The Efficacy and Safety of Metastasis-directed Therapy in Patients with Prostate Cancer:A Systematic Review and Meta-analysis of Prospective Studies

CONTEXT: Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are continuously emerging from well-designed prospective studies.OBJECTIVE: To summarise and report the evidence on oncological and safety outcomes of MDT in the management of mPCa patients.EVIDENCE ACQUISITION: We searched the PubMed, Scopus, and Web of Science databases for prospective studies assessing progression-free survival (PFS), local control (LC), androgen deprivation therapy (ADT)-free survival (ADT-FS), overall survival (OS), and/or adverse events (AEs) in mPCa patients treated with MDT. A meta-analysis was performed for 1- and 2-yr PFS, LC, ADT-FS, OS, and rate of AEs. Meta-regression and sensitivity analysis were performed to account for heterogeneity and identify moderators.EVIDENCE SYNTHESIS: We identified 22 prospective studies (n = 1137), including two randomised controlled trials (n = 116). Two studies were excluded from the meta-analysis (n = 120). The estimated 2-yr PFS was 46% (95% confidence interval [CI]: 36-56%) or 42% (95% CI: 33-52%) after excluding studies using biochemical or ADT-related endpoints. The estimated 2-yr LC, ADT-FS, and OS were 97% (95% CI: 94-98%), 55% (95% CI: 44-65%), and 97% (95% CI: 95-98%), respectively. Rates of treatment-related grade 2 and ≥3 AEs were 2.4% (95% CI: 0.2-7%) and 0.3% (95% CI: 0-1%), respectively.CONCLUSIONS: MDT is a promising treatment strategy associated with favourable PFS, excellent LC, and a low toxicity profile that allows oligorecurrent hormone-sensitive patients to avoid or defer ADT-related toxicity. Integration of MDT with other therapies offers a promising research direction, in particular, in conjunction with systemic treatments and as a component of definitive care for oligometastatic PCa. However, in the absence of randomised trials, using MDT for treatment intensification remains an experimental approach, and the impact on OS is uncertain.PATIENT SUMMARY: Direct treatment of metastases is a promising option for selected prostate cancer patients. It can delay hormone therapy and is being investigated as a way of intensifying treatment at the expense of manageable toxicity.</p

Community Violence Exposure and Conduct Problems in Children and Adolescents with Conduct Disorder and Healthy Controls

Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self-report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD

Metastases-directed local therapies (MDT) beyond genuine oligometastatic disease (OMD):Indications, endpoints and the role of imaging

To further personalise treatment in metastatic cancer, the indications for metastases-directed local therapy (MDT) and the biology of oligometastatic disease (OMD) should be kept conceptually apart. Both need to be vigorously investigated. Tumour growth dynamics – growth rate combined with metastatic seeding efficiency – is the single most important biological feature determining the likelihood of success of MDT in an individual patient, which might even be beneficial in slowly developing polymetastatic disease. This can be reasonably well assessed using appropriate clinical imaging. In the context of considering appropriate indications for MDT, detecting metastases at the edge of image resolution should therefore suggest postponing MDT. While three to five lesions are typically used to define OMD, it could be argued that countability throughout the course of metastatic disease, rather than a specific maximum number of lesions, could serve as a better parameter for guiding MDT. Here we argue that the unit of MDT as a treatment option in metastatic cancer might best be defined not as a single procedure at a single point in time, but as a series of treatments that can be delivered in a single or multiple sessions to different lesions over time. Newly emerging lesions that remain amenable to MDT without triggering the start of a new systemic treatment, a change in systemic therapy, or initiation of best supportive care, would thus not constitute a failure of MDT. This would have implications for defining endpoints in clinical trials and registries: Rather than with any disease progression, failure of MDT would only be declared when there is progression to polymetastatic disease, which then precludes further options for MDT.</p

Strahlentherapie und Onkologie / Postoperative radiotherapy for prostate cancer : Morbidity of local-only or local-plus-pelvic radiotherapy

