Bhattacharya, I.S., Haviland, J.S., Kirby, A.M., Kirwan, C.C., Hopwood, P., Yarnold, J.R., Bliss, J.M., Coles, C.E. & IMPORT Trialists,
(2019). Patient-Reported Outcomes Over 5 Years After Whole- or Partial-Breast Radiotherapy: Longitudinal Analysis of the IMPORT LOW (CRUK/06/003) Phase III Randomized Controlled Trial. J clin oncol,
PURPOSE: IMPORT LOW demonstrated noninferiority of partial-breast and reduced-dose radiotherapy versus whole-breast radiotherapy for local relapse and similar or reduced toxicity at 5 years. Comprehensive patient-reported outcome measures collected at serial time points are now reported. PATIENTS AND METHODS: IMPORT LOW recruited women with low-risk breast cancer after breast-conserving surgery. Patients were randomly assigned to 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast and 40 Gy partial-breast radiotherapy (reduced-dose), or 40 Gy partial-breast radiotherapy only (partial-breast) in 15 fractions. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 and Breast Cancer-Specific Module, Body Image Scale, protocol-specific items, and the Hospital Anxiety and Depression Scale were administered at baseline, 6 months, and 1, 2, and 5 years. Patterns of moderate/marked adverse effects (AEs) were assessed using longitudinal regression models, and baