CHHiP Trial Research Articles

Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity-Modulated Radiotherapy in Prostate Cancer

AimsThe CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme. Materials and methodsQuality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire. ResultsIn total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT. ConclusionOverall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.

Impact of Prostate Cancer Hypofractionation on Patient Reported Outcomes: Baseline to 5 Years Change in the CHHIP Trial

Impact of Prostate Cancer Hypofractionation on Patient Reported Outcomes: Baseline to 5 Years Change in the CHHIP Trial

Extracting primary care records for prostate cancer patients in the CHHiP multicentre randomised control trial: A healthcare data linkage study

IntroductionThe aim is to investigate the effect of cardiovascular and diabetes comorbidities on radiotherapy-related side-effects in prostate cancer. Previous research suggests that comorbidities increase the risk of side-effects, but some cardiovascular medications may reduce symptoms by protecting against radiation damage. The evidence is inconclusive and mechanisms are not fully understood.
 ObjectiveTo explore whether routine primary care data can supplement clinical trial data in evaluating the impact of comorbidities and prescription medications on patient outcomes.
 ApproachThe CHHiP radiotherapy trial (CRUK/06/16) recruited 3,216 prostate cancer patients from 71 centres in UK, Ireland, Switzerland, and New Zealand between 2002 and 2011. Baseline comorbidity and radiotherapy-related side-effects over time were recorded. This was linked to computerised medical records (CMRs) from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. RCGP RSC is a network of 192 English general practices with over 2 million patients (2.8% of the population).
 ResultsThe English population of CHHiP patients (N=2811) was used. 120 CMRs were linked, which exceeded the estimation of 79 linked records. However, six CMRs showed no evidence of regular GP care and a further eight patients were not recruited into the CHHiP trial until after they had de-registered from an RCGP RSC practice.
 Information on cardiovascular and diabetes comorbidities was extracted for 106 patients. The mean age was 69±7 years, representative of the CHHiP population. From the CMRs, 23 (22%) patients had diabetes and 47 (44%) had hypertension including 37 (35%) who took angiotensin converting enzyme (ACE) inhibitors (medications lowering blood pressure). In addition, 44 (41%) patients took aspirin, 65 (61%) statins (lowering blood lipids) and 14 (13%) took metformin (lowering blood sugar levels). 
 Conclusion/ImplicationsThe small sample limits statistical analysis. However, a clinical trial was successfully linked to GP data to determine comorbidities and medications of patients. This will serve as a pilot for further research. The advantage of data linkage is that it may provide a mechanism for long-term follow-up of radiotherapy-related side-effects.

Assessment of Ki67 in relation to radiotherapy (RT) fractionation and prognosis in the CHHiP (CRUK/06/016) trial.

98 Background: A uniform fractionation schedule is used to deliver external beam RT for localised prostate tumours Individualising fractionation according to tumour biology may improve outcomes. In addition recurrence rates after RT vary considerably and better prognostic markers are needed to guide treatment choices. This study aims to identify if the cell proliferation marker Ki67 predicts response to RT fractionation in CHHiP, a randomised trial of 3 RT fractionation schedules. It also aims to identify if Ki67 predicts prognosis. Methods: A matched case:control study design was used, patients with biochemical or clinical failure > 2 years after RT (BCR) were matched to patients without recurrence according to established prognostic factors (Gleason score, PSA, Tumour-stage) and fractionation schedule. Immunohistochemical (IHC) staining of diagnostic biopsy sections was carried out using the MIB1 Ki67 antibody. Two independent investigators scored Ki67 using the unweighted global method (1) to derive a mean and maximum percentage of cells staining positive (mean Ki67 and maximum Ki67 respectively). Conditional logistic regression models were fitted with interaction terms between the biomarker and the fractionation schedules to determine whether Ki67 predicted BCR according to fractionation. Secondly models were fitted using the entire case:control study sample to estimate the prognostic value of Ki67 on risk of BCR. Results: Ki67 results were available for 173 matched pairs. The interaction terms between Ki67 and the fractionation schedules were not significant. However mean and maximum Ki67 were significant prognostic markers for BCR in a model adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR is estimated to increase by 9% per 1 point increase in mean Ki67 (OR = 1.09, 95%CI:1.04–1.15, p = 0.001). Conclusions: Ki67 did not predict BCR according to fractionation schedule in CHHiP, however it did predict prognosis independently of established prognostic factors. Additional IHC biomarkers are under evaluation.

Derivation of dose/volume constraints for the anorectum from clinician-reported outcomes (CRO) in the CHHiP trial of radiotherapy (RT) fractionation.

87 Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30Gy≤80%, V40Gy≤70%, V50Gy≤60%, V60Gy≤50%, V70Gy≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval >0.5 were considered statistically significant. Any constraint derived in <99% of bootstraps was excluded. Results: Statistically significant dose constraints were derived for rectal bleeding, increased bowel frequency, faecal incontinence and rectal pain (table). Conclusions: Dose constraints differed between symptoms, indicating potentially different pathogenesis of each radiation-induced side effect. Derived dose constraints were tighter than those used in CHHiP; use of these may reduce anorectal symptoms post RT. Comparable data derived from the hypofractionated cohorts will be presented. [Table: see text]

5-year patient-reported outcomes of bowel and urinary bother in the CHHiP trial (CRUK/06/016).

