Faculty Bibliography

Brachytherapy is an ideal treatment approach for radiorecurrent prostate cancer given the highly conformal treatment. Increasingly, multiparametric magnetic resonance imaging is being utilized to enhance our ability to assess intraprostatic tumor characteristics. This article aims to review the current literature on whole gland salvage brachytherapy for radiorecurrent prostate cancer as well as the methodology and progress towards a focal approach to salvage brachytherapy. Particular emphasis is placed on the potential role of multiparametric MRI in achieving optimal outcomes with focal salvage brachytherapy.

BACKGROUND:Salvage brachytherapy is a treatment option for patients with locally recurrent prostate cancer after primary radiation therapy. We reviewed our experience using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy to compare the outcome and toxicity profiles of each approach in the salvage brachytherapy setting. METHODS AND MATERIALS:Ninety-eight patients with biopsy-proven locally recurrent prostate cancer who underwent salvage brachytherapy (LDR = 37; HDR = 61) following an initial course of definitive radiotherapy between 4/2003 and 4/2015 were retrospectively reviewed. All patients underwent salvage brachytherapy using LDR or HDR. Androgen deprivation therapy was used in 45% of the patients. Prostate-specific antigen (PSA) failure was determined using the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and patient-reported questionnaires. RESULTS:Median followup was 31 months. The 3-year PSA relapse-free survival (RFS) was 60.1% (95% CI, 49.6-72.5%). There was no difference between LDR and HDR brachytherapy in terms of PSA RFS (p = 0.84 by log-rank test). On multivariate analysis, only prostate-specific antigen doubling time (PSADT) <12 months was significantly associated with PSA relapse. The 3-year PSA RFS for patients with a PSADT <12 months was 39% compared with 73% for PSADT ≥12 months (p = 0.002 by long-rank test). There were no statistically significant differences in toxicity between LDR and HDR brachytherapy. There was a higher peak in urinary symptoms in LDR patients; however by 24-36 months, most patients in both groups returned to baseline. CONCLUSIONS:Both LDR and HDR salvage brachytherapy are an excellent treatment options for appropriately selected patients with comparable outcome and toxicity. Patients with a PSADT < 12 months seem to have worse outcomes.

BACKGROUND:The authors characterized the genetic landscape of chemoradiation-treated urothelial carcinoma of the bladder (UCB) with the objective of identifying potential correlates of response. METHODS:Primary tumors with (n = 8) or without (n = 40) matched recurrent tumors from 48 patients who had non-metastatic, high-grade UCB and received treatment primarily with chemoradiation were analyzed using a next-generation sequencing assay enriched for cancer-related and canonical DNA damage response (DDR) genes. Protein expression of meiotic recombination 11 homolog (MRE11), a previously suggested biomarker, was assessed in 44 patients. Recurrent tumors were compared with primary tumors, and the clinical impact of likely deleterious DDR gene alterations was evaluated. RESULTS:The profile of alterations approximated that of prior UCB cohorts. Within 5 pairs of matched primary-recurrent tumors, a median of 92% of somatic mutations were shared. A median 33% of mutations were shared between 3 matched bladder-metastasis pairs. Of 26 patients (54%) who had DDR gene alterations, 12 (25%) harbored likely deleterious alterations. In multivariable analysis, these patients displayed a trend toward reduced bladder recurrence (hazard ratio, 0.32; P = .070) or any recurrence (hazard ratio, 0.37; P = .070). The most common of these alterations, ERCC2 (excision repair cross-complementation group 2) mutations, were associated with significantly lower 2-year metastatic recurrence (0% vs 43%; log-rank P = .044). No impact of MRE11 protein expression on outcome was detected. CONCLUSIONS:A similar mutation profile between primary and recurrent tumors suggests that pre-existing, resistant clonal populations represent the primary mechanism of chemoradiation treatment failure. Deleterious DDR genetic alterations, particularly recurrent alterations in ERCC2, may be associated with improved chemoradiation outcomes in patients with UCB. A small sample size necessitates independent validation of these observations. Cancer 2016;122:3715-23. © 2016 American Cancer Society.

