To monitor noninvasively potentially therapeutic adenoviruses for cancer, we have developed a methodology based on the sodium iodide symporter (NIS). Men with clinically localized prostate cancer were administered an intraprostatic injection of a replication-competent adenovirus, Ad5-yCD/utTKSR39rep-hNIS, armed with two suicide genes and the NIS gene. NIS gene expression (GE) was imaged noninvasively by uptake of Na99mTcO4 in infected cells using single photon emission–computed tomography (SPECT). The investigational therapy was safe with 98% of the adverse events being grade 1 or 2. GE was detected in the prostate in seven of nine (78%) patients at 1 × 1012 virus particles (vp) but not at 1 × 1011 vp. Volume and total amount of GE was quantified by SPECT. Following injection of 1 × 1012 vp in 1 cm3, GE volume (GEV) increased to a mean of 6.6 cm3, representing, on average, 18% of the total prostate volume. GEV and intensity peaked 1–2 days after the adenovirus injection and was detectable in the prostate up to 7 days. Whole-body imaging demonstrated intraprostatic gene expression, and there was no evidence of extraprostatic dissemination of the adenovirus by SPECT imaging. The results demonstrate that noninvasive imaging of adenovirus-mediated gene therapy in humans is feasible and safe.

Replication-competent adenovirus-mediated suicide gene therapy is an investigational cancer treatment in which an oncolytic adenovirus armed with chemo-radiosensitizing genes is used to destroy tumor cells. Previously, we evaluated the toxicity and efficacy of this approach in two clinical trials of prostate cancer using a first-generation adenovirus. Here, we report the toxicity and preliminary efficacy of this approach in combination with intensity-modulated radiotherapy (IMRT) in patients with newly diagnosed prostate cancer using an improved, second-generation adenovirus. The investigational therapy was associated with low toxicity, and there were no dose-limiting toxicities or treatment-related serious adverse events. Relative to a previous trial using a first-generation adenovirus, there was no increase in hematologic, hepatic, gastrointestinal (GI), or genitourinary (GU) toxicities. Post-treatment prostate biopsies yielded provocative preliminary results. When the results of two similar trials were combined, 22% of evaluable patients were positive for adenocarcinoma at their last biopsy, which is better than expected (>or=40%) for this cohort of patients (P=0.038). When the results were categorized by prognostic risk, most of the treatment effect was observed in the intermediate-risk group, with 0 of 12 patients (0%) being positive for cancer at their last biopsy (P<0.01). These results further demonstrate the safety of this investigational approach and raise the possibility that it may have the potential to improve the outcome of conformal radiotherapy in select patient groups.

Purpose To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days’) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the two arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Purpose This study aimed to evaluate the clinical utility of a novel iterative cone beam computed tomography (CBCT) reconstruction algorithm for prostate and head and neck (HN) cancer. Methods and Materials A total of 10 patients with HN and 10 patients with prostate cancer were analyzed. For each patient, raw CBCT acquisition data were used to reconstruct images with a currently available algorithm (FDK_CBCT) and novel iterative algorithm (Iterative_CBCT). Quantitative contouring variation analysis was performed using structures delineated by several radiation oncologists. For prostate, observers contoured the prostate, proximal 2 cm seminal vesicles, bladder, and rectum. For HN, observers contoured the brain stem, spinal canal, right-left parotid glands, and right-left submandibular glands. Observer contours were combined to form a reference consensus contour using the simultaneous truth and performance level estimation method. All observer contours then were compared with the reference contour to calculate the Dice coefficient, Hausdorff distance, and mean contour distance (prostate contour only). Qualitative image quality analysis was performed using a 5-point scale ranging from 1 (much superior image quality for Iterative_CBCT) to 5 (much inferior image quality for Iterative_CBCT). Results The Iterative_CBCT data sets resulted in a prostate contour Dice coefficient improvement of approximately 2.4% ( P = .029). The average prostate contour Dice coefficient for the Iterative_CBCT data sets was improved for all patients, with improvements up to approximately 10% for 1 patient. The mean contour distance results indicate an approximate 15% reduction in mean contouring error for all prostate regions. For the parotid contours, Iterative_CBCT data sets resulted in a Hausdorff distance improvement of approximately 2 mm ( P < .01) and an approximate 2% improvement in Dice coefficient ( P = .03). The Iterative_CBCT data sets were scored as equivalent or of better image quality for 97.3% (prostate) and 90.0% (HN) of the patient data sets. Conclusions Observers noted an improvement in image uniformity, noise level, and overall image quality for Iterative_CBCT data sets. In addition, expert observers displayed an improved ability to consistently delineate soft tissue structures, such as the prostate and parotid glands. Thus, the novel iterative reconstruction algorithm analyzed in this study is capable of improving the visualization for prostate and HN cancer image guided radiation therapy.

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