Optimizing Target Volume for Adjuvant Radiation Therapy in Penile Cancer.

PURPOSE: Recent studies have reported improved outcomes with adjuvant radiation therapy in penile cancer. However, the appropriate target volumes to be irradiated in this group of patients for optimal outcomes are still unclear. This study aims to report the patterns of failure and define target volumes to be irradiated in patients with pN3 penile cancer. METHODS AND MATERIALS: Patients with pT1-T4, pN3, cM0, and squamous cell carcinoma of the penis who received adjuvant radiation therapy (involved field or extended field), with or without concurrent chemotherapy were included in the study. Complete information on disease characteristics, radiation therapy target details, and patterns of failure were available for 75 patients. Disease-free (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and log-rank test was used to compare survival outcomes between the involved field and extended field radiation therapy groups. Multivariate analysis was performed using the Cox proportional hazards model to analyze factors correlating with survival outcomes. RESULTS: At a median follow-up of 39 months, 38.6% (29/75) of patients had relapsed either locally, regionally, or at distant sites. Of the 24 patients who received extended field radiation therapy (EFRT), only 1 (4%) patient experienced relapse. Twenty-eight (55%) patients experienced relapse after involved-field radiation therapy (IFRT), of which 28.5% were regional-only relapses and 64% relapses were associated with a regional component. The 2-year DFS and OS of the entire cohort were 62.2% and 70.8%, respectively. The 2-year DFS was 67.9% in patients who received IFRT and 94.1% in those who received EFRT (P = .002), and the 2-year OS was 62.4% with IFRT and 91.1% with EFRT (P = .014). Extended field radiation therapy was associated with an improved DFS (hazard ratio, 12.2; 95% confidence interval, 1.5-97.4; P = .02) and OS (hazard ratio, 4.6; 95% confidence interval, 1-21.5; P = .05) on multivariate analysis. CONCLUSIONS: Extended field radiation therapy significantly improves clinical outcomes compared with involved-field radiation in patients with pN3 penile cancer.

Common Iliac Node-Positive Prostate Cancer Treated With Curative Radiation Therapy: N1 or M1a?

PURPOSE: Common iliac (CI) nodes are staged as (oligo)metastatic M1a for prostate cancer. Whether outcomes of pelvic node-positive (cN1) differ from CI node-positive (CI-M1a) prostate cancer after curative treatment is unclear. The present study compares outcomes in patients treated with radical whole pelvic radiation therapy (RT) and long-term androgen deprivation therapy (ADT). METHODS AND MATERIALS: Patients with a node-positive adenocarcinoma prostate were identified, either CI-M1a or cN1, from a prospectively maintained database. More than 75% of patients were staged with Gallium (Ga) 68 prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) at the time of diagnosis. All patients received long-term ADT and moderately or extremely hypofractionated RT to the prostate and pelvis, including the CI region. At the time of biochemical failure (BCF), restaging was done with Ga68-PSMA-PET/CT to establish the patterns of failure. The CI-M1a cohort was classified as proximal or distal CI nodal location, and studied for outcomes. RESULTS: Of the 130 patients analyzed, 87 had cN1 and 43 had CI-M1a stage disease. The median duration of ADT before RT was 7 months, and total duration was at least 24 months. The majority of patients (65%) had Gleason grade group IV to V, and 75% had ≥T3 disease. After a median follow up of 61 months, BCF in the 2 groups was similar (cN1: n = 21 of 87; 24.1%; CI-M1a: n = 11 of 43; 25.6%; P = .86). At the time of BCF, restaging Ga68-PSMA-PET/CT located distant metastases in 20 of 32 patients (63%; 57% in cN1 and 73% in CI-M1a; P = .47). In addition, the 5-year biochemical failure-free (cN1: 77.4%; CI-M1a: 70.4%; P = .43), distant metastasis-free (cN1: 86.9%; CI-M1a: 79.4%; P = .23), and overall (cN1: 92.6%; CI-M1a 90.1%; P = .80) survival were similar in the 2 groups. Outcomes within CI-M1a were similar for proximal versus distal CI nodal location and 5-year biochemical failure-free survival (73.6% vs 58.6%; P = .81). CONCLUSIONS: Patients with oligometastatic CI-M1a and cN1 prostate cancer showed similar outcomes when treated with curative whole pelvic RT and long-term ADT. The treatment for these oligometastatic patients should be prospectively evaluated.