PURPOSE:Accurate identification of the source of a detectable serum prostate-specific antigen (PSA) in the postprostatectomy setting is a major challenge among the urologic community. The aim of this study was to assess positivity rates of imaging examinations performed in patients with early PSA rise after prostatectomy and to summarize the management strategies adopted in this clinical scenario. METHODS:F-sodium fluoride-PET/CT at a single tertiary cancer center. Imaging results were summarized per modality and compared with pathology findings. RESULTS:Pelvic MRI was positive in 15/142 (11%) patients (14 patients with local recurrence in the surgical bed and 1 patient with pelvic osseous metastases). Of these 15, 10 patients underwent additional imaging examinations; none revealed positive findings. Of the 127 patients with negative pelvic MRI, 54 (43%) underwent additional imaging examinations; only 1/54 had positive findings (false-positive T8 lesion on bone scintigraphy and FDG-PET/CT; biopsy was negative for cancer). Overall, 12/16 patients with positive imaging findings and 75/126 (60%) patients with negative imaging received treatment (radiation, hormones or chemotherapy). CONCLUSION:The conventional imaging identified sites of disease, almost always in the form of local recurrence, in a minority of patients with early PSA rise postprostatectomy.

BACKGROUND AND PURPOSE:To evaluate the incidence and predictors of hip toxicity postradiotherapy for localized prostate cancer. METHODS AND MATERIALS:4067 prostate cancer patients were treated with external beam radiotherapy (EBRT; n=2569; 63%) or brachytherapy with or without supplemental EBRT (n=1508; 27%). 43% (n=1738) were treated with neo-adjuvant and concurrent ADT and 57% (n=2329) with radiotherapy alone. Hip toxicity was defined as moderate or severe pain upon ambulation with or without the need for hip-revision surgery. Median follow-up was 7years (range, 3-21years). RESULTS:One hundred twenty-one (2.7%) patients developed moderate-to-severe hip pain after radiotherapy affecting ambulation. Of these, 73 (60%) required hip replacement secondary to persistent hip pain. Among patients with baseline degenerative joint disease (DJD) changes on scans, 10-year incidence of hip-related toxicity was 11% versus 3% for those without such changes (P<.001). The only variables on multivariate analysis associated with hip-related toxicity post-radiotherapy were baseline DJD on imaging (P<.0001) and prolonged ADT for salvage therapy (P<.0001). CONCLUSIONS:Prostate EBRT or brachytherapy is associated with low incidence of long-term hip-related toxicity. The only variables identified associated with hip toxicity posttherapy was the presence of baseline DJD and prolonged salvage ADT posttreatment for patients developing recurrence.

OBJECTIVES:High-dose, hypofractionated radiotherapy (HFRT) is sometimes used to treat malignancy in the head-and-neck (HN), both in the curative and palliative setting. Its safety and efficacy have been reported in small studies and are still controversial. MATERIALS AND METHODS:We retrospectively evaluated the outcomes and toxicities of HFRT, including ultra-high-dose fractionation schemes (⩾8Gray per fraction), for HN malignancies. RESULTS:A total of 62 sites of measurable gross disease in 48 patients were analyzed. The median follow-up was 54.3months among five survivors and 6.0months in the remaining patients. Median RT dose was 30Gray in 5 fractions; 20/62 lesions (32%) received dose-per-fraction of ⩾8Gray. Overall response rate at first follow-up was 79%. One-year local-progression free rate was 50%. On multivariate analysis for locoregional control, dose-per-fraction ⩾6Gray was associated with control (p=0.04) and previous radiation was associated with inferior control (p=0.04). Patients who achieved complete response to RT had longer survival than those who did not (p=0.01). Increased toxicity rates were not observed among patients treated with dose-per-fraction ⩾8Gray; only re-irradiation increased toxicity rates. CONCLUSION:Despite the poor prognostic features noted in this cohort of patients with HN malignancies, HFRT was associated with high response rates, good local control, and acceptable toxicity. Sites that were treated with 6Gray per fraction or higher and had not been previously irradiated had the best disease control. A prospective trial is warranted to further refine the use and indications of HFRT in this setting.

