Despite survival improvements achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. ...Germinal and/or somatic alterations of DNA-damage response pathway genes are found in a substantial number of patients with advanced prostate cancers, mainly of poor prognosis. Such alterations induce a dependency for single strand break reparation through the poly(adenosine diphosphate-ribose) polymerase (PARP) system, providing the rationale to develop PARP inhibitors. In solid tumors, the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies. Although this represents a major milestone, a number of issues relating to PARP inhibitors remain. This timely review synthesizes and discusses the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways.
Purpose
The aim of this study was to evaluate the role of preoperative and postoperative external beam radiation therapy (EBRT) in the treatment of resectable soft tissue sarcomas (STSs) of different ...tumor locations.
Methods
A systematic literature search was performed to identify studies investigating the effects of EBRT (versus no EBRT) on local recurrence (LR) and overall survival (OS) or comparing different EBRT sequences. Random effects meta-analyses were calculated and presented as cumulative odds ratios (ORs).
Results
Sixteen studies (
n
= 3958 patients) comparing EBRT versus no EBRT, including one randomized controlled trial (RCT) in extremity sarcoma, were analyzed. EBRT appeared to reduce LR in both retroperitoneal tumors (OR 0.47,
p
< 0.0001) and other locations (OR 0.49,
p
= 0.001). OS was improved by EBRT in retroperitoneal STSs (OR 0.37,
p
< 0.0001) but not in other tumor locations. Eleven studies (
n
= 2140), including one RCT, compared preoperative and postoperative radiotherapy. LR was less frequent following preoperative EBRT in retroperitoneal STSs (OR 0.03,
p
= 0.02), as well as in other tumor locations (OR 0.67,
p
= 0.01), while wound complications in extremity sarcoma were more frequent following preoperative EBRT (OR 2.92,
p
< 0.0001). Several studies included in this meta-analysis bear a high risk of bias and no RCT has been published for retroperitoneal STS.
Conclusions
This meta-analysis supports the use of EBRT for local tumor control in patients with resectable STSs. Based on a small number of non-randomized studies, a positive effect on OS may exist in the subgroup of retroperitoneal STSs.
Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals.
The patterns of care, ...outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed.
The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis.
The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.
Purpose
Radiotherapy (RT), as part of trimodal therapy, is an attractive alternative treatment in patients with urothelial muscle-invasive bladder cancer (MIBC). There is accumulating evidence ...suggesting the immunomodulatory effects of RT and its potential synergy when combined with immunotherapy. The aim of this review was to report on the most recent advances on this combination, including the mechanisms of RT immunomodulation, practical approach to combining RT and immunotherapy, and ongoing clinical trials in bladder cancer.
Methods
Using the PubMed database, we identified articles published between March 2004 and April 2020 on the combination of RT with immunotherapy in localized or metastatic MIBC. A search of the Clinicaltrials.gov and Clinicaltrialsregister.eu/ retrieved ongoing clinical trials on the topic as well.
Results
Combination of RT with immunotherapy leads to immunogenic cell death and an increase in immune markers thus leading to improved tumor control. For localized MIBC, there are safety concerns related to the use of concurrent immunotherapy with hypofractionated RT, thus neoadjuvant or adjuvant immunotherapy is preferred. In the metastatic setting, the combination of multi-site RT with SBRT-like doses (≥ 6 Gy per fraction) and concurrent immunotherapy seems most efficacious at harnessing the abscopal effect. At least 25 clinical trials combining immunotherapy and RT in MIBC are currently ongoing and will answer pending questions on safety, efficacy, and practical considerations on RT scheduling, fractionation, and targets volumes.
Conclusion
RT has the potential to synergize with immunotherapy to improve oncological outcomes in patient with localized or metastatic MIBC. Clinical trials results are eagerly awaited.
•Plan Complexity Metrics (PCM) are variables that aim to quantify IMRT and VMAT plan complexities.•PCM has been published in heterogeneous formalism, this work class and synthetize them.•Use of PCM ...is still institution-dependent.•PCM could now be seen as a quality indicator.
Fixed-field intensity modulated radiation therapy (FF-IMRT) or volumetric modulated arc therapy (VMAT) beams complexity is due to fluence fluctuation. Pre-treatment Quality Assurance (PTQA) failure could be linked to it. Several plan complexity metrics (PCM) have been published to quantify this complexity but in a heterogeneous formalism. This review proposes to gather different PCM and to discuss their eventual PTQA failure identifier abilities.
