Farzan Siddiqui

Radiation Pulmonary Toxicity: From Mechanisms to Management

The goal of radiation therapy is to reduce or eliminate tumor burden while sparing normal tissues from long-term injury. Thoracic radiation presents a unique challenge because of the inherent sensitivity of normal lung tissue to radiation. Damage to normal lung tissue presents a major obstacle in the treatment of individuals. To overcome this problem, a number of strategies are being used, including the modulation of dose volume, the use of image-guided radiotherapy, and the use of agents designed to reduce lung injury from radiation. Herein we discuss our current knowledge of the molecular and cellular events that occur after radiation therapy, the clinical manifestations of radiation-induced lung injury, current strategies to minimize lung injury, and recent experimental methods to reduce lung injury and their potential for translation into the clinic.

Phase I Study of Noninvasive Imaging of Adenovirus-mediated Gene Expression in the Human Prostate

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/utTK(SR39)rep-hNIS, armed with two suicide genes and the NIS gene. NIS gene expression (GE) was imaged noninvasively by uptake of Na(99 m)TcO(4) 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 x 10(12) virus particles (vp) but not at 1 x 10(11) vp. Volume and total amount of GE was quantified by SPECT. Following injection of 1 x 10(12) vp in 1 cm(3), GE volume (GEV) increased to a mean of 6.6 cm(3), 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.

Stereotactic body radiation therapy for primary, recurrent, and metastatic tumors in the head-and-neck region.

PURPOSE To determine the feasibility, safety, and efficacy of stereotactic body radiation therapy (SBRT), also known as radiosurgery, in patients with head-and-neck cancers. METHODS AND MATERIALS Patients with pathologically proven malignant lesions in the head-and-neck region were treated using single-dose SBRT (S-SBRT) or fractionated SBRT (F-SBRT). Radiation doses were either single-fraction 13-18 Gy for S-SBRT or 36-48 Gy in five to eight fractions for F-SBRT. Response evaluation was based on clinical examinations and computed tomography/magnetic resonance imaging scans. Pre- and post-SBRT tumor dimensions were measured in three axes, and tumor volumes were calculated. Response evaluation also was performed using World Health Organization criteria. RESULTS Fifty-five lesions were treated in 44 patients (25 men, 19 women). There were three groups of patients: those with primary (n = 10), recurrent (n = 21), and metastatic tumors (n = 13). The predominant histologic type was squamous cell carcinoma (n = 33). The majority of lesions were treated using F-SBRT (n = 37). Based on radiographic and clinical assessment, a 77% (complete + partial response) response rate was noted. Percentage of reduction in tumor volume was 52% +/- 38% based on follow-up scans in 24 patients. Tumor control rates at 1 year were 83.3% and 60.6% in the primary and recurrent groups, respectively. Median overall survival was 28.7, 6.7, and 5.6 months for the primary, recurrent, and metastatic groups, respectively. Radiation Therapy Oncology Group Grade 1-2 mucositis was noted in all patients treated for oropharyngeal or laryngeal lesions. CONCLUSIONS The SBRT in single or fractionated doses offers a viable treatment option for selected patients with primary, recurrent, and metastatic head-and-neck cancers with functional preservation.

Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

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 2 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.

Emerging applications of stereotactic body radiation therapy for head and neck cancer.

Head and neck cancer is typically managed with surgery, radiation therapy, chemotherapy or various combinations of the above. In patients who develop recurrence after radiation therapy, treatment options are limited. Reirradiation can be offered but the amount of additional radiation that can be given is limited and there is an increased risk of serious complications. Stereotactic radiation therapy has been used as a boost or salvage therapy at recurrence for nasopharyngeal carcinoma. The use of stereotactic body radiation therapy for head and neck cancer has expanded to include sites outside of the base of skull region, especially in the recurrent setting, and clinical data are emerging. This article will highlight some of the technical and clinical advances in this area.

Prophylactic versus Reactive PEG Tube Placement in Head and Neck Cancer

Objective To understand the impact of percutaneous endoscopic gastrostomy (PEG) tube placement timing on tube duration, weight loss, and disease control in patients with head and neck cancer (HNC). Setting A tertiary academic center. Study Design Historical cohort study. Subjects and Methods Seventy-four patients with HNC were reviewed. Patients underwent cisplatinum-based chemoradiation therapy with or without surgical resection. They received a PEG tube either before radiation therapy began (prophylactic) or after (reactive). Patients were matched on the basis of age, gender, TNM stage, tumor subsite, human papillomavirus (HPV) status, and chemoradiation dose. Results Patients receiving reactive PEG tubes had them in place for fewer days than those placed prophylactically (227 vs 139 days, P < .01). There was no difference in percentage weight loss at 2, 6, or 12 months. There was no difference in survival or disease control between the groups. Conclusions Reactive PEG tube placement may afford patients a shorter duration of usage without incurring greater weight loss or poorer oncologic outcomes.

The influence of gender, race, and marital status on survival in lung cancer patients: analysis of Radiation Therapy Oncology Group trials.

