Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension. MATERIALS AND METHODS: Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS. RESULTS: Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41). CONCLUSIONS: Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder.

Radiologically Occult Lung Cancer Curatively Treated with High-Dose Rate Endobronchial Brachytherapy.

Most patients diagnosed with early-stage non-small cell lung cancer (NSCLC) can be easily cured with surgery or stereotactic body radiotherapy (SBRT). Modalities such as photodynamic therapy, cryotherapy, or laser therapy only offer temporary palliation. A 79-year-old gentleman with early-stage NSCLC who underwent a left lower lobe lobectomy in 2009 presented to us again in 2010 with hemoptysis. A friable ~5 cm tumor along the bifurcation of anterior and the posterior segment of the right upper lobe was noted on bronchoscopic examination, and biopsy confirmed this to be squamous cell carcinoma. Because of his previous surgery, the patient was not a candidate for another surgery. SBRT was not possible as the lesion could not be seen on radiologic imaging. The patient was, therefore, treated with curative intent high-dose rate endobronchial brachytherapy (HDR-EBBT) in 4 weekly sessions of 7 Gy per fraction delivered at a depth of 8 mm, covering ~5 cm tumor plus 1 cm margin proximally and distally. He tolerated the treatment well without any acute or late side effects and was followed every 3 months thereafter with bronchoscopy examinations for 6 months and subsequently with computerized tomography (CT) imaging. In July 2018, the patient started having episodes of hemoptysis and evaluation leads to diagnosis of a third primary lung cancer, which was successfully treated with SBRT with image-guided radiotherapy using a five-fraction regimen. The patient's most recent CT from July 2019 showed no evidence of disease. We conclude that in patients with early-stage NSCLC, when surgery or SBRT is not feasible due to radiologic occult nature, HDR-EBBT can yield excellent long-term outcome.

Building a High-Dose-Rate Prostate Brachytherapy Program With Real-Time Ultrasound-Based Planning: Initial Safety, Quality, and Outcome Results.

PURPOSE: Growing evidence supports the efficacy and safety of high-dose-rate (HDR) brachytherapy as a boost or monotherapy in prostate cancer treatment. We initiated a new HDR prostate brachytherapy practice in April 2014. Here, we report the learning experiences, short-term safety, quality, and outcome. METHODS AND MATERIALS: From April 2014 to December 2017, 164 men were treated with HDR brachytherapy with curative intent. Twenty-eight men (17.1%) underwent HDR brachytherapy as monotherapy, receiving 25 to 27 Gy in 2 fractions. Men treated with HDR brachytherapy as a boost received 19 to 21 Gy in 2 fractions. Fifty-two men (31.7%) had high-risk disease. HDR procedure times, dosimetry, and response were recorded and analyzed. Genitourinary (GU) and gastrointestinal (GI) toxicities were recorded according to the toxicity criteria of the Radiation Therapy Oncology Group. RESULTS: Mean HDR procedure times decreased yearly from 179 minutes in 2014 to 115 minutes in 2017. Median follow-up was 18.6 months (range, 3-55 months). At last review, 79% of patients reported returning to baseline GU status, and 100% of patients noted no change in GI status from their baseline. Four patients experienced acute urinary retention. Treatment planning target volume (PTV) was defined as prostate with margins. Dosimetrically, 97.5% of all HDR implants had PTV D90 ≥100%, 81.5% had PTV V100 ≥95%, 73.6% had maximal urethral doses ≤120%, and 77.5% had rectal 1 mL dose ≤70% (all but one ≤10.8 Gy). The estimated 3-year overall survival was 98.7% (95% confidence interval, 91.4%-99.8%), and disease-free survival was 96.2% (95% confidence interval, 89.5%-98.7%). CONCLUSIONS: The low incidence of GU and GI complications in our cohort demonstrates that a HDR brachytherapy program can be successfully developed as a treatment option for patients with localized prostate cancer.

Utility of topical agents for radiation dermatitis and pain: a randomized clinical trial.

