Mitchell Kamrava

Utilizing time-driven activity-based costing to understand the short- and long-term costs of treating localized, low-risk prostate cancer.

Given the costs of delivering care for men with prostate cancer remain poorly described, this article reports the results of time‐driven activity‐based costing (TDABC) for competing treatments of low‐risk prostate cancer.

A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

PURPOSE Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Intraoperative Ultrasonography-Guided Positioning of Iodine 125 Plaque Brachytherapy in the Treatment of Choroidal Melanoma

PURPOSE To report intraoperative ultrasonography-guided positioning of iodine 125 (I(125)) plaques for brachytherapy of choroidal melanoma as a quality improvement measure. DESIGN Retrospective, single-center, consecutive case-cohort study. PARTICIPANTS One hundred fifty consecutive patients with choroidal melanoma. METHODS Patients with choroidal melanoma who were treated with I(125) plaque brachytherapy from January 2007 through January 2011 with at least 6 months of clinical follow-up were included. MAIN OUTCOME MEASURES Patient and tumor characteristics at diagnosis were tabulated. The need for plaque repositioning if intraoperative ultrasonography showed the plaque to be either not centered on the tumor or if there was less than 1.0 mm of plaque margin beyond the tumor border was recorded. The rate of local treatment failure and occurrence of distant metastasis were determined. RESULTS The average interval from surgery to last follow-up was 21.5 months. Fifty-four (36%) of 150 patients required plaque repositioning. Of tumors located in the macula, equator, and periphery, 15 (36.6%), 26 (36.6%), and 13 (34.2%) required repositioning. There was no case of local treatment failure during a mean follow-up of 21.5 months (range, 6-48 months). Clinical evidence of choroidal melanoma metastasis developed in 9 patients. The cumulative 2-year Kaplan-Meier rate of local treatment failure in the cohort was statistically lower compared with the Collaborative Ocular Melanoma Study, which did not require ultrasonography-guided plaque positioning. CONCLUSIONS Intraoperative ultrasonography identified the need to reposition I(125) plaques to achieve centration and plaque margin (>1.0 mm) beyond the tumor border in 36% of eyes. Neither tumor size nor tumor location correlated with the need to reposition the plaque. There was no case of local treatment failure during follow-up in this series. Correct plaque position is an essential component of quality outcomes in brachytherapy. Intraoperative ultrasonography reduces geographic errors in placement in eye plaque therapy and may help to reduce local treatment failure in choroidal melanoma.

Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis

BACKGROUND The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons. OBJECTIVE To compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP. DESIGN, SETTING, PARTICIPANTS Retrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p<0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT+BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p=0.0005) or RP (79.1% and 61.5%, p<0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts. CONCLUSIONS Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP. PATIENT SUMMARY While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival.

Prostate-Specific Antigen Bounce After High-Dose-Rate Monotherapy for Prostate Cancer.

PURPOSE To characterize the magnitude and kinetics of prostate-specific antigen (PSA) bounces after high-dose-rate (HDR) monotherapy and determine relationships between certain clinical factors and PSA bounce. METHODS AND MATERIALS Longitudinal PSA data and various clinical parameters were examined in 157 consecutive patients treated with HDR monotherapy between 1996 and 2005. We used the following definition for PSA bounce: rise in PSA ≥threshold, after which it returns to the prior level or lower. Prostate-specific antigen failure was defined per the Phoenix definition (nadir +2 ng/mL). RESULTS A PSA bounce was noted in 67 patients (43%). The number of bounces per patient was 1 in 45 cases (67%), 2 in 19 (28%), 3 in 2 (3%), 4 in 0, and 5 in 1 (1%). The median time to maximum PSA bounce was 1.3 years, its median magnitude was 0.7, and its median duration was 0.75 years. Three patients (2%) were noted to have PSA failure. None of the 3 patients who experienced biochemical failure exhibited PSA bounce. In the fully adjusted model for predicting each bounce, patients aged <55 years had a statistically significant higher likelihood of experiencing a bounce (odds ratio 2.22, 95% confidence interval 1.38-3.57, P=.001). There was also a statistically significant higher probability of experiencing a bounce for every unit decrease in Gleason score (odds ratio 1.52, 95% confidence interval 1.01-2.04, P=.045). CONCLUSIONS A PSA bounce occurs in a significant percentage of patients treated with HDR monotherapy, with magnitudes varying from <1 in 28% of cases to ≥1 in 15%. The median duration of bounce is <1 year. More bounces were identified in patients with lower Gleason score and age <55 years. Further investigation using a model to correlate magnitude and frequency of bounces with clinical variables are under way.