Objective: A meta-analysis was conducted to determine the influence of gender, race, and marital status on overall survival (OS) in Radiation Therapy Oncology Group nonoperative non-small cell lung cancer trials. Materials and Methods: Data from 1365 patients treated on nine prospective Radiation Therapy Oncology Group studies activated during the 1990s were analyzed. Impact of gender, marital status, and race was considered in the Cox proportional hazards models. Age, Karnofsky performance status, weight loss, stage, histology, location of primary tumor, biologic equivalent dose, deviation from protocol dose, and education level were adjusted in the model. A two-sided p value <0.05 was considered statistically significant. Results: Males had significantly higher mortality than females adjusted for other covariates (hazard ratio [HR] = 1.22, 95% confidence interval = 1.08–1.38). Race and marital status were not independently predictive for OS. Single females had significantly better OS than single males (HR = 0.72), and married males had lower OS than single females (HR = 1.36). Conclusions: These results suggest that although certain subgroups of gender, race, and/or marital status have better outcomes with respect to OS; gender seems to be the most significant factor influencing survival results among nonoperative non-small cell lung cancer patients.

Characteristics of a novel treatment system for linear accelerator–based stereotactic radiosurgery

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image‐guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter‐free (FFF) beams for both high definition (HD120) MLC and conical cone‐based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end‐to‐end accuracy tests, have been performed. The end‐to‐end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone‐beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth‐dose curves acquired on the new linac‐based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond Dmax were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2−1.8 mm (80%‐20%) and 1.9−3.8 mm (90%‐10%) relative to 10X FFF, which has 1.2−2.2 mm and 2.3−5.1 mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails‐in), oblique, oblique (rails‐out), oblique (rails‐in) were: −2.0%, −2.5%, −15.6%, −2.5%, −5.0% for 6X FFF and −1.4%, −1.5%, −12.2%, −2.5%, −5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was −0.4±0.2 mm, 0.1±0.3 mm, and 0.0±0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston‐Lutz tests over three months are 0.20±0.03 mm and 0.66±0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac‐based SRS and SBRT treatment. PACS number: 87.56.J‐

Influence of Comorbidity on the Risk of Death: A Single Institution Study of 1132 Women With Early-stage Uterine Cancer

Purpose/Objective(s): The impact of competing medical comorbidity on survival endpoints in women with early stage endometrial carcinoma (EC) is not well studied. The study goal was to utilize a validated comorbidity scoring system to determine its impact on all-cause mortality as well as on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with early-stage EC. Materials and Methods: For this IRB-approved study, we reviewed our prospectively maintained uterine cancer database of 1720 patients. We identified 1132 patients with EC FIGO stages I-II who underwent hysterectomy from 1984 to 2011. Age-adjusted Charlson Comorbidity Index (AACCI) at time of hysterectomy was retrospectively calculated by physician chart review. The cause of death (uterine cancer-related and unrelated) was correlated with AACCI. Univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of OS, DSS, and RFS. The Kaplan-Meier and the log-rank test methods were used to evaluate survival outcomes. Results: After a median follow-up of 51 months, 262 deaths were recorded (42 from EC [16%], and 220 [84%] from other causes). Median AACCI score for the study cohort was 3 (range, 0 to 15). On the basis of AACCI, patients were grouped as follows: 0 to 2 (group 1, n=379), 3 to 4 (group 2, n=532), and ≥5 (group 3, n=221). By AACCI grouping, the 5-year RFS, DSS, and OS were 95%, 98%, and 97% for group 1, 89%, 95%, and 87% for group 2, and 86%, 95% and 72% for group 3 (P<0.0001). The cause of death in the first 10 years after hysterectomy in our study was mainly non-uterine cancer-related (78% vs. 22% for uterine cancer-related) causes. On multivariate analyses, higher AACCI, lymphovascular space invasion (LVSI), higher tumor grade, age, and involvement of the lower uterine segment were significant predictors of shorter OS. On multivariate analysis for DSS and RFS, only high tumor grade and LVSI were significant predictors. Conclusions: The cause of death for women with early stage EC is mainly nonuterine cancer-related. Comorbidity score is a significant predictor of OS in our study cohort. Comorbidity scores may be useful as a stratification factor in any prospective clinical trial for women with early-stage EC.

Analysis of outcomes in radiation oncology: An integrated computational platform

Radiotherapy research and outcome analyses are essential for evaluating new methods of radiation delivery and for assessing the benefits of a given technology on locoregional control and overall survival. In this article, a computational platform is presented to facilitate radiotherapy research and outcome studies in radiation oncology. This computational platform consists of (1) an infrastructural database that stores patient diagnosis, IMRT treatment details, and follow-up information, (2) an interface tool that is used to import and export IMRT plans in DICOM RT and AAPM/RTOG formats from a wide range of planning systems to facilitate reproducible research, (3) a graphical data analysis and programming tool that visualizes all aspects of an IMRT plan including dose, contour, and image data to aid the analysis of treatment plans, and (4) a software package that calculates radiobiological models to evaluate IMRT treatment plans. Given the limited number of general-purpose computational environments for radiotherapy research and outcome studies, this computational platform represents a powerful and convenient tool that is well suited for analyzing dose distributions biologically and correlating them with the delivered radiation dose distributions and other patient-related clinical factors. In addition the database is web-based and accessible by multiple users, facilitating its convenient application and use.