A systematic literature search and outcome extraction from MEDLINE/PubMed (National Center for Biotechnology Information, NCBI) was performed. First, a list and a synthesis of available PCM is made in a homogeneous formalism. Second, main results relying on the link between PCM and PTQA results but also on other uses are listed.
A total of 163 studies were identified and n = 19 were selected after inclusion and exclusion criteria application. Difference is made between fluence and degree of freedom (DOF)-based PCM. Results about the PCM potential as PTQA failure identifier are described and synthesized. Others uses are also found in quality, big data, machine learning and audit procedure.
A state of the art is made thanks to this homogeneous PCM classification. For now, PCM should be seen as a planning procedure quality indicator although PTQA failure identifier results are mitigated. However limited clinical use seems possible for some cases. Yet, addressing the general PTQA failure prediction case could be possible with the big data or machine learning help.
Although salvage prostate bed radiotherapy is highly effective in biochemically-relapsing prostate cancer patients following prostatectomy, relapses remain frequent and improvements are needed. ...Randomized phase 3 trials have shown the benefit of adding androgen-depriving therapy to irradiation, but not all patients benefit from this combination. Preclinical studies have shown that novel agents targeting the androgen receptor, DNA repair, PI3K/AKT/mTOR pathways, or the hypoxic microenvironment may help increase the response to prostate bed irradiation while minimizing potential side effects. This perspective review focuses on the most relevant molecules that may have an impact when combined with salvage radiotherapy, and underlines the strategies that need to be developed to increase the efficacy of salvage post-prostatectomy radiotherapy in prostate cancer patients.
The objective of this study was to describe the outcome and prognostic factors for adults treated for localized myxofibrosarcoma.
We conducted a retrospective multicenter study of 425 nonmetastatic ...patients who underwent surgery between January 1996 and December 2015 in French National Group and were enrolled in the Conticabase. Pathologic diagnosis was systematically reviewed by expert pathologists. The endpoints were relapse-free and metastasis-free survival. Log-rank tests and Cox models have been used to identified prognostic factors.
Median age was 66 years; 53% were males; 85% of cases occurred in limbs or superficial trunk; median size was 60 mm; 47% and 39% were grades 2 and 3, respectively; 66% had R0 resection and 34% R1 resection. Adjuvant radiation therapy was given to 65% of patients, neoadjuvant radiation therapy to 3%, neoadjuvant chemotherapy to 7%, and adjuvant chemotherapy to 13%. The median follow-up was 51 months. The 5-year local relapse-free survival was 67%; independent prognostic factors for local relapse were R1 resection (hazard ratio HR = 1.26; P = .001) and adjuvant radiation therapy (HR = 0.35; P = .0001) (ie, R1 resection and no adjuvant radiation therapy increase the hazard ratio). In stratified analysis, adjuvant radiation therapy was beneficial after R0 resection (P = .0020) and after R1 resection (P = .0001). The 5-year overall survival was 80%. The 5-year metastasis-free survival was 83%. Independent prognostic factors for metastatic relapse were grade 3 disease (HR = 1.975; P = .0001) and tumor size (HR = 1.006; P = .001).
This large series of myxofibrosarcoma confirms the high rate of local relapse. Combination of R0 resection and adjuvant radiation therapy provided the best local control. In parallel with an increasing rate of R0 resection and adjuvant radiation therapy, we observed a constant improvement in both metastatic and local relapse-free survival during the study.
The majority of patients with prostate cancer who later develop lethal metastatic disease have high-risk localized disease at presentation, emphasizing the importance of effective treatment ...strategies at this stage. Multimodal treatment approaches that combine systemic and local therapies offer a promising strategy for improving the clinical outcomes of patients with high-risk localized prostate cancer. Combinations of neoadjuvant and adjuvant chemotherapy, hormonal therapy, or chemohormonal therapy are considered to be the standard of care in most solid tumours and should be investigated in the future for the treatment of prostate cancer to improve patient outcomes. However, although the combination of androgen deprivation therapy and radiotherapy is a standard of care in high-risk localized or locally advanced prostate cancer, the benefit of chemotherapy or chemohormonal therapy has yet to be demonstrated outside of the metastatic setting. Moreover, the benefit of neoadjuvant and/or adjuvant systemic therapies in combination with radical prostatectomy has not been proved. The development of next-generation hormonal agents, which have been approved for the treatment of castration-resistant prostate cancer, offers further therapeutic possibilities that are being assessed in early-phase clinical trials.
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