PURPOSE/OBJECTIVE:Robust detection of implanted fiducials is essential for monitoring intrafractional motion during hypofractionated treatment. The authors developed a plan optimization strategy to ensure clear visibility of implanted fiducials and facilitate 3D localization during volumetric modulated arc therapy (VMAT). METHODS:Periodic kilovoltage (kV) images were acquired at 20° gantry intervals and paired with simultaneously acquired 4.4° short arc megavoltage digital tomosynthesis (MV-DTS) to localize three fiducials during VMAT delivery for hypofractionated prostate cancer treatment. Beginning with the original optimized plan, control point segments where fiducials were consistently blocked by multileaf collimator (MLC) within each 4.4° MV-DTS interval were first identified. For each segment, MLC apertures were edited to expose the fiducial that led to the least increase in the cost function. Subsequently, MLC apertures of all control points not involved with fiducial visualization were reoptimized to compensate for plan quality losses and match the original dose-volume histogram. MV dose for each MV-DTS was also kept above 0.4 MU to ensure acceptable image quality. Different imaging (gantry) intervals and visibility margins around fiducials were also evaluated. RESULTS:Fiducials were consistently blocked by the MLC for, on average, 36% of the imaging control points for five hypofractionated prostate VMAT plans but properly exposed after reoptimization. Reoptimization resulted in negligible dosimetric differences compared with original plans and outperformed simple aperture editing: on average, PTV D98 recovered from 87% to 94% of prescription, and PTV dose homogeneity improved from 9% to 7%. Without violating plan objectives and compromising delivery efficiency, the highest imaging frequency and largest margin that can be achieved are a 10° gantry interval, and 15 mm, respectively. CONCLUSIONS:VMAT plans can be made to accommodate MV-kV imaging of fiducials. Fiducial visualization rate and workflow efficiency are significantly improved with an automatic modification and reoptimization approach.

BACKGROUND:The purpose of this study was to examine patterns of failure and the relationship to radiation doses in patients with head and neck carcinoma of unknown primary (HNCUP). METHODS:We reviewed 85 patients with HNCUP treated with curative-intent radiation therapy (RT) during 1995 to 2012. RESULTS:There have been no failures in the pharyngeal axis. Relapse at initial neck sites of disease developed in 7 patients (8.2%). The median dose to these sites was 70 Gy (range, 63-70 Gy). Failure at neck sites without initial disease occurred in 4 patients (4.7%). The median dose was 54 Gy (range, 50-58.8 Gy). There were no contralateral failures in a small cohort of patients receiving unilateral treatment (n = 6). Percutaneous endoscopic gastrostomy (PEG) tube dependence at 12 months was 7.4%, and 2.5% at 3 years. Esophageal stricture developed in 5 patients (5.9%). CONCLUSION:RT for HNCUP produces excellent locoregional control rates with acceptably low levels of late toxicity. Doses prescribed to sites of eventual failure did not vary significantly from those sites that were treated and remain in control. © 2015 Wiley Periodicals, Inc. Head Neck 38: E426-E431, 2016.

The purpose of this study was to evaluate the accuracy and clinical feasibility of a motion monitoring method employing simultaneously acquired MV and kV images during volumetric-modulated arc therapy (VMAT). Short-arc digital tomosynthesis (SA-DTS) is used to improve the quality of the MV images that are then combined with orthogonally acquired kV images to assess 3D motion. An anthropomorphic phantom with implanted gold seeds was used to assess accuracy of the method under static, typical prostatic, and respiratory motion scenarios. Automatic registra-tion of kV images and single MV frames or MV SA-DTS reconstructed with arc lengths from 2° to 7° with the appropriate reference fiducial template images was performed using special purpose-built software. Clinical feasibility was evaluated by retrospectively analyzing images acquired over four or five sessions for each of three patients undergoing hypofractionated prostate radiotherapy. The standard deviation of the registration error in phantom using MV SA-DTS was similar to single MV images for the static and prostate motion scenarios (σ = 0.25 mm). Under respiratory motion conditions, the standard deviation of the registration error increased to 0.7mm and 1.7 mm for single MV and MV SA-DTS, respectively. Registration failures were observed with the respiratory scenario only and were due to motion-induced fiducial blurring. For the three patients studied, the mean and standard deviation of the difference between automatic registration using 4° MV SA-DTS and manual registration using single MV images results was 0.07±0.52mm. The MV SA-DTS results in patients were, on average, superior to single-frame MV by nearly 1 mm - significantly more than what was observed in phantom. The best MV SA-DTS results were observed with arc lengths of 3° to 4°. Registration failures in patients using MV SA-DTS were primarily due to blockage of the gold seeds by the MLC. The failure rate varied from 2% to 16%. Combined MV SA-DTS and kV imaging is feasible for intratreatment motion monitoring during VMAT of anatomic sites where limited motion is expected, and improves registration accuracy compared to single MV/kV frames. To create a clinically robust technique, further improvements to ensure visualization of fiducials at the desired control points without degradation of the treatment plan are needed.