Acute and Late Adverse Effects of Prostate-Only or Pelvic Stereotactic Radiation Therapy in Prostate Cancer: A Comparative Study.

PURPOSE: To compare the urinary and gastrointestinal adverse effects with or without the inclusion of pelvic nodal regions in patients treated with extreme hypofractionated stereotactic radiation therapy (SBRT) for prostate cancer. METHODS AND MATERIALS: Patients treated with definitive SBRT for nonmetastatic adenocarcinoma prostate were identified from prospectively maintained institutional database, and details of radiation therapy volume, dose, acute, and late adverse effects were analyzed. Symptoms of acute (within 90 days of completing SBRT) and late gastrointestinal and urinary toxic effects were graded using Common Terminology Criteria for Adverse Effects version 5.0. Each symptom was scored according to the worst reported grading during treatment and the follow-up period. Cumulative rates of adverse effects between prostate-only SBRT (PO-SBRT) and whole pelvic SBRT (WP-SBRT) were compared using the χ2 test. Univariable and multivariable analysis was performed for possible factors affecting acute gastrointestinal and late urinary toxic effects. RESULTS: A total of 220 patients were analyzed (PO-SBRT = 118, WP-SBRT = 102), with a median follow-up of 28 months (interquartile range, 14-40). Most patients had locally advanced disease (PO-SBRT 60% high risk and 40% intermediate risk, WP-SBRT 79% node positive, and 21% high risk). The median SBRT dose was 36.25Gy (interquartile range, 35-36.25) to the prostate (2-Gy equivalent, EQD2 = 90.6Gy, a/b = 1.5Gy) and simultaneous integrated 25Gy to the pelvis (EQD2 = 46.3Gy) in 5 fractions on alternate days. No grade 3 to 4 acute adverse effects were observed except 1 grade 3 urinary obstruction (PO-SBRT). WP-SBRT was associated with a significantly higher rate of acute grade 2 gastrointestinal toxic effects (29.4% vs 14.7%, P = .008) and late grade 2 urinary adverse effects (45.6% vs 25.0%, P = .003). Both groups had low incidence of late grade 3 adverse effects (urinary 2.5%, gastrointestinal 1%). CONCLUSIONS: WP-SBRT was associated with significantly higher acute gastrointestinal and late urinary adverse effects compared with PO-SBRT, although overall incidence of severe adverse effects was low.

Locoregional recurrence after cystectomy in muscle invasive bladder cancer: Implications for adjuvant radiotherapy.

PURPOSE: We report the patterns of locoregional recurrence (LRR) in muscle invasive bladder cancer (MIBC), and propose a risk stratification to predict LRR for optimizing the indication for adjuvant radiotherapy. MATERIALS AND METHODS: The study included patients of urothelial MIBC who underwent radical cystectomy with standard perioperative chemotherapy between 2013 and 2019. Recurrences were classified into local and/or cystectomy bed, regional, systemic, or mixed. For risk stratification modelling, T stage (T2, T3, T4), N stage (N0, N1/2, N3) and lymphovascular invasion (LVI positive or negative) were given differential weightage for each patient. The cohort was divided into low risk (LR), intermediate risk (IR) and high risk (HR) groups based on the cumulative score. RESULTS: Of the 317 patients screened, 188 were eligible for the study. Seventy patients (37.2%) received neoadjuvant chemotherapy (NACT) while 128 patients (68.1%) had T3/4 disease and 66 patients (35.1%) had N+ disease. Of the 55 patients (29%) who had a recurrence, 31 (16%) patients had a component of LRR (4% cystectomy bed, 11.5% regional 0.5% locoregional). The median time to LRR was 8.2 (IQR 3.3-18.8) months. The LR, IR and HR groups for LRR based on T, N and LVI had a cumulative incidence of 7.1%, 21.6%, and 35% LRR, respectively. The HR group was defined as T3, N3, LVI positive; T4 N1/2, LVI positive; and T4, N3, any LVI. The odds ratio for LRR was 3.37 (95% CI 1.16-9.73, P = 0.02) and 5.27 (95% CI 1.87-14.84, P = 0.002) for IR and HR respectively, with LR as reference. CONCLUSION: LRR is a significant problem post radical cystectomy with a cumulative incidence of 35% in the HR group. The proposed risk stratification model in our study can guide in tailoring adjuvant radiotherapy in MIBC.

Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized Controlled Trial.

PURPOSE: We report the clinical outcomes of a randomized trial comparing prophylactic whole-pelvic nodal radiotherapy to prostate-only radiotherapy (PORT) in high-risk prostate cancer. METHODS: This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk ≥ 20%. Randomization was 1:1 to PORT (68 Gy/25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy/25# to prostate, 50 Gy/25# to pelvic nodes, including common iliac) using computerized stratified block randomization, stratified by Gleason score, type of androgen deprivation, prostate-specific antigen at diagnosis, and prior transurethral resection of the prostate. All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of androgen deprivation therapy. The primary end point was 5-year biochemical failure-free survival (BFFS), and secondary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: From November 2011 to August 2017, a total of 224 patients were randomly assigned (PORT = 114, WPRT = 110). At a median follow-up of 68 months, 36 biochemical failures (PORT = 25, WPRT = 7) and 24 deaths (PORT = 13, WPRT = 11) were recorded. Five-year BFFS was 95.0% (95% CI, 88.4 to 97.9) with WPRT versus 81.2% (95% CI, 71.6 to 87.8) with PORT, with an unadjusted hazard ratio (HR) of 0.23 (95% CI, 0.10 to 0.52; P < .0001). WPRT also showed higher 5-year DFS (89.5% v 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; P = .002), but 5-year OS did not appear to differ (92.5% v 90.8%; HR, 0.92; 95% CI, 0.41 to 2.05; P = .83). Distant metastasis-free survival was also higher with WPRT (95.9% v 89.2%; HR, 0.35; 95% CI, 0.15 to 0.82; P = .01). Benefit in BFFS and DFS was maintained across prognostic subgroups. CONCLUSION: Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and DFS as compared with PORT, but OS did not appear to differ.

Deciphering the anti-Parkinson's activity of sulphated polysaccharides from Chlamydomonas reinhardtii on the α-Synuclein mutants A30P, A53T, E46K, E57K and E35K.

Parkinsonism-linked mutations in alanine and glutamic acid residues of the pre-synaptic protein α-Synuclein (α-Syn) affect specific tertiary interactions essential for stability of the native state and make it prone to more aggregation. Many of the currently available drugs used for the treatment of Parkinson's disease (PD) are not very effective and are associated with multiple side effects. Recently, marine algae have been reported to have sulphated polysaccharides which offers multiple pharmaceutical properties. With this background, we have isolated sulphated polysaccharides from Chlamydomonas reinhardtii (Cr-SPs) and investigated their effects on inhibition of fibrillation/aggregation of α-Syn mutants through a combination of spectroscopic and microscopic techniques. The kinetics of α-Syn fibrillation establishes that Cr-SPs are very effective in inhibiting fibrillation of α-Syn mutants. The morphological changes associated with the fibrillation/aggregation process have been monitored by transmission electron microscopy. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis gel image suggests that Cr-SPs increase the amount of soluble protein after completion of the fibrillation/aggregation process. The circular dichroism results showed that Cr-SPs efficiently delay the conversion of native protein into ß-sheet-rich structures. Thus, the current work has considerable therapeutic implications towards deciphering the potential of Cr-SPs to act against PD and other protein aggregation-related disorders.