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Radiation-induced malignancies after intensity-modulated versus conventional mediastinal radiotherapy in a small animal model.

ABSTRACT: A long-standing hypothesis in radiotherapy is that intensity-modulated radiotherapy (IMRT) increases the risk of second cancer due to low-dose exposure of large volumes of normal tissue. Therefore, young patients are still treated with conventional techniques rather than with modern IMRT. We challenged this hypothesis in first-of-its-kind experiments using an animal model. Cancer-prone Tp53+/C273X knockout rats received mediastinal irradiation with 3?×?5 or 3?×?8?Gy using volumetric-modulated arc therapy (VMAT, an advanced IMRT) or conventional anterior-posterior/posterior-anterior (AP/PA) beams using non-irradiated rats as controls (n?=?15/group, ntotal?=?90). Tumors were assigned to volumes receiving 90-107%, 50-90%, 5-50%, and <5% of the target dose and characterized by histology and loss-of-heterozygosity (LOH). Irradiated rats predominantly developed lymphomas and sarcomas in areas receiving 50-107% (n?=?26) rather than 5-50% (n?=?7) of the target dose. Latency was significantly shortened only after 3?×?8?Gy vs. controls (p?

SUBMITTER: Gomarteli K

PROVIDER: S-EPMC6820874 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Radiation-induced malignancies after intensity-modulated versus conventional mediastinal radiotherapy in a small animal model.

Gomarteli Kaga K Fleckenstein Jens J Kirschner Stefanie S Bobu Vladimir V Brockmann Marc A MA Henzler Thomas T Meyer Mathias M Riffel Philipp P Schönberg Stefan O SO Veldwijk Marlon R MR Kränzlin Bettina B Hoerner Christian C Glatting Gerhard G Wenz Frederik F Herskind Carsten C Giordano Frank A FA

Scientific reports 20191029 1

A long-standing hypothesis in radiotherapy is that intensity-modulated radiotherapy (IMRT) increases the risk of second cancer due to low-dose exposure of large volumes of normal tissue. Therefore, young patients are still treated with conventional techniques rather than with modern IMRT. We challenged this hypothesis in first-of-its-kind experiments using an animal model. Cancer-prone Tp53<sup>+/C273X</sup> knockout rats received mediastinal irradiation with 3 × 5 or 3 × 8 Gy using volumetric-m ...[more]

PMID: 31664066

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Project description:BackgroundXerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia.MethodsWe undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537.Findings47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0-59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival.InterpretationSparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck.FundingCancer Research UK (CRUK/03/005).

Project description:IntroductionTechnological advancements in treatment planning and delivery have propelled the use of intensity-modulated radiation therapy (IMRT) in head and neck squamous cell carcinoma (HNSCC). This review compares IMRT with conventional two-dimensional (2D) and/or three-dimensional (3D) radiotherapy (RT) in curative-intent management of HNSCC.MethodsOnly randomized controlled trials (RCTs) offering curative-intent RT in patients with non-metastatic HNSCC were included. Outcome data was extracted independently by two reviewers, pooled using the Cochrane methodology, and expressed as risk ratio (RR) or hazard ratio (HR) as appropriate with 95% confidence intervals (CIs). Xerostomia was the primary outcome of interest whereas loco-regional control, overall survival and quality-of-life (QOL) were secondary endpoints.ResultsSeven RCTs involving 1155 patients directly comparing IMRT with 2D/3D-RT in HNSCC were included. The primary objective in five of seven index RCTs was reduction in xerostomia, with only one trial each using loco-regional control and overall survival as primary endpoints for sample size calculation. The use of IMRT was associated with a 36% relative risk reduction in ≥grade 2 acute xerostomia (RR = 0.64, 95%CI = 0.49-0.84; p = 0.001) compared to 2D/3D-RT. More importantly, IMRT significantly reduced the risk of ≥grade 2 late xerostomia (RR = 0.44, 95%CI = 0.34-0.57; p = 0.00001) compared to non-IMRT techniques at all time-points. Within the limitations of inadequate sample size and low statistical power, IMRT also resulted in 24% relative reduction in the risk of loco-regional relapse (HR = 0.76, 0.57-1.01; p = 0.06) and 30% relative reduction in risk of death (HR = 0.70, 95%CI = 0.57-0.88; p = 0.002) compared to 2D/3D-RT. However, this benefit of IMRT for loco-regional control and overall survival was limited to nasopharyngeal cancer patients alone, with no significant difference in efficacy between the two techniques in patients with cancers of the laryngo-pharynx in this analysis, highlighting the inconsistency in results of subgroup analyses stratified by primary site. Inadequate reporting of data precluded statistically pooling of results for QOL outcomes.ConclusionsThere is consistent moderate-quality evidence that IMRT significantly reduces the risk of moderate to severe acute and late xerostomia compared to 2D/3D-RT in curative-intent radiotherapeutic management of HNSCC. However, the quality of evidence regarding the superiority of IMRT over conventional techniques for disease-related endpoints is rather low due to relative lack of power and inconsistency of results precluding robust conclusions.

Project description:BackgroundProstate 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.

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Radiation-induced malignancies after intensity-modulated versus conventional mediastinal radiotherapy in a small animal model.

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Radiation-induced malignancies after intensity-modulated versus conventional mediastinal radiotherapy in a small animal model.

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