Charlotte E. Coles

Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype

A key challenge in radiotherapy is to maximize radiation doses to cancer cells while minimizing damage to surrounding healthy tissue. As severe toxicity in a minority of patients limits the doses that can be safely given to the majority, there is interest in developing a test to measure an individuals radiosensitivity before treatment. Variation in sensitivity to radiation is an inherited genetic trait and recent progress in genotyping raises the possibility of genome-wide studies to characterize genetic profiles that predict patient response to radiotherapy.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study

BACKGROUND Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. METHODS 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2. FINDINGS None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance. INTERPRETATION We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed. FUNDING Cancer Research UK, The Royal College of Radiologists, Addenbrookes Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.

Randomized Controlled Trial of Intensity-Modulated Radiotherapy for Early Breast Cancer: 5-Year Results Confirm Superior Overall Cosmesis

PURPOSE There are few randomized controlled trial data to confirm that improved homogeneity with simple intensity-modulated radiotherapy (IMRT) decreases late breast tissue toxicity. The Cambridge Breast IMRT trial investigated this hypothesis, and the 5-year results are reported. PATIENTS AND METHODS Standard tangential plans of 1,145 trial patients were analyzed; 815 patients had inhomogeneous plans (≥ 2 cm(3) receiving 107% of prescribed dose: 40 Gy in 15 fractions over 3 weeks) and were randomly assigned to standard radiotherapy (RT) or replanned with simple IMRT; 330 patients with satisfactory dose homogeneity were treated with standard RT and underwent the same follow-up as the randomly assigned patients. Breast tissue toxicities were assessed at 5 years using validated methods: photographic assessment (overall cosmesis and breast shrinkage compared with baseline pre-RT photographs) and clinical assessment (telangiectasia, induration, edema, and pigmentation). Comparisons between different groups were analyzed using polychotomous logistic regression. RESULTS On univariate analysis, compared with standard RT, fewer patients in the simple IMRT group developed suboptimal overall cosmesis (odds ratio [OR], 0.68; 95% CI, 0.48 to 0.96; P = .027) and skin telangiectasia (OR, 0.58; 95% CI, 0.36 to 0.92; P = .021). No evidence of difference was seen for breast shrinkage, breast edema, tumor bed induration, or pigmentation. The benefit of IMRT was maintained on multivariate analysis for both overall cosmesis (P = .038) and skin telangiectasia (P = .031). CONCLUSION Improved dose homogeneity with simple IMRT translates into superior overall cosmesis and reduces the risk of skin telangiectasia. These results are practice changing and should encourage centers still using two-dimensional RT to implement simple breast IMRT.

Hypofractionated whole-breast radiotherapy for women with early breast cancer: myths and realities.

JOHN YARNOLD, F.R.C.R.,* SOREN M. BENTZEN, D.SC.,y CHARLOTTE COLES, PH.D.,z AND JOANNE HAVILAND, M.SC.{ *Section of Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom; yDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; zOncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; {Institute of Cancer Research Clinical Trials and Statistics Unit, Section of Clinical Trials, Sutton, United Kingdom

Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years.

PURPOSE This single-center randomized trial was designed to investigate whether intensity-modulated radiotherapy (IMRT) reduces late toxicity in patients with early-stage breast cancer. METHODS AND MATERIALS The standard tangential plans of 1,145 nonselected patients were analyzed. The patients with inhomogeneous plans were randomized to a simple method of forward-planned IMRT or standard radiotherapy (RT). The primary endpoint was serial photographic assessment of breast shrinkage. RESULTS At 2 years, no significant difference was found in the development of any photographically assessed breast shrinkage between the patients randomized to the interventional or control group (odds ratio, 1.51; 95% confidence interval, 0.83-1.58; p = .41). The patients in the control group were more likely to develop telangiectasia than those in the IMRT group (odds ratio, 1.68; 95% confidence interval 1.13-2.40; p = .009). Poor baseline surgical cosmesis resulted in poor overall cosmesis at 2 years after RT. In patients who had good surgical cosmesis, those randomized to IMRT were less likely to deteriorate to a moderate or poor overall cosmesis than those in the control group (odds ratio, 0.63; 95% confidence interval, 0.39-1.03, p = .061). CONCLUSIONS IMRT can lead to a significant reduction in telangiectasia at comparatively early follow-up of only 2 years after RT completion. An important component of breast induration and shrinkage will actually result from the surgery and not from the RT. Surgical cosmesis is an important determinant of overall cosmesis and could partially mask the longer term benefits of IMRT at this early stage.