23 Background: Hypofractionated radiotherapy (hRT) has been shown to be non-inferior to conventional fractionation (cRT) in the CHHiP trial. Clinician reported toxicity was low across all fractionation schedules at 5 years (y), as were patient reported outcomes (PRO) to 2y. Here we aim to confirm these findings with PRO data at 5y. Methods: The CHHiP trial randomised patients (pts) in a 1:1:1 ratio to cRT: 74Gy/37 fractions (f) or hRT: 60Gy/20f or 57Gy/19f. Overall bowel bother (BB) and urinary bother (UB) were assessed as single items of the UCLA-PCI and EPIC-50 instruments. PRO were completed before hormone therapy and RT (pRT). Late symptoms were assessed 6 monthly from 6-24 months and yearly to 5y. Differences in the distribution of scores were assessed using a chi2 trend test. Odds of an increase in bother were modelled using ordered logistic regression. Kaplan-Meier methods were used to estimate time to “small” or worse bother, with RT schedules compared using the log-rank test. Results: Between Oct, 2002 and Nov, 2009 2100 pts were recruited into the PRO sub-study (696 74Gy, 698 60Gy and 706 57Gy). Return rates at 5y were 355 (51%), 388 (56%) and 402 (57%) for the 74, 60 and 57Gy schedules respectively. Cross-sectional analyses at 5y showed no difference between groups (Table 1). The odds of an increase in BB from pRT to 5y for hRT compared to cRT were (Odds Ratio (OR) (99% CI), p-value): 60Gy: 0.78 (0.52-1.18), 0.12; 57Gy: 0.75 (0.50-1.12), 0.06, and for UB were: 60Gy: 1.00 (0.67-1.50), 1.00; 57Gy: 1.08 (0.72-1.61), 0.62. Time to first late “small” or worse BB was also similar across groups (Hazard ratio (HR) (99% CI), p-value): 60Gy: 1.08 (0.85-1.37), 0.42; 57Gy: 0.92 (0.71-1.18), 0.36 or UB: 60Gy: 0.93 (0.73-1.20), 0.48; 57Gy: 0.91 (0.71, 1.17), 0.34. Conclusions: After 5 years follow-up, cRT and hRT showed a similar low level of patient reported BB and UB. Clinical trial information: ISRCTN97182923. [Table: see text]

Hypofractionated Radiotherapy for Prostate Cancer

Hypofractionated Radiotherapy for Prostate Cancer

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

SummaryBackgroundProstate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.MethodsCHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.FindingsBetween Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.InterpretationHypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Concurrent boost technique in prostate IMRT and accuracy of planning target volume (PTV) at the periphery.

e16615Background: The CHHiP trial, (ISRCTN 97182923), supports the hypothesis that alpha-beta ratio is low for prostate cancer & larger fractions (3Gy/#) of radiation have better cell kill. Paradox...

Comparison of hypofractionated high-dose intensity-modulated radiotherapy schedules for prostate cancer: Results from the phase III randomized CHHiP trial (CRUK/06/016).

2 Background: We aimed to explore the dose response relationship for two 3 Gray (Gy) hypofractionated radiotherapy (hRT) schedules for localised prostate cancer (PCa). Methods: hRT schedules of 60Gy/20 fractions (f) and 57Gy/19f were compared with conventional RT (cRT) 74Gy/37f; iso-effective for alpha-beta ratios of 2.5Gy and 1.5Gy respectively. The trial was powered to demonstrate non-inferiority between each hRT schedule and cRT, with 3,213 patients (pt) needed to rule out 5% inferiority (80% power, 1-sided alpha 5%) assuming 70% event-free rate in cRT, corresponding to a critical hazard ratio (HR) of 1.21. The trial was not formally powered to directly compare the two hRT schedules. Pt with N0 T1b-T3a localised PCa were randomized (1:1:1 ratio). The primary endpoint was PCa progression (freedom from biochemical failure by Phoenix consensus guidelines or PCa recurrence). Acute toxicity was assessed up to 18 weeks post treatment and late side effects to 5 years (yr) by RTOG, LENT-SOM and patient reported outcomes (PROs). Results: 3,216 pts were randomized between 2002 and 2011; 1,065 (74Gy), 1,074 (60Gy), 1,077 (57Gy). Baseline characteristics were well balanced across groups: median age 69 yr; NCCN risk group 15% low, 73% intermediate, 12% high. With median follow up 5.2yr, 5yr progression-free rate (95% CI) was 74Gy: 88.3% (86.0%, 90.2%); 60Gy: 90.6% (88.5%, 92.3%), 57Gy: 85.9 (83.4, 88.0); HR60/74: 0.83, 90% CI (0.68, 1.03), HR57/74: 1.20, 90% CI (0.99, 1.45). Significantly more events were observed with 57Gy compared to 60Gy; HR57/60: 1.44, 90% CI (1.18, 1.75), log-rank p=0.003. No significant difference in acute RTOG bladder or bowel toxicity was observed between hRT schedules. Late toxicity profile was favorable; with grade 2+ RTOG bladder (60Gy: 16/960 (1.7%); 57Gy: 11/962 (1.1%), p=0.34) and bowel (60Gy: 28/960 (2.9%); 57Gy: 17/962 (1.8%), p=0.10) toxicity at 2yr. Analysis of LENT-SOM and PROs supported these results. Conclusions: With 5 yr follow-up treatment with a 3Gy schedule of 60Gy/20f shows improved treatment efficacy compared to 57Gy/19f and is non-inferior to 74Gy/37f with a similar low level of acute and late normal tissue damage. Clinical trial information: ISRCTN97182923.

Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

SummaryBackgroundPatient-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.

PO-0720: Patient reported outcomes of overall bowel and urinary bother in the CHHiP trial (CRUK: 8262/A7257)

PO-0720: Patient reported outcomes of overall bowel and urinary bother in the CHHiP trial (CRUK: 8262/A7257)

Forward and inverse-planned intensity-modulated radiotherapy (IMRT) in the CHHiP trial: A comparison of dosimetry and normal tissue toxicity.

37 Background: CHHiP (CRUK/06/016) is a multicentre randomised controlled trial investigating the use of hypofractionated radiotherapy dose schedules for treatment of localised prostate cancer. RT treatment employs a complex target volume treated with either a multi-segment “forward” plan or inverse-planned intensity-modulated radiotherapy (IMRT). This study compares dose-volume histogram (DVH) and toxicity data for rectum and bladder for the two planning techniques. Methods: Three hundred thirty seven patients (230 forward-planned [F]; 107 inverse-planned [I]) with prospectively collected 2 year toxicity and DVH data for rectum and bladder dose constraints were included. Patients were paired for comparison by matching on (1) rectum and prostate + seminal vesicle PTV volumes for the rectal dose comparison (53 matched pairs available); and (2) bladder and prostate-alone PTV volumes for bladder dose comparison (61 matched pairs). For the toxicity comparison patients were additionally matched on randomised dose schedule. Results: Forward-planned patients had significantly larger volumes of rectum irradiated to 50 to 70Gy and bladder at 50 to 60Gy. In contrast, inverse-planned patients had significantly larger volumes of bladder irradiated to 74 Gy. Acute bowel toxicity (G2+ toxicity within 18 weeks of start of RT) was significantly worse in forward-planned patients (27/53 [52%] F vs 11/53 [21%] I; Mann-Whitney p=0.0002). There were no significant differences in acute urinary symptoms. Late toxicity was rare in both planning groups with only two patients (0 F; 2 I) reporting RTOG G2+ bowel/bladder effects at 24 months. Considering LENTSOM data, there was a suggestion of less late bowel toxicity in the inverse group (G1+ at 18 months: 16/53 (30%) F vs. 6/53 (11%) I; p=0.008). Patient reported outcomes of bowel habits showed no consistent differences between planning methods, although there was a tendency for worse urinary function scores in the inverse group at 12 months. Conclusions: Both planning techniques were associated with low late toxicity. Significant differences were found between DVHs from forward and inverse plans. There were some associations between DVH differences and normal tissue effects; these resolved by 2 years. Clinical trial information: CRUK/06/016.

SU-FF-T-174: Evaluation of a New Dynamic Arc IMRT Optimization

Purpose: The quality and accuracy of delivery of both prostate and esophagus plans generated using of a new dynamic arc optimization algorithm (SmartArc) within the Pinnacle TPS have been evaluated and compared with standard step-and-shoot (SS) techniques. Method and Materials: Two types of single-arc plans have been evaluated, one that is delivered using a constant dose-rate (CDR) and gantry speed, and one that is delivered using both a variable dose-rate and gantry speed (VMAT). The former can be delivered on most linear accelerators; the latter requires an accelerator that has been licensed for VMAT treatments. Prostate plans were all optimized following the UK CHHIP trial protocol, which has three PTV dose levels. Esophagus plans were optimized following a local protocol. In both cases plans were created for Varian accelerators equipped with a 120-leaf MLC. The delivery of plans was evaluated using Delta-4 (ScandiDos). Results: In all prostate cases plans met the target coverage criteria. The CDR arc plans tended to give the highest hot-spot. For the prostate plans the CDR arc plans and SS plans gave approximately equivalent rectal and bladder DVHs, with the arc-plan femoral head DVHs being better. The VMAT plans gave improved DVHs for all outlined organs-at-risk for prostate plans. For esophagus plans, the CDR arc plans struggled to meet the target coverage criteria, whereas the VMAT plans gave acceptable coverage and improved organ-at-risk sparing. In all cases the measured quality assurance results were good with no significant differences between the different delivery methods. For the VMAT plans delivery time was 75–90 seconds and 2.5–3.0 minutes for the CDR-arc plans. Conclusion: The Pinnacle SmartArc optimizer provides a very useful tool for generating accurately deliverable IMRT plans on a wide range of accelerators. Conflict of Interest: This work was performed in collaboration with Philips Radiation Oncology Systems