Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which ...harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.
► Glucose and fatty acids are differentially utilized in molecular subsets of DLBCL ► Mitochondria are predominant in the metabolic signature of BCR-independent DLBCLs ► Fatty acid oxidation and glutathione synthesis are relevant to OxPhos-DLBCL survival ► Fuel utilization pathways define additional levels of heterogeneity in DLBCL
The integration of adaptive radiation therapy (ART), or modifying the treatment plan during the treatment course, is becoming more widely available in clinical practice. ART offers strong potential ...for minimizing treatment-related toxicity while escalating or de-escalating target doses based on the dose to organs at risk. Yet, ART workflows add complexity into the radiation therapy planning and delivery process that may introduce additional uncertainties. This work sought to review presently available ART workflows and technological considerations such as image quality, deformable image registration, and dose accumulation. Quality assurance considerations for ART components and minimum recommendations are described. Personnel and workflow efficiency recommendations are provided, as is a summary of currently available clinical evidence supporting the implementation of ART. Finally, to guide future clinical trial protocols, an example ART physician directive and a physics template following standard NRG Oncology protocol is provided.
Utilization of stereotactic body radiation therapy (SBRT) for treatment of localized prostate cancer is increasing. Guidelines and payers variably support the use of prostate SBRT. We therefore ...sought to systematically analyze biochemical recurrence-free survival (bRFS), physician-reported toxicity, and patient-reported outcomes after prostate SBRT.
A systematic search leveraging Medline via PubMed and EMBASE for original articles published between January 1990 and January 2018 was performed. This was supplemented by abstracts with sufficient extractable data from January 2013 to March 2018. All prospective series assessing curative-intent prostate SBRT for localized prostate cancer reporting bRFS, physician-reported toxicity, and patient-reported quality of life with a minimum of 1-year follow-up were included. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were performed with random-effect modeling. Extent of heterogeneity between studies was determined by the I
and Cochran's Q tests. Meta-regression was performed using Hartung-Knapp methods.
Thirty-eight unique prospective series were identified comprising 6116 patients. Median follow-up was 39 months across all patients (range, 12-115 months). Ninety-two percent, 78%, and 38% of studies included low, intermediate, and high-risk patients. Overall, 5- and 7-year bRFS rates were 95.3% (95% confidence interval CI, 91.3%-97.5%) and 93.7% (95% CI, 91.4%-95.5%), respectively. Estimated late grade ≥3 genitourinary and gastrointestinal toxicity rates were 2.0% (95% CI, 1.4%-2.8%) and 1.1% (95% CI, 0.6%-2.0%), respectively. By 2 years post-SBRT, Expanded Prostate Cancer Index Composite urinary and bowel domain scores returned to baseline. Increasing dose of SBRT was associated with improved biochemical control (P = .018) but worse late grade ≥3 GU toxicity (P = .014).
Prostate SBRT has substantial prospective evidence supporting its use, with favorable tumor control, patient-reported quality of life, and levels of toxicity demonstrated. SBRT has sufficient evidence to be supported as a standard treatment option for localized prostate cancer while ongoing trials assess its potential superiority.
Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current ...definitions of oligometastasis are solely numerical.
To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.
This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.
We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).
The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio IRR 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio HR 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.
Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.
Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.
The frequency of putative driver mutations increases across the metastatic hormone-sensitive prostate cancer spectrum and can stratify clinical outcomes. Somatic mutational profiles help in redefining oligometastasis beyond simple lesion enumeration by providing a biological definition.
Studies have provided high-level evidence on various aspects of salvage radiation therapy (SRT) for recurrence of prostate cancer after radical prostatectomy, including field design, dose and ...fractionation, and additional hormonal therapy regimens. For patients with higher prostate-specific antigen (PSA) at SRT, addition of hormonal therapy and pelvic nodal radiation will improve PSA-based endpoints. By contrast, dose escalation is not supported by level 1 evidence in this setting.
Management of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity ...associated with any local salvage modality.
To quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low–dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy.
We performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities.
A total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p < 0.01), with no other differences identified.
Large differences in 5-yr outcomes were not uncovered when comparing all salvage treatment modalities against RP. Reirradiation with SBRT, HDR brachytherapy, or LDR brachytherapy appears to result in less severe GU toxicity than RP, and reirradiation with HDR brachytherapy yields less severe GI toxicity than RP. Prospective studies of local salvage for radiorecurrent disease are warranted.
In a large study-level meta-analysis, we looked at treatment outcomes and toxicity for men treated with a number of salvage treatments for radiorecurrent prostate cancer. We conclude that relapse-free survival at 5 years is equivalent among salvage modalities, but reirradiation may lead to lower toxicity.
This meta-analysis provides pooled estimates of surgical and nonsurgical local salvage treatments for radiorecurrent prostate cancer. Five-year recurrence-free survival (RFS) was similar across modalities on meta-regression, although differences in severe genitourinary and gastrointestinal toxicity appear to favor reirradiation, particularly high-dose-rate brachytherapy. Pretreatment prostate-specific antigen emerged as a powerful predictor of 5-yr RFS. Additional prospective and randomized data are required to better define how to optimally select and treat patients with isolated local failures after definitive radiotherapy.
Purpose
For a cohort of prostate cancer patients treated on an MR-guided radiotherapy (MRgRT) system, we retrospectively analyzed urethral interfractional geometric and dosimetric variations based on ...onboard MRIs acquired at different timepoints and evaluated onboard prostatic urethra visualization for urethra-focused online adaptive RT.
Methods
Twenty-six prostate cancer patients were prospectively scanned on a 0.35-T MRgRT system using an optimized T2-weighted HASTE sequence at simulation and final fraction. Two radiation oncologists (RO1 and RO2) contoured the urethras on all HASTE images. The simulation and final fraction HASTE images were rigidly registered, and urethral interobserver and interfractional geometric variation was evaluated using the 95th percentile Hausdorff distance (HD95), mean distance to agreement (MDA), center-of-mass shift (COMS), and DICE coefficient. For dosimetric analysis, simulation and final fraction HASTE images were registered to the 3D bSSFP planning MRI and 3D bSSFP final setup MRI, respectively. Both ROs’ urethra contours were transferred from HASTE images for initial treatment plan optimization and final fraction dose estimation separately. Stereotactic body radiotherapy (SBRT) plans, 40 Gy in 5 fractions, were optimized to meet clinical constraints, including urethral V42Gy ≤0.03 cc, on the planning MRI. The initial plan was then forward calculated on the final setup MRI to estimate urethral dose on the final fraction and evaluate urethral dosimetric impact due to anatomy change.
Results
The average interobserver HD95, MDA, COMS, and DICE were 2.85 ± 1.34 mm, 1.02 ± 0.36 mm, 3.16 ± 1.61 mm, and 0.58 ± 0.15, respectively. The average interfractional HD95, MDA, COMS, and DICE were 3.26 ± 1.54 mm, 1.29 ± 0.54 mm, 3.34 ± 2.01 mm, and 0.49 ± 0.18, respectively. All patient simulation MRgRT plans met all clinical constraints. For RO1 and RO2, 23/26 (88%) and 21/26 (81%) patients’ final fraction estimated urethral dose did not meet the planned constraint. The average urethral V42Gy change was 0.48 ± 0.58 cc.
Conclusion
Urethral interfractional motion and anatomic change can result in daily treatment violating urethral constraints. Onboard MRI with good visualization of the prostatic urethra can be a valuable tool to help better protect the urethra through patient setup or online adaptive RT.
PDF
