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Prostate cancer dose-response, fractionation sensitivity and repopulation parameters evaluation from 25 international radiotherapy outcome data sets.

ABSTRACT: OBJECTIVE:This study was undertaken to model the biochemical free survival at 5 years and to evaluate the parameters defining dose-response curve, dose-fractionation radiosensitivity and repopulation. METHODS:It was carried out a literature search on Pubmed to retrieve data sets of patients treated with external beam radiation therapy of 1.8-4.0?Gy per fraction and overall treatment time of 3 to 10 weeks. 10 groups were identified, based on risk class and androgen deprivation therapy (ADT). Dose-response curve D50 (dose at 50% probability of control) and g50 (steepness), ?/? (dose-fractionation radiosensitivity), and repopulation parameters, dprolif and Tprolif , were calculated. Bootstrap-based cross-validation was performed and median and 95%?CI (confidence interval) were evaluated. RESULTS:25 data sets, including 20,310 patients, were considered. The median (95%?CI) D50 and g50 values were 62 (CI 53 - 66)?Gy and 1.6 (0.8 - 2.4). ADT patients showed lower values of D50 and g50 (57 ± 5?Gy and 1.1 ± 0.4) compared to no-ADT patients (65 ± 2?Gy and 2.3 ± 0.6), with p < 0.0001?and p = 0.002. If we did not consider any dependence on overall treatment time, the median (95%?CI) value of ?/? was 1.4 (1.0 - 1.9)?Gy with p < 0.0001 for all patients. The median values of dproli f and Tprolif were 0.0 to 0.3?Gy/d and 18-40 days. CONCLUSION:Dose-response curve resulted dependent on risk class and ADT, with higher steepness for no-ADT patients. Low values of dose-fractionation radiosensitivity were found, supporting the use of moderate hypofractionated radiotherapy in each risk class. A limited dependence on repopulation was observed. ADVANCES IN KNOWLEDGE:Prostate cancer response to moderate hypofractionated radiotherapy was reliably quantified considering risk class and androgen deprivation therapy.

SUBMITTER: Tamponi M

PROVIDER: S-EPMC6592096 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Project description:The paper considers the fractionation problem in intensity modulated proton therapy (IMPT). Conventionally, IMPT fields are optimized independently of the fractionation scheme. In this work, we discuss the simultaneous optimization of fractionation scheme and pencil beam intensities.This is performed by allowing for distinct pencil beam intensities in each fraction, which are optimized using objective and constraint functions based on biologically equivalent dose (BED). The paper presents a model that mimics an IMPT treatment with a single incident beam direction for which the optimal fractionation scheme can be determined despite the nonconvexity of the BED-based treatment planning problem.For this model, it is shown that a small α∕β ratio in the tumor gives rise to a hypofractionated treatment, whereas a large α∕β ratio gives rise to hyperfractionation. It is further demonstrated that, for intermediate α∕β ratios in the tumor, a nonuniform fractionation scheme emerges, in which it is optimal to deliver different dose distributions in subsequent fractions. The intuitive explanation for this phenomenon is as follows: By varying the dose distribution in the tumor between fractions, the same total BED can be achieved with a lower physical dose. If it is possible to achieve this dose variation in the tumor without varying the dose in the normal tissue (which would have an adverse effect), the reduction in physical dose may lead to a net reduction of the normal tissue BED. For proton therapy, this is indeed possible to some degree because the entrance dose is mostly independent of the range of the proton pencil beam.The paper provides conceptual insight into the interdependence of optimal fractionation schemes and the spatial optimization of dose distributions. It demonstrates the emergence of nonuniform fractionation schemes that arise from the standard BED model when IMPT fields and fractionation scheme are optimized simultaneously. Although the projected benefits are likely to be small, the approach may give rise to an improved therapeutic ratio for tumors treated with stereotactic techniques to high doses per fraction.

Project description:Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering-via synergistic effects-the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a "hot" immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death).

Project description:Objective: To investigate predictors of patient-reported urinary incontinence (PRUI) in the first 2 years after post-prostatectomy radiotherapy (PORT) with particular emphasis on possible dose-effect relationships. Patients and Methods: Two-hundred-thirteen patients, whose clinical and dosimetric data were prospectively collected within a registered multi-institutional cohort study, underwent PORT with adjuvant (n = 106) or salvage (n = 107) intent with conventional (n = 123, prescribed dose to the prostatic bed: 66.6-79.8Gy in 1.8-2.0Gy/fr) or moderately hypo- (n = 90, 65.8-76.8Gy in 2.1-2.7Gy/fr) fractionation during the period 2011-2017. PRUI was evaluated through the ICIQ-SF questionnaire filled in at baseline and every 6 months thereafter. The analysis focused on three ICIQ-based clinically relevant endpoints: (a) very frequent leakage (FREQUENCY, ICIQ3 score >3), (b) moderate to severe amount of urine loss (AMOUNT, ICIQ4>2) (c) objective severe symptoms (OBJECTIVE, ICIQ3+4>5). Predictors of the incidence within 2 years for the three endpoints were investigated focusing only on patients without endpoint symptoms at baseline. A uni-variable logistic regression analysis was performed in order to determine the best dose metrics describing PRUI risk in terms of 2-Gy equivalent dose (EQD2) calculated with different α/β values reported in the literature (0.8, 3, 5Gy), and to identify the most significant clinical variables. Variables showing p < 0.20 at uni-variable analysis were entered into a backward stepwise multi-variable logistic regression analysis. Lastly, the goodness of fit and model calibration were evaluated and internally validated. Results: Patients without symptoms at baseline experienced (a), (b), and/or (c) within 2 years in 41/130 (32%), 40/192 (21%), and 41/129 (32%) of the cases, respectively. EQD2 for α/β = 0.8Gy was the best dose metric associated with PRUI. Multi-variable analysis identified baseline incontinence levels as the strongest predictor for all endpoints (p < 0.006). Both FREQUENCY and OBJECTIVE were significantly influenced also by EQD2(α/β = 0.8Gy). The goodness of fit was excellent, as was the calibration; internal calibration confirmed apparent performance. Conclusion: Baseline mild urinary incontinence symptoms strongly modulate the 2-year risk of PRUI. In addition, FREQUENCY is characterized by a marked dose-effect relationship also influencing the trend of OBJECTIVE, with results more reliable than AMOUNT as an objective index. A strong impact of fractionation on severe PRUI after post-prostatectomy radiotherapy also emerged.

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Prostate cancer dose-response, fractionation sensitivity and repopulation parameters evaluation from 25 international radiotherapy outcome data sets.

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