Contemporary Systemic Therapy Intensification for Prostate Cancer: A Review for General Practitioners in Oncology.

Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Over the past decade, the therapeutic landscape for the management of metastatic prostate cancer has undergone rapid changes. Novel strategies use hormonal agents, chemotherapy, homologous recombination repair inhibitors, and radioligand therapy or combination strategies in addition to androgen deprivation therapy. In this review, we summarize the available data addressing key therapeutic areas along the disease continuum and focus on practical aspects for general practitioners in oncology managing patients with metastatic prostate cancer.

Efficacy of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer Needing Treatment Interruption Because of Adverse Events: A Retrospective Multicenter Analysis.

INTRODUCTION: The programmed death 1 antibodies (PD-1 Ab) nivolumab and pembrolizumab improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). We evaluated the correlation between immune-related adverse events (irAE) and treatment interruption due to irAE on clinical efficacy of PD-1 Ab in advanced NSCLC. PATIENTS AND METHODS: Advanced NSCLC patients treated with PD-1 Ab between June 2015 to November 2017 at BC Cancer were identified. Demographic, tumor, treatment details, and frequency and grade (Common Terminology Criteria for Adverse Events, version 4.0) of irAE were abstracted from chart review. Kaplan-Meier curves of OS from initiation of PD-1 Ab were generated. Multivariable analysis with 6- and 12-week landmark analysis was performed by Cox proportional hazard regression models. RESULTS: In a cohort of 271 patients, irAEs were observed in 116 patients (42.8%). Nivolumab recipients developing colitis had lower OS compared to those who did not at the 6-week landmark (P = .010) and 12-week landmark (P = .072). For the entire cohort, 56 patients (20.7%) needed treatment interruption because of an irAE. Treatment interruption correlated with lower OS at the 6-week landmark (P = .005) and 12-week landmark (P = .008). Six-week landmark multivariable analysis identified Charlson Comorbidity Index score of 3 or higher, Eastern Cooperative Oncology Group Performance Status of 2 or higher, presence of liver metastases, and irAE greater than grade 2 versus no irAE to be associated with decreased OS (each P < .05). CONCLUSION: Treatment interruption due to irAE was associated with a lower median OS compared to continuous PD-1 Ab therapy. Shorter OS seen with severe irAE might reflect the need for improved physician education in irAE treatment algorithms.

Population-based phase II trial of stereotactic ablative radiotherapy (SABR) for up to 5 oligometastases: SABR-5.

BACKGROUND: Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1-3 or 1-5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates. METHODS: This is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity. DISCUSSION: SABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of its efficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardized doses and organ at risk constraints, while we await data on efficacy from randomized phase III trials. TRIAL REGISTRATION: Registered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively before patient accrual.

SUNSET: Stereotactic Radiation for Ultracentral Non-Small-Cell Lung Cancer-A Safety and Efficacy Trial.

BACKGROUND: Lung stereotactic body radiotherapy (SBRT) is considered a standard curative treatment for medically inoperable early stage non-small-cell lung cancer (NSCLC). Patients with ultracentral tumors (signifying tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, or pulmonary artery) may be at higher risk of serious toxicities such as bronchial stricture and collapse, esophageal strictures, tracheal-esophageal fistula, and hemorrhage. The primary objective of the study is to determine the maximum tolerated dose of radiotherapy for ultracentral NSCLC. METHODS: This multicenter phase 1 dose-escalation study will use a time-to-event continual reassessment method (TITE-CRM). Accrual will start at level 1 (60 Gy in 8 fractions delivered daily). The model will use all available information from previously accrued patients to assign the highest dose with a predicted risk of grade 3-5 toxicity of 30% or less. All patients with newly diagnosed stage T1-3 N0M0 NSCLC (International Union Against Cancer, 8th edition) with tumor size ≤ 6 cm and meeting the criteria for ultracentral location (ie, tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery) will be eligible for this study. DISCUSSION: It is important to identify a safe dose-fractionation regimen for treating ultracentral tumors with SBRT. In addition, the data from this study may be informative in guiding future studies on the use of SBRT in treating malignancies within the mediastinum-for example, for salvage treatment of mediastinal lymph nodes for recurrent NSCLC or mediastinal oligometastases.

Low Incidence of Esophageal Toxicity After Lung Stereotactic Body Radiation Therapy: Are Current Esophageal Dose Constraints Too Conservative?

PURPOSE: To explore and quantify the relationship between esophageal dose and toxicity in the setting of lung stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: This analysis was conducted on the basis of a prospective study of patients treated with SBRT at our institution from October 2004 to December 2015. Most patients were treated with 54 Gy/3 fractions, 48 Gy/4 fractions alternate days, or 60 Gy/8 fractions daily. Toxicity was prospectively graded using Common Terminology Criteria for Adverse Events version 3.0. Logistic regression was used to estimate the risk of esophageal toxicity as a function of radiation therapy dose, in 2-Gy-equivalent dose, using an α/ß ratio of 3 Gy in the linear-quadratic model. RESULTS: A total of 632 patients were analyzed. The median follow-up was 20.8 months. Median overall survival was 35.3 months. The rate of late or acute grade ≥1 esophageal toxicity, including dysphagia, odynophagia, and esophagitis, was 3.3% (n = 21). The median (range) esophageal doses were 11.8 Gy (0.2-48.2 Gy), 10.34 Gy (0.17-44.5 Gy), and 9.63 Gy (0.08-43 Gy) for Dmax, D1cc, and D2cc, respectively. A 15% risk of esophageal toxicity was associated with a 2-Gy-equivalent dose of Dmax 141.6 Gy, D1cc 123.61 Gy, and D2cc 117.6 Gy. Of the 21 patients who experienced esophageal toxicity, only 1 patient had grade 3 toxicity, and the remainder had grade 2 or lower toxicity. CONCLUSIONS: The observed rate of toxicity was low, despite some patients receiving relatively high doses to the esophagus. A prospective study in a targeted population, for example patients with ultracentral tumors, may provide more accurate dose-toxicity parameters.