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies.

Brachytherapy in the treatment of cervical cancer: a review.

Dramatic advances have been made in brachytherapy for cervical cancer. Radiation treatment planning has evolved from two-dimensional to three-dimensional, incorporating magnetic resonance imaging and/or computed tomography into the treatment paradigm. This allows for better delineation and coverage of the tumor, as well as improved avoidance of surrounding organs. Consequently, advanced brachytherapy can achieve very high rates of local control with a reduction in morbidity, compared with historic approaches. This review provides an overview of state-of-the-art gynecologic brachytherapy, with a focus on recent advances and their implications for women with cervical cancer.

Multiparametric magnetic resonance imaging for prostate cancer improves Gleason score assessment in favorable risk prostate cancer

PURPOSE Magnetic resonance imaging (MRI) guidance may improve the accuracy of Gleason score (GS) determination by directing the biopsy to regions of interest (ROI) that are likely to harbor high-grade prostate cancer (CaP). The aim of this study was to determine the frequency and predictors of GS upgrading when a subsequent MRI-guided biopsy is performed on patients with a diagnosis of GS 6 disease on the basis of conventional, transrectal ultrasound-guided biopsy. METHODS AND MATERIALS A consecutive series of 245 men with a diagnosis of low-risk CaP (ie, cT1c, GS 6, prostate-specific antigen <10) based on transrectal ultrasound-guided biopsy was enrolled in an active surveillance protocol that used subsequent MRI-guided biopsy for confirmation of GS. ROIs were categorized on a scale of 1 to 5. The Artemis ultrasound-MRI fusion device was used to perform targeted biopsies of ROIs as well as systematic biopsies from a software-based 12-point map. Predictors of GS upgrading were analyzed using univariate and multivariate analyses. RESULTS Fusion biopsy resulted in 26% of patients having GS upgrading (GS 3+4 in 18%, 4+3 in 5%, and 8-9 in 3%). Of the 72% of patients with ROIs appropriate for targeting, targeted cores upgraded the GS in 18%, whereas systematic cores upgraded the GS in 24%. In patients without targeted biopsy, GS upgrading was seen in 14%. On multivariate analysis, a category 5 ROI was the most significant predictor of GS upgrading with an odds ratio of 10.56 (P < .01). CONCLUSIONS Nearly 25% of men with GS 6 CaP diagnosed by standard transrectal ultrasound biopsy may experience GS upgrading when a subsequent MRI-ultrasound fusion biopsy is performed. The most important single predictor of upgrading is a category 5 ROI on multiparametric MRI. GS upgrading may influence treatment decisions. Therefore, MRI-guided biopsy should be considered prior to formulating a management strategy in patients whose conventional biopsy reveals low-risk CaP.

High-Dose-Rate Prostate Brachytherapy Consistently Results in High Quality Dosimetry

