dose-rate (HDR) brachytherapy monotherapy for prostate cancer. Materials and Methods We conducted a prospective study of HRQOL changes due to HDR brachytherapy monotherapy for low risk or favorable intermediate risk prostate cancer. Sixty-four of 84 (76%) patients who were treated between February 2011 and April 2013 completed 50 questions comprising the Expanded Prostate Cancer Index Composite (EPIC) before treatment and 6 and/or 12 months after treatment. Results Six months after treatment, there was a significant decrease (p<0.05) in EPIC urinary, bowel, and sexual scores, including urinary overall, urinary function, urinary bother, urinary irritative, bowel overall, bowel bother, sexual overall, and sexual bother scores. By one year after treatment, EPIC urinary, bowel, and sexual scores had increased and only the bowel overall and bowel bother scores remained significantly below baseline values. Conclusions HDR brachytherapy monotherapy is well-tolerated in patients with low and favorable intermediate risk prostate cancer. EPIC urinary and sexual domain scores returned to close to baseline 12 months after HDR brachytherapy.