Clinical Impact of Computed Tomography-based Image-guided Brachytherapy for Cervix Cancer using the Tandem-ring Applicator — the Addenbrooke's Experience

AIMS We report our initial 3-year experience of chemoradiotherapy for cervical cancer with computed tomography-based image-guided high dose rate (HDR) brachytherapy using the tandem-ring applicator. MATERIALS AND METHODS Twenty-eight patients were treated between February 2005 and December 2007. All patients received initial external beam radiotherapy (EBRT) followed by HDR brachytherapy (planned dose 21 Gy to point A in three fractions over 8 days). For each insertion, a computed tomography scan was obtained with the brachytherapy applicator in situ. The cervix, uterus and organs at risk (OAR) were contoured on the computed tomography images to create an individualised dosimetry plan. The D(90) (the dose delivered to 90% of the tumour target), V(100) (the percentage of tumour target volume receiving 100% of the prescribed dose) and the minimum dose in the most exposed 2 cm(3) volume (D(2 cc)) of rectum, bladder and bowel were recorded. The equivalent dose in 2 Gy fractions delivered by EBRT and brachytherapy was calculated. RESULTS The 3-year cancer-specific survival was 81%, with a pelvic control rate of 96%. In 24 patients, a D(90)>or=74 Gy (alpha/beta10) was achieved. The only patient with local recurrence had a D(90) of 63.8 Gy(alpha/beta10). The overall actuarial risk of serious late morbidity was 14%. Seventeen patients had satisfactory OAR doses using the standard loading pattern. Seven patients had modifications to reduce the risk of toxicity, whereas two had modifications to improve the tumour dose. Comparison with a previous cohort of patients treated with chemoradiotherapy and a conventionally planned low dose rate triple source brachytherapy technique showed an improvement in local pelvic control of 20% (P=0.04). CONCLUSIONS The implementation of a computed tomography-based tandem-ring HDR brachytherapy technique in conjunction with individual dose adaptation has resulted in a significant improvement in local control at Addenbrookes without increasing the risk of serious toxicity, and with little effect on radiotherapy resources.

A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: baseline characteristics and dosimetry results.

BACKGROUND AND PURPOSE This large trial was designed to investigate whether correction of dose inhomogeneities using intensity-modulated radiotherapy (IMRT) reduces late toxicity and improves quality of life in patients with early breast cancer. This paper reports baseline characteristics of trial participants and dosimetry results. MATERIALS AND METHODS Standard tangential plans of 1145 trials were analysed. Patients with inhomogeneous plans, defined by ICRU recommendations, were randomised to forward-planned IMRT or standard radiotherapy. RESULTS Twenty-nine percentage of patients had adequate dosimetry with standard 2D radiotherapy. In the randomised patients, the decreases in mean volumes receiving greater than 107% (Vol>107) and less than 95% (Vol<95) of the prescribed dose in the IMRT compared with the control group were 34.0 cm(3) (95% CI 26.4-41.6; P<0.0001) and 48.1 cm(3) (95% CI 34.4-61.9; P<0.0001), respectively. In this study, 90% of patients who had a breast separation greater > or = 21 cm had Vol>107>2 cm(3) on standard radiotherapy plans. CONCLUSION This large trial, in which patients with all breast sizes were eligible, confirmed that breast dosimetry can be significantly improved with a simple method of forward-planned IMRT and has little impact on radiotherapy resources. It is shown that patients with larger breasts are more likely to have dose inhomogeneities and breast separation gives some indication of this likelihood. Photographic assessment of patients at 2 years after radiotherapy, as the next part of this randomised controlled trial, will show whether these results for IMRT translate into improved cosmetic outcome in patients with early breast cancer. This would provide impetus for the widespread adoption of 3D planning and IMRT.

A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

BACKGROUND AND PURPOSE This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery – Audit on behalf of the IMPORT Trial Management Group

INTRODUCTION Accurate tumour bed (TB) localisation is a key requirement for the UK IMPORT (Intensity Modulated Partial Organ Radiotherapy) trial. We audited the value of titanium clips for TB localisation following breast conserving surgery (BCS) in breast radiotherapy (RT) planning. PATIENTS AND METHODS At surgery, paired clips were positioned around the TB as follows: 1. Medial, lateral, superior and inferior: half-way between skin and fascia; 2. Posterior: at the pectoral fascia; 3. Anterior: close to the suture line. Thirty consecutive patients with clips inserted were audited at the time of RT planning. Audit standards were set as follows: (i) 5/6 pairs of clips identified on RT planning computed tomography (CT) scan - 100%; (ii) possible clip migration: <10%; (iii) TB localisation improved with clips: >50%. Inter- and intra-observer variability in clinician outlining of the TB was studied in a subset of 12 randomly selected patients to see if this impacted on positioning of radiotherapy field borders. RESULTS Five or six pairs of clips were identified in all 30 cases. The TB could be successfully identified using CT seroma alone in only 8/30 (27%) patients. Clips were essential for the TB localisation of the other 22/30 (73%) patients. There was no evidence of clip migration. TB localisation led to modified RT field borders in 18/30 (60%) patients. Five of these patients had highly visible seromas, so the addition of clips modified field borders in 13/30 (43%) patients. Both inter- and intra-observer variability was reasonable and did not impact on positioning of radiotherapy field borders. CONCLUSION Titanium clips provide an accurate and reliable method of TB localisation following BCS. We anticipate that the audit results will lead to clips being adopted as best practice by the Association of Breast Surgeons (ABS) at BASO (British Association of Surgical Oncology).