PURPOSE We performed a dosimetry analysis to determine how well the goals for clinical target volume coverage, dose homogeneity, and normal tissue dose constraints were achieved with high-dose-rate (HDR) prostate brachytherapy. METHODS AND MATERIALS Cumulative dose-volume histograms for 208 consecutively treated HDR prostate brachytherapy implants were analyzed. Planning was based on ultrasound-guided catheter insertion and postoperative CT imaging; the contoured clinical target volume (CTV) was the prostate, a small margin, and the proximal seminal vesicles. Dosimetric parameters analyzed for the CTV were D90, V90, V100, V150, and V200. Dose to the urethra, bladder, bladder balloon, and rectum were evaluated by the dose to 0.1 cm(3), 1 cm(3), and 2 cm(3) of each organ, expressed as a percentage of the prescribed dose. Analysis was stratified according to prostate size. RESULTS The mean prostate ultrasound volume was 38.7 ± 13.4 cm(3) (range: 11.7-108.6 cm(3)). The mean CTV was 75.1 ± 20.6 cm(3) (range: 33.4-156.5 cm(3)). The mean D90 was 109.2% ± 2.6% (range: 102.3%-118.4%). Ninety-three percent of observed D90 values were between 105 and 115%. The mean V90, V100, V150, and V200 were 99.9% ± 0.05%, 99.5% ± 0.8%, 25.4% ± 4.2%, and 7.8% ± 1.4%. The mean dose to 0.1 cm(3), 1 cm(3), and 2 cm(3) for organs at risk were: Urethra: 107.3% ± 3.0%, 101.1% ± 14.6%, and 47.9% ± 34.8%; bladder wall: 79.5% ± 5.1%, 69.8% ± 4.9%, and 64.3% ± 5.0%; bladder balloon: 70.3% ± 6.8%, 59.1% ± 6.6%, and 52.3% ± 6.2%; rectum: 76.3% ± 2.5%, 70.2% ± 3.3%, and 66.3% ± 3.8%. There was no significant difference between D90 and V100 when stratified by prostate size. CONCLUSIONS HDR brachytherapy allows the physician to consistently achieve complete prostate target coverage and maintain normal tissue dose constraints for organs at risk over a wide range of target volumes.

SBRT and HDR brachytherapy produce lower PSA nadirs and different PSA decay patterns than conventionally fractionated IMRT in patients with low- or intermediate-risk prostate cancer

PURPOSE To compare patterns of prostate-specific antigen (PSA) response following stereotactic body radiation therapy (SBRT), high-dose-rate (HDR) brachytherapy, and conventionally fractionated intensity modulated radiation therapy (IMRT) in patients with low- or intermediate-risk prostate cancer (CaP). METHODS AND MATERIALS Eligible study patients included 439 patients with low- or intermediate-risk prostate cancer who were treated with radiation therapy (RT) alone between 2003 and 2013, remained free of biochemical recurrence, and had at least 2 PSA values within the first year following RT. Of these, 130 were treated with SBRT, 220 with HDR brachytherapy, and 89 with IMRT. Multivariate regression analysis was used to compare PSA nadirs (nPSA), time to nPSA, and PSA bounce parameters among the 3 modalities. Indicator variable analysis was used to develop empirical models of PSA decay using the treatment modalities as indicator variables. RESULTS Significantly more patients treated with SBRT or HDR brachytherapy achieved raw nPSAs of <0.5 ng/mL compared with patients treated with IMRT (76.2% and 75.9% vs 44.9%, respectively; P < .0001 for SBRT or HDR brachytherapy vs IMRT). On multivariate analysis, nPSA was significantly lower with SBRT and HDR compared with IMRT (P < .0001). Time to nPSA and bounce parameters was not significantly different among IMRT, SBRT, and HDR. Overall, SBRT and HDR brachytherapy caused significantly larger PSA decay rates (P < .001). When truncating follow-up at 1000 days, the corresponding decay rates were larger for all 3 modalities, with no significant differences between them. CONCLUSIONS Stereotactic body radiation therapy and HDR brachytherapy produce lower nPSAs than IMRT. Within 1000 days of follow-up, the modalities produce similar rates of PSA decay; subsequently, decay continues (albeit at a slower pace) after SBRT and HDR brachytherapy but plateaus with IMRT. Because nPSA is a validated predictor of long-term outcome, these data not only suggest a distinct radiobiological effect with SBRT and HDR brachytherapy, but also predict for clinical outcomes that might equal or surpass those of IMRT.