Patient-reported Outcomes and Late Toxicity After Postprostatectomy Intensity-modulated Radiation Therapy.

BACKGROUND: Limited long-term data characterize patient-reported quality of life (QOL) following postprostatectomy intensity-modulated radiation therapy (PPRT), and predictors of decline are poorly defined. OBJECTIVE: To identify modifiable dosimetric and clinical risk factors impacting QOL and late toxicity following PPRT. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of consecutive men with prostate cancer who received PPRT between 2007 and 2015 at a single academic institution. INTERVENTION: Patients were prospectively evaluated using the Expanded Prostate Cancer Index Composite (EPIC-26) QOL instrument. Radiation Therapy Oncology Group/Common Toxicity Criteria for Adverse Events toxicity grades were assigned at every follow-up visit. Treatment was delivered to the prostate bed (median 68Gy)±pelvic lymphatics (65%, median 50.4Gy) with daily image guidance. Androgen deprivation therapy was concomitantly administered to 132 (66%) men for a median of 4mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes were deemed relevant if they exceeded the minimally clinically important difference (MCID), as calculated by a distribution-based method. Generalized estimating equation models and Cox regression were used for QOL and late toxicity univariate and multivariable analysis. RESULTS AND LIMITATIONS: Overall, 199 men were identified with a median follow-up of 33mo. Overall urinary function (UF), bowel function (BF), sexual function (SF), and urinary irritation/obstruction (UI/UO) scores were never lower than the MCID. Between 8% and 18% of men experienced a small multidomain (1× MCID) decline, and 0-8% experienced a moderate multidomain decline (2× MCID) at a given time point up to 84mo after PPRT. The rates of freedom from grade 2 or higher (Gr2+) genitourinary (GU) and gastrointestinal (GI) toxicity were 94% and 95%, respectively, at 4yr. Factors associated with worse QOL or toxicity included longer time to PPRT (UC and UF), higher BMI (UF, BF, and late GI toxicity), older age (BF, SF, and late GU toxicity); hormone therapy (SF), total dose (late GI toxicity), tobacco history (BF), and higher bladder V70Gy (UC, UF, and late GU toxicity). CONCLUSIONS: Long-term QOL and late toxicity are favorable following postprostatectomy radiation therapy. Identifiable clinical and dosimetric risk factors may guide decision making to optimize urinary, sexual, and bowel function. PATIENT SUMMARY: The following study provides a detailed report of favorable patient-reported quality of life and late side-effect profiles of radiation therapy following surgery for localized prostate cancer. Our findings provide patients guidance on what symptoms to expect if they are planning to undergo radiation therapy in this setting. It also allows physicians to counsel patients appropriately, and modify certain clinical and radiation-related risk factors to optimize quality of life.

Safety and Efficacy of Hypofractionated Radiotherapy With Capecitabine in Elderly Patients With Urothelial Carcinoma.

BACKGROUND: Bladder cancer is commonly diagnosed in patients ineligible for radical cystectomy or chemoradiotherapy (chemo-RT) with cisplatin or fluorouracil with mitomycin. We assessed tolerability, efficacy, and toxicity of hypofractionated radiotherapy with capecitabine in this challenging population. PATIENTS AND METHODS: Patients with high-grade urothelial bladder cancer ineligible for radical cystectomy or high-intensity chemo-RT underwent maximal transurethral resection of bladder tumor followed by capecitabine (median, 825 mg/m2 per day 2 times a day) and radiation (median, 55 Gy in 2.2 Gy per fraction). Patients underwent surveillance cystoscopy and imaging, and were evaluated for toxicity, freedom from local failure and freedom from distant metastasis, progression-free survival, and overall survival. RESULTS: Eleven patients (median age, 80 years) with localized disease (n = 7), locally advanced disease (n = 3), or local-only recurrence after cystectomy (n = 1) were treated. Four patients (35%) had an Eastern Cooperative Oncology Group performance status of 2; median Charlson comorbidity index was 5. There was 1 acute grade 3 genitourinary event (9%), 6 acute grade 3 hematologic events (55%) of lymphopenia, and no acute grade 4 or higher events or hospitalizations. Ten patients (91%) completed radiotherapy, while 4 patients (36%) temporarily discontinued capecitabine. The complete response rate in the bladder was 64%. Two patients (18%) experienced late grade 1/2 genitourinary toxicities, and 1 (9%) experienced a transient late grade 4 genitourinary toxicity. With a median follow-up of 16.6 months, overall survival, progression-free survival, freedom from local failure, and freedom from distant metastasis at 1 year were 82%, 55%, 100%, and 55%, respectively, and at 2 years were 61%, 41%, 80%, and 55%, respectively. CONCLUSION: Hypofractionated chemo-RT was well tolerated and was associated with a high rate of local control in this comorbid population, thus providing a treatment option for select bladder cancer patients.

Late toxicity after post-prostatectomy intensity modulated radiation therapy: Evaluating normal-tissue sparing guidelines.

PURPOSE: Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. METHODS AND MATERIALS: 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. RESULTS: With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. CONCLUSIONS: More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

Interdisciplinary Oncology Education: a National Survey of Trainees and Program Directors in the United States.

