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On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

ABSTRACT: Emerging evidence demonstrates that radiotherapy induces immunogenic death on tumor cells that emit immunostimulating signals resulting in tumor-specific immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we use a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Simulations analysis suggests that radiotherapy success depends on the functional tumor vascularity extent and reveals that the pre-treatment tumor size is not a consistent determinant of treatment outcomes. The one-size-fits-all approach of conventionally fractionated radiotherapy is predicted to result in some overtreated patients. In addition, model simulations also suggest that an arbitrary increase in treatment duration does not necessarily result in better tumor control. This study highlights the potential benefits of tumor-immune ecosystem profiling during treatment planning to better harness the immunogenic potential of radiotherapy.

SUBMITTER: Alfonso JCL

PROVIDER: S-EPMC7038527 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

Alfonso Juan Carlos L JCL Papaxenopoulou Lito A LA Mascheroni Pietro P Meyer-Hermann Michael M Hatzikirou Haralampos H

iScience 20200211 3

Emerging evidence demonstrates that radiotherapy induces immunogenic death on tumor cells that emit immunostimulating signals resulting in tumor-specific immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we use a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Simulations analysis suggests t ...[more]

PMID: 32092699

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Project description:BackgroundEvidence supporting the efficacy of stereotactic body radiotherapy (SBRT) for localized prostate cancer is accumulating, but comparative studies of patient-reported quality of life (QOL) following SBRT versus conventionally fractionated external beam radiotherapy (EBRT) or active surveillance (AS) are limited.ObjectiveTo compare QOL of patients pursuing SBRT and EBRT versus AS.Design, setting, and participantsA population-based cohort of 680 men with newly diagnosed localized prostate cancer was prospectively enrolled from 2011 to 2013.InterventionSBRT, EBRT without androgen deprivation therapy, or AS.Outcome measurements and statistical analysisQOL was prospectively assessed before treatment (baseline), and at 3, 12, and 24mo after treatment using the validated Prostate Cancer Symptom Indices, which contain four domains: sexual dysfunction, urinary obstruction/irritation, urinary incontinence, and bowel problems. Propensity weighting via logistic regression models was used to balance baseline characteristics, and the mean QOL scores of EBRT and SBRT patients were compared against AS patients as the control group.Results and limitationsCompared with AS patients, EBRT patients had worse urinary obstructive/irritative symptoms and sexual dysfunction at 3mo, and worse bowel symptoms at 3 and 24mo. SBRT patients had similar scores as AS patients in all domains and across all time points; however, due to small sample size, worse sexual function and urinary incontinence in SBRT patients cannot be ruled out. Further research is needed to assess long-term outcomes.ConclusionsIn a nonrandomized cohort of men with localized prostate cancer, SBRT appeared to result in favorable QOL results through 2yr of follow-up, but worse sexual function and urinary incontinence compared with AS cannot be ruled out completely. Larger studies with longer follow-up are needed to confirm these findings.Patient summaryStereotactic body radiotherapy (SBRT) and active surveillance appear to have similar quality of life outcomes through 2yr, although worse sexual function and urinary incontinence from SBRT cannot be ruled out completely.

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Project description:BackgroundPatient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.MethodsThe CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.Findings2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4-64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.InterpretationThe incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Dataset Information

On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

Publications

On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

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