Survival Impact of Cardiac Dose Following Lung Stereotactic Body Radiotherapy.

INTRODUCTION: The purpose of this study was to determine the impact of radiation dose to substructures of the heart in lung stereotactic body radiotherapy (SBRT) patients on non-cancer-related deaths. METHODS: Patients treated with lung SBRT at a single institution from 2005 to 2013 were included. The heart and its substructures were contoured, and dose was calculated including mean, max, and max 10 cc dose. Clinical variables including stage, histology, age, gender, Charlson comorbidity index (CCI), preexisting cardiac disease, pulmonary function (forced expiratory volume in 1 second, diffusion capacity), and smoking status were explored for association with non-cancer-related deaths in univariable (UVA) and multivariable (MVA) analyses. Heart dosimetric parameters were correlated with the risk of radiation pneumonitis (RP) using UVA and MVA. RESULTS: A total of 189 patients were included with median age of 76 years (range, 48-93 years). Of these patients, 45.5% were female, 27.5% were T2, 16.9% were current smokers, 64% had preexisting cardiac risk factors, and 34.5% had CCI score of ≥ 3. Mean lung dose ± SD was 456 ± 231 cGy. Heart max, mean, and 10 cc doses were 1867 ± 1712 cGy, 265 ± 269 cGy, and 1150 ± 1075 cGy, respectively. There were 14 (7.4%) ≥ Grade 2 RP and 3 (1.6%) were ≥ Grade 3. The median overall survival was 37.3 months (95% confidence interval, 29.8-45.3 months). On UVA, female gender (P < .01), higher Eastern Cooperative Oncology Group (P = .01), cardiac risk (P < .01), CCI (P < .01), and bilateral ventricles max dose (P = .02) were associated with non-cancer-related deaths; on MVA, bilateral ventricles max dose was significant (P = .05). No heart parameters were associated with RP. CONCLUSIONS: Higher bilateral ventricles max dose is associated with poorer survival. Heart dose parameters should be considered when planning patients for SBRT.

Impact of Pretreatment Interstitial Lung Disease on Radiation Pneumonitis and Survival in Patients Treated With Lung Stereotactic Body Radiation Therapy (SBRT).

INTRODUCTION: The purpose of this study was to determine the impact of interstitial lung disease (ILD) on radiation pneumonitis (RP) and overall survival (OS) in lung stereotactic body radiation therapy (SBRT). METHODS: Patients treated with lung SBRT from 2004 to 2015 were included. Pretreatment computed tomography scans were reviewed and classified for interstitial changes by thoracic radiologists using American Thoracic Society guidelines and Washko and Kazerooni scores. RP was scored prospectively using Common Terminology Criteria for Adverse Events, version 3.0. Pretreatment imaging characteristics, clinical variables, and dosimetry were assessed by univariate (UVA) and multivariate analysis (MVA). OS was assessed by the log-rank test, and the impact of ILD on OS was assessed by Cox regression. RESULTS: Of the 537 patients assessed, 39 had interstitial changes (13 usual interstitial pneumonia [UIP], 24 possible UIP, and 2 inconsistent with UIP). RP was significantly higher in patients with ILD than in patients without ILD (grade ≥ 2, 20.5% vs. 5.8%; P < .01; grade ≥ 3, 10.3% vs. 1.0%; P < .01). Two of 3 grade 5 RP had imaging features of ILD. On UVA, ILD, Washko score, lung parameters performance status, and dose were significant predictors of grade ≥ 2 RP. On MVA, ILD (odds ratio, 5.81; 95% confidence interval, 2.28-14.83; P < .01) and mean lung dose (odds ratio, 1.40; 95% confidence interval, 1.14-1.71; P < .01) were predictors of RP. ILD did not significantly affect OS on UVA or MVA. Median survival was 27.4 months in the ILD cohort and 34.8 in the ILD-negative cohort (P = .17). DISCUSSION: ILD is a significant risk factor for RP in patients treated with lung SBRT. Computed tomography scans should be reviewed for evidence of ILD prior to SBRT.

Defining conditions that lead to the retention of water: the importance of the arterial sodium concentration.

BACKGROUND: A water diuresis occurs when a large volume of water is ingested rapidly. Nevertheless, water conservation is required to provide a source of water for evaporative heat dissipation throughout the day. Therefore, the objective was to define conditions that permit the retention of ingested water. METHODS: Volunteers collected urine q2h plus an overnight specimen; water loading was conducted after overnight food and water restriction; paired arterialized and venous blood samples were analyzed. RESULTS: When 20 mL water/kg was consumed in <15 minutes, the peak urine flow rate was 11 +/- 0.6 mL/min. The volume of water retained after water intake stopped, and when the urine was hyperosmolar, correlated directly with the daily excretion of sodium plus potassium (r(2)= 0.63). The plasma sodium concentration (P(Na)) was 4.0 +/- 0.5 mmol/L lower in arterialized than paired venous blood 30 to 40 minutes after water ingestion began (P < 0.01). In preliminary studies, the smallest water load consumed in 15 minutes that would reproducibly cause a water diuresis was defined in each subject. This same acute water load was retained, however, if it contained 150-mmol/L fructose, but not glucose, or if it was consumed slowly (sipping). The arterialized P(Na) was not significantly lower than in paired venous samples when water was sipped. CONCLUSION: A large fall in arterialized and not venous P(Na) best reflected the signal to induce a water diuresis. Although a very large water load can induce a water diuresis, smaller water loads can be retained for future heat dissipation.