Oncologists must have a strong understanding of collaborating specialties in order to deliver optimal cancer care. The objective of this study was to quantify current interdisciplinary oncology education among oncology training programs across the USA, identify effective teaching modalities, and assess communication skills training. Web-based surveys were sent to oncology trainees and program directors (PDs) across the USA on April 1, 2013 and October 8, 2013, respectively. Question responses were Yes/No, five-point Likert scales (1 = not at all, 2 = somewhat, 3 = moderately, 4 = quite, 5 = extremely), or free response. Respondents included the following (trainees/PDs): 254/55 medical oncology, 160/42 surgical oncology, 102/24 radiation oncology, and 41/20 hospice and palliative medicine (HPM). Trainees consistently reported lower rates of interdisciplinary education for each specialty compared with PDs as follows: medical oncology 57 vs. 77% (p < 0.01), surgical oncology 30 vs. 44% (p < 0.01), radiation oncology 70 vs. 89% (p < 0.01), geriatric oncology 19 vs. 30% (p < 0.01), and HPM 55 vs. 74% (p < 0.01). The predominant teaching method used (lectures vs. rotations vs. tumor board attendance vs. workshop vs. other) varied according to which discipline was being taught. The usefulness of each teaching method was rated statistically different by trainees for learning about select disciplines. Furthermore, statistically significant differences were found between PDs and trainees for the perceived usefulness of several teaching modalities. This study highlights a deficiency of interdisciplinary education among oncology training programs in the USA. Efforts to increase interdisciplinary education opportunities during training may ultimately translate into improved collaboration and quality of cancer care.

Effect of Endoscopic Bronchial Ultrasound on Outcomes for Stage I Non-Small-Cell Lung Cancer Patients Receiving Hypofractionated Radiotherapy.

BACKGROUND: In this study we sought to determine if staging endoscopic bronchial ultrasound (EBUS) improves outcomes in stage I non-small-cell lung cancer (NSCLC) patients who received hypofractionated radiation therapy (HFRT). PATIENTS AND METHODS: Patients with stage I NSCLC treated with HFRT from 2008 to 2015 were retrospectively identified from 3 affiliated institutions. All patients underwent positron emission tomography/computed tomography staging and a subset of patients received pretreatment EBUS. Patients with and without pre-radiation therapy EBUS were compared for baseline characteristics. The log rank test was used to compare Kaplan-Meier estimates. Univariate analysis (UVA) and multivariable analysis (MVA) were used to analyze the effect of factors on disease-free survival (DFS) and overall survival (OS). RESULTS: Ninety-two patients met study criteria. Median follow-up for the entire cohort was 21 months. Two-year DFS and OS were 63% and 81%, respectively. Two-year freedom from local, regional, and distant failure were 93%, 87%, and 87%, respectively. Thirty-seven of 92 patients (40%) received pretreatment EBUS. There were no statistically significant differences in 2-year freedom from regional failure rates, DFS, or OS for EBUS-staged versus non-EBUS-staged patients. On UVA, smaller tumor size (P = .03) and higher performance status (P = .05) were associated with improved OS. On MVA, tumor size retained significance for improved OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19-0.97; P = .04) and higher performance status showed a trend toward improved OS (HR, 0.51; 95% CI, 0.23-1.11; P = .09). CONCLUSION: In this retrospective series, we did not detect a difference in regional failure or survival outcomes among stage I NSCLC patients who received invasive staging with EBUS before HFRT.

Limitations of PET/CT in the Detection of Occult N1 Metastasis in Clinical Stage I(T1-2aN0) Non-Small Cell Lung Cancer for Staging Prior to Stereotactic Body Radiotherapy.

PURPOSE/OBJECTIVES: Patients receiving stereotactic body radiotherapy for stage I non-small cell lung cancer are typically staged clinically with positron emission tomography-computed tomography. Currently, limited data exist for the detection of occult hilar/peribronchial (N1) disease. We hypothesize that positron emission tomography-computed tomography underestimates spread of cancer to N1 lymph nodes and that future stereotactic body radiotherapy patients may benefit from increased pathologic evaluation of N1 nodal stations in addition to N2 nodes. MATERIALS/METHODS: A retrospective study was performed of all patients with clinical stage I (T1-2aN0) non-small cell lung cancer (American Joint Committee on Cancer, 7th edition) by positron emission tomography-computed tomography at our institution from 2003 to 2011, with subsequent surgical resection and lymph node staging. Findings on positron emission tomography-computed tomography were compared to pathologic nodal involvement to determine the negative predictive value of positron emission tomography-computed tomography for the detection of N1 nodal disease. An analysis was conducted to identify predictors of occult spread. RESULTS: A total of 105 patients with clinical stage I non-small cell lung cancer were included in this study, of which 8 (7.6%) patients were found to have occult N1 metastasis on pathologic review yielding a negative predictive value for N1 disease of 92.4%. No patients had occult mediastinal nodes. The negative predictive value for positron emission tomography-computed tomography in patients with clinical stage T1 versus T2 tumors was 72 (96%) of 75 versus 25 (83%) of 30, respectively ( P = .03), and for peripheral versus central tumor location was 77 (98%) of 78 versus 20 (74%) of 27, respectively ( P = .0001). The negative predictive values for peripheral T1 and T2 tumors were 98% and 100%, respectively; while for central T1 and T2 tumors, the rates were 85% and 64%, respectively. Occult lymph node involvement was not associated with primary tumor maximum standard uptake value, histology, grade, or interval between positron emission tomography-computed tomography and surgery. CONCLUSION: Our results support pathologic assessment of N1 lymph nodes in patients with stage Inon-small cell lung cancer considered for stereotactic body radiotherapy, with the greatest benefit in patients with central and T2 tumors. Diagnostic evaluation with endoscopic bronchial ultrasound should be considered in the evaluation of stereotactic body radiotherapy candidates.

Cardiac thromboxane A2 receptor activation does not directly induce cardiomyocyte hypertrophy but does cause cell death that is prevented with gentamicin and 2-APB.

BACKGROUND: We have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling. METHODS: U46619 (0.1-10 µM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured. RESULTS: We found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, ß-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 µM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619. CONCLUSIONS: Our data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.