Ziel Ziel der vorgestellten Arbeit ist es, die Häufigkeit früher und später Nebenwirkungen nach postoperativer Bestrahlung von Prostatakarzinompatienten zu analysieren. Verglichen wurden dabei die Nebenwirkungen von lokaler Bestrahlung mit denen nach lokaler Bestrahlung plus Beckenbestrahlung (4-Felder-Box-Technik). Material und Methoden Basierend auf einem risikoadaptierten Protokoll erhielten 575 Patienten nach Prostatektomie entweder eine konventionelle lokale Bestrahlung (n = 447) oder eine Beckenbestrahlung (n = 128). Gastrointestinale und urogenitale Nebenwirkungen Grad 2 wurden prospektiv anhand der RTOG/EORTC-Klassifikation erhoben. Verglichen wurden die maximale Morbidität sowie die aktuarischen Inzidenz- und Prävalenzraten in beiden Gruppen. Ergebnisse Bei lokaler Bestrahlung waren die mediane Nachsorgezeit 68 Monate und die mittlere Dosis 66,7 Gy, bei Beckenbestrahlung waren die mediane Beobachtungszeit 49 Monate und die lokale Dosis bzw. die Beckendosis 66,9 und 48,3 Gy. Frühe gastrointestinale Nebenwirkungen wurden bei 26 % (lokal) bzw. bei 42 % (Becken) beobachtet (p < 0,001), eine späte gastrointestinale Morbidität bei jeweils 14 % in beiden Gruppen (p = 0,77). Die aktuarischen Fünfjahresinzidenzraten waren 14 bzw. 14 %, die Prävalenz lag bei 2 bzw.Purpose The aim of this work was to characterise actuarial incidence and prevalence of early and late side effects of local versus pelvic three-dimensional conformal postoperative radiotherapy for prostate cancer. Materials and methods Based on a risk-adapted protocol, 575 patients received either local (n = 447) or local-plus-pelvic (n = 128) radiotherapy. Gastrointestinal (GI) and genitourinary (GU) side effects (grade 2 RTOG/EORTC criteria) were prospectively assessed. Maximum morbidity, actuarial incidence rate, and prevalence rates were compared between the two groups. Results For local radiotherapy, median follow-up was 68 months, and the mean dose was 66.7 Gy. In pelvic radiotherapy, the median follow-up was 49 months, and the mean local and pelvic doses were 66.9 and 48.3 Gy respectively. Early GI side effects G2 were detected in 26% and 42% of patients respectively (p < 0.001). Late GI adverse events were detected in 14% in both groups (p = 0.77). The 5year actuarial incidence rates were 14% and 14%, while the prevalence rates were 2% and 0% respectively. Early GU G2 side effects were detected in 15% and 16% (p = 0.96), while late GU morbidity was detected in 18% and 24% (p = 0.001). The 5year actuarial incidence rates were 16% and 35% (p = 0.001), while the respective prevalence rates were 6% and 8%. Conclusions Despite the low prevalence of side effects, postoperative pelvic radiotherapy results in significant increases in the actuarial incidence of early GI and late GU morbidity using a conventional 4field box radiotherapy technique. Advanced treatment techniques like intensity-modulated radiotherapy (IMRT) or volumetric modulated arc radiotherapy (VMAT) should therefore be considered in pelvic radiotherapy to potentially reduce these side effects.(VLID)364358

Metastases-directed local therapies (MDT) beyond genuine oligometastatic disease (OMD): Indications, endpoints and the role of imaging

To further personalise treatment in metastatic cancer, the indications for metastases-directed local therapy (MDT) and the biology of oligometastatic disease (OMD) should be kept conceptually apart. Both need to be vigorously investigated. Tumour growth dynamics – growth rate combined with metastatic seeding efficiency – is the single most important biological feature determining the likelihood of success of MDT in an individual patient, which might even be beneficial in slowly developing polymetastatic disease. This can be reasonably well assessed using appropriate clinical imaging. In the context of considering appropriate indications for MDT, detecting metastases at the edge of image resolution should therefore suggest postponing MDT. While three to five lesions are typically used to define OMD, it could be argued that countability throughout the course of metastatic disease, rather than a specific maximum number of lesions, could serve as a better parameter for guiding MDT. Here we argue that the unit of MDT as a treatment option in metastatic cancer might best be defined not as a single procedure at a single point in time, but as a series of treatments that can be delivered in a single or multiple sessions to different lesions over time. Newly emerging lesions that remain amenable to MDT without triggering the start of a new systemic treatment, a change in systemic therapy, or initiation of best supportive care, would thus not constitute a failure of MDT. This would have implications for defining endpoints in clinical trials and registries: Rather than with any disease progression, failure of MDT would only be declared when there is progression to polymetastatic disease, which then precludes further options for MDT

Automated volumetric modulated arc therapy planning for whole pelvic prostate radiotherapy Automatisierte volumenmodulierte Arc-Therapieplanung für Ganzbecken-Prostatabestrahlung

markdownabstractBackground: For several tumor entities, automated treatment planning has improved plan quality and planning efficiency, and may enable adaptive treatment approaches. Whole-pelvic prostate radiotherapy (WPRT) involves large concave target volumes, which present a challenge for volumetric arc therapy (VMAT) optimization. This study evaluates automated VMAT planning for WPRT-VMAT and compares the results with manual expert planning. Methods: A system for fully automated multi-criterial plan generation was configured for each step of sequential-boost WPRT-VMAT, with final “autoVMAT” plans being automatically calculated by the Monaco treatment planning system (TPS; Elekta AB, Stockholm, Sweden). Configuration was based on manually generated VMAT plans (manualVMAT) of 5 test patients, the planning protocol, and discussions with the treating physician on wishes for plan improvements. AutoVMAT plans were then generated for another 30 evaluation patients and compared to manualVMAT plans. For all 35 patients, manualVMAT plans were optimized by expert planners using the Monaco TPS. Results: AutoVMAT plans exhibited strongly improved organ sparing and higher conformity compared to manualVMAT. On average, mean doses (Dmean) of bladder and rectum were reduced by 10.7 and 4.5 Gy, respectively, by autoVMAT. Prostate target coverage (V95%) was slightly higher (+0.6%) with manualVMAT. In a blinded scoring session, the radiation oncologist preferred autoVMAT plans to manualVMAT plans for 27/30 patients. All treatment plans were considered clinically acceptable. The workload per patient was reduced by > 70 min. Conclusion: Automated VMAT planning for complex WPRT dose distributions is feasible and creates treatment plans that are generally dosimetrically superior to manually optimized plans