Development and Multicenter Case-Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction.

PURPOSE: Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. EXPERIMENTAL DESIGN: This is a multicenter case-control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology. RESULTS: uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%. CONCLUSIONS: uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients.

Cross-linked hyaluronan gel improves the quality of life of prostate cancer patients undergoing radiotherapy.

PURPOSE: To test the hypothesis that cross-linked hyaluronan gel (Hylaform) does not affect the quality of life (QOL) of prostate cancer patients undergoing radiotherapy. METHODS AND MATERIALS: Thirty-five patients with early stage prostate cancer underwent high-dose-rate brachytherapy to 2200 cGy and intensity modulated radiation therapy to 5040 cGy on a prospective study. Thirty patients received a single transperineal injection of 9-mL Hylaform between the prostate and rectum under transrectal ultrasound guidance immediately before the start of radiotherapy. Hylaform increased the separation between the prostate and rectum by 6-19 mm (median, 13 mm) at the start of radiotherapy. Five patients did not receive Hylaform and served as controls. We assessed gastrointestinal-related QOL using Expanded Prostate Cancer Index Composite Bowel Bother scores immediately before the start of and during the last week of radiotherapy. RESULTS: At the beginning of intensity modulated radiation therapy, daily mean rectal doses were 74±8 cGy (mean±standard deviation) and 105±25 cGy (mean±standard deviation) with vs. without Hylaform, respectively (p=0.01). Expanded Prostate Cancer Index Composite Bowel Bother scores decreased by 0±3 (mean±standard deviation) and 11±14 (mean±standard deviation) in patients who did and did not receive Hylaform, respectively (p=0.03). CONCLUSIONS: Hylaform increased the separation between the prostate and rectum and decreased the mean rectal dose, thereby improving the gastrointestinal-related acute QOL of prostate cancer patients undergoing radiotherapy. Patients will be followed up long term to determine if the improvement in acute QOL also translates into an improvement in late QOL.

Cross-linked hyaluronan gel reduces the acute rectal toxicity of radiotherapy for prostate cancer.

PURPOSE: To prospectively analyze whether cross-linked hyaluronan gel reduces the mean rectal dose and acute rectal toxicity of radiotherapy for prostate cancer. METHODS AND MATERIALS: Between September 2008 and March 2009, we transperitoneally injected 9 mL of cross-linked hyaluronan gel (Hylaform; Genzyme Corporation, Cambridge, MA) into the anterior perirectal fat of 10 early-stage prostate cancer patients to increase the separation between the prostate and rectum by 8 to 18 mm at the start of radiotherapy. Patients then underwent high-dose rate brachytherapy to 2,200 cGy followed by intensity-modulated radiation therapy to 5,040 cGy. We assessed acute rectal toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading scheme. RESULTS: Median follow-up was 3 months. The anteroposterior dimensions of Hylaform at the start and end of radiotherapy were 13 +/- 3mm (mean +/- SD) and 10 +/- 4mm, respectively. At the start of intensity-modulated radiation therapy, daily mean rectal doses were 73 +/- 13 cGy with Hylaform vs. 106 +/- 20 cGy without Hylaform (p = 0.005). There was a 0% incidence of National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 Grade 1, 2, or 3 acute diarrhea in 10 patients who received Hylaform vs. a 29.7% incidence (n = 71) in 239 historical controls who did not receive Hylaform (p = 0.04). CONCLUSIONS: By increasing the separation between the prostate and rectum, Hylaform decreased the mean rectal dose. This led to a significant reduction in the acute rectal toxicity of radiotherapy for prostate cancer.

Preliminary results in prostate cancer patients treated with high-dose-rate brachytherapy and intensity modulated radiation therapy (IMRT) vs. IMRT alone.

PURPOSE: To analyze results with high-dose-rate (HDR) brachytherapy and intensity modulated radiation therapy (IMRT) vs. IMRT alone for prostate cancer. METHODS AND MATERIALS: Between October 2003 and August 2008, 284 patients with early stage prostate cancer underwent HDR brachytherapy to 2200cGy and IMRT to 5040cGy (n=240) or IMRT alone to 7920-8100cGy (n=44). RESULTS: The median followup was 2.2 years. There was no significant difference in terms of the proportions of patients who had diabetes mellitus (p=0.07) or who received hormonal therapy (p=0.75) by radiotherapy technique. The 3-year biochemical disease-free survival rates in low-risk, intermediate-risk, and high-risk patients treated with HDR brachytherapy and IMRT are 100%, 98%, and 93%, respectively. The 3-year biochemical disease-free survival rates in low-risk, intermediate-risk, and high-risk patients treated with IMRT alone are 100%, 100%, and 67%, respectively. There was no significant difference in biochemical disease-free survival or toxicity between treatment groups. The similarity in outcomes between treatment groups remained unchanged when we examined only hormone-naive patients. CONCLUSIONS: The HDR brachytherapy and IMRT yielded similar biochemical disease-free survival and toxicity to IMRT alone. As a result, we continue to base treatment on physician and patient preference. Longer followup will help to determine the role of HDR brachytherapy and IMRT in the treatment of early stage prostate cancer, particularly because a number of patients received androgen deprivation therapy and we delivered a higher biologically effective dose with combined modality therapy.