PURPOSE: Although topical agents are often provided during radiation therapy, there is limited consensus and evidence for their use prophylactically to prevent or reduce radiation dermatitis. METHODS: This was a multi-site, randomized, placebo-controlled, blinded study of 191 breast cancer patients to compare the prophylactic effectiveness of three topical agents (Curcumin, HPR Plus™, and Placebo) for reducing radiation dermatitis and associated pain. Patients applied the topical agent to their skin in the radiation area site three times daily starting the first day of radiation therapy (RT) until 1 week after RT completion. RESULTS: Of the 191 randomized patients, 171 patients were included in the final analyses (87.5% white females, mean age = 58 (range = 36-88)). Mean radiation dermatitis severity (RDS) scores did not significantly differ between study arms (Curcumin = 2.68 [2.49, 2.86]; HPR Plus™ = 2.64 [2.45, 2.82]; Placebo = 2.63 [2.44, 2.83]; p = 0.929). Logistic regression analyses showed that increased breast field separation positively correlated with increased radiation dermatitis severity (p = 0.018). In patients with high breast field separation (≥ 25 cm), RDS scores (Curcumin = 2.70 [2.21, 3.19]; HPR Plus™ = 3.57 [3.16, 4.00]; Placebo = 2.95 [2.60, 3.30]; p = 0.024) and pain scores (Curcumin = 0.52 [- 0.28, 1.33]; HPR Plus™ = 0.55 [- 0.19, 1.30]; Placebo = 1.73 [0.97, 2.50]; p = 0.046) significantly differed at the end of RT. CONCLUSIONS: Although there were no significant effects of the treatment groups on the overall population, our exploratory subgroup analysis suggests that prophylactic treatment with topical curcumin may be effective for minimizing skin reactions and pain for patients with high breast separation (≥ 25 cm) who may have the worst skin reactions.

Prognostic Significance of Sites of Visceral Metastatic Disease in Prostate Cancer: A Population-based Study of 12,180 Patients.

INTRODUCTION: Metastatic prostate cancer (MPC) prognosis is variable. Few population-based studies have examined the impact of particular visceral metastatic sites on MPC survival outcomes. We investigated this using the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS: We analyzed the overall survival (OS) and prostate cancer mortality (PCM) risk of 12,180 patients, from SEER 18 registries, diagnosed with MPC from 2010 to 2014. We identified those with metastatic disease in bone, brain, liver, and lung. Kaplan-Meier analyses, competing risks regression, and Cox proportional hazards models were used to assess the impact of visceral metastatic disease sites on OS and PCM. RESULTS: Most patients were coded as having metastatic disease in the bone without disease in the brain, liver, or lung (bone group, n = 10,620; 87% of total). On Cox multivariable regression analysis, patients with lung metastases, with or without bone metastases, did not differ significantly from patients in the bone group with respect to OS (hazard ratio, 0.82; 95% confidence interval, 0.63-1.06; P = .13 and hazard ratio, 1.12; 95% confidence interval, 0.98-1.28; P = .10, respectively). These patients also did not differ from the bone group with respect to PCM incidence on competing risks regression analysis. CONCLUSIONS: This study suggests that patients with MPC confined to bone and/or lung may have improved survival relative to those with MPC affecting other visceral sites. Although it was anticipated that patients with bone metastases would represent a favorable subgroup, the favorable outcomes in patents with lung metastases (with or without bone metastases) was unexpected. These findings may inform future therapeutic investigations to improve the prognosis of patients with MPC.

Bladder cancer in the elderly patient: challenges and solutions.

Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC.

Is there a subset of patients with recurrent cancer in the vagina who are not candidates for interstitial brachytherapy that can be treated with multichannel vaginal brachytherapy using graphic optimization?

PURPOSE: To evaluate recurrent vaginal cancer treated with vaginal brachytherapy (VBT) using graphic optimization in patients not amenable to surgery and interstitial brachytherapy (ISBT). MATERIAL AND METHODS: We retrospectively reviewed the records of 5 patients with recurrent cancer in the vagina that were deemed not to be good candidates for ISBT implant because of medical reasons. All patients received computed tomography/magnetic resonance imaging (CT/MRI) based evaluation in addition to a detailed clinical examination, and were noted to have recurrent nodules in the vagina with size ranging from 10-25 mm. Four of the 5 patients had recurrent disease in the vaginal apex, whereas one patient had recurrence in the lateral vaginal wall. Subsequently, all patients were treated with external beam radiation therapy (EBRT) followed by multichannel vaginal cylinder (MVC)-based VBT using graphic optimization for shaping the isodose to improve the clinical target volume (CTV) coverage, as well as to spare the organs at risk (OAR). The dose to the bladder and rectum with regard to 0.1 cc, 1 cc, and 2 cc were recorded. RESULTS: Median age of the patients was 78 years (range 58-86 years). Thickness of the lesions before VBT ranged from 6-15 mm. All patients were followed up with MRI at 3 months. All patients but one demonstrated complete clinical/ radiological response of the tumor. No patient had any grade III/IV toxicity at 24 months. CONCLUSIONS: MVC-based VBT using graphic optimization is safe and yields favorable results if used judiciously.

Split-course palliative radiotherapy for advanced non-small cell lung cancer.

PURPOSE: Palliative chest radiotherapy (RT) for lung malignancies is effective in relieving serious chest symptoms from tumor bleeding or mass effect on major airways, vessels, and nerves. Albeit an important subject, there is a lack of consensus for an optimal palliative RT regimen. We report the outcomes of a split-course palliative chest RT, a frequently used schema at our institution. METHODS AND MATERIALS: Records of 140 patients treated between 1995 and 2006 were reviewed. Treatment was prescribed to an initial 25 Gy in 10 fractions through anterior-posterior/posterior-anterior beam arrangements. After a 2-week rest period, patients were selected to receive an additional 10 Gy (anterior-posterior/posterior-anterior) followed by off-cord beams to a final dose of 50 to 62.5 Gy. Symptom relief and toxicity during RT and after completion of RT were assessed from clinician notes and patient-reported symptom inventory forms. Second, the impact on survival was assessed. RESULTS: Symptomatic relief was observed in 52 to 84% of patients with durable palliation in 58%. There were no grade 3 to 5 toxicities. Grades 1 and 2 esophagitis and pneumonitis were observed in 34 and 8% patients, respectively. Median survival was 5 months. CONCLUSIONS: A majority of patients experienced symptomatic improvement. The built-in 2-week break allowed for selection of patients for high-dose palliative radiation and balanced treatment benefits with potential side effects. Cancer survival was not adversely affected by treatments in this population with mostly advanced disease. This regimen is a viable option for patients who cannot tolerate a protracted, uninterrupted course of treatment.

Analysis of interfraction prostate motion using megavoltage cone beam computed tomography.

PURPOSE: Determine the degree of interfraction prostate motion and its components measured by using daily megavoltage (MV) cone beam computed tomography (CBCT) imaging. METHODS AND MATERIALS: A total of 984 daily MV CBCT images from 24 patients undergoing definitive intensity-modulated radiotherapy for localized prostate cancer were analyzed retrospectively. Pretreatment couch shifts, based on physician registration of MV CBCT to planning CT data sets, were used as a measure of daily interfraction motion. Off-line bony registration was performed to separate bony misalignment from internal organ motion. Interobserver and intraobserver variation studies were performed on 20 MV CBCT images. RESULTS: Mean interfraction prostate motion was 6.7 mm, with the greatest single-axis deviation in the anterior-posterior (AP) direction. The largest positional inaccuracy was accounted for by systematic deviations in bony misalignment, whereas random deviations occurred from bony misalignment and internal prostate motion. In the aggregate, AP motion did not correlate with days elapsed since beginning therapy or on average with rectal size at treatment planning. Interobserver variation was greatest in the AP direction, decreased in experienced observers, and further decreased in intraobserver studies. Mean interfraction motion during the first 6 days of therapy, when used as a subsequent offset, reduced acceptable AP planning target volume margins by 50%. CONCLUSION: The MV CBCT is a practical direct method of daily localization that shows significant interfraction motion with respect to conventional three-dimensional conformal and intensity-modulated radiotherapy margins, similar to that measured in other modalities.

Real-time sonoelastography of hepatic thermal lesions in a swine model.

Sonoelastography has been developed as an ultrasound-based elasticity imaging technique. In this technique, external vibration is induced into the target tissue. In general, tissue stiffness is inversely proportional to the amplitude of tissue vibration. Imaging tissue vibration will provide the elasticity distribution in the target region. This study investigated the feasibility of using real-time sonoelastography to detect and estimate the volume of thermal lesions in porcine livers in vivo. A total of 32 thermal lesions with volumes ranging from 0.2 to 5.3 cm3 were created using radiofrequency ablation (RFA) or high-intensity focused ultrasound (HIFU) technique. Lesions were imaged using sonoelastography and coregistered B-mode ultrasound. Volumes were reconstructed from a sequence of two-dimensional scans. The comparison of sonoelastographic measurements and pathology findings showed good correlation with respect to the area of the lesions (r2 = 0.8823 for RFA lesions, r2 = 0.9543 for HIFU lesions). In addition, good correspondence was found between three-dimensional sonoelastography and gross pathology (3.6% underestimate), demonstrating the feasibility of sonoelastography for volume estimation of thermal lesions. These results support that sonoelastography outperforms conventional B-mode ultrasound and could potentially be used for assessment of thermal therapies.

Soft tissue sarcoma in the setting of chronic cutaneous graft versus host disease after allogenic bone marrow transplantation.

Second primary cancers are approximately 2.1-2.8 times more common in survivors of bone marrow transplant than in the age-matched general population. We describe a patient who developed high-grade sarcoma in two disparate sites that were clinically involved by chronic cutaneous graft versus host disease (GVHD). This occurred 3.5 years after bone marrow transplant for acute myelogenous leukemia (AML). This suggests that malignant sarcomas may develop in the setting of chronic GVHD, and close surveillance of GVHD-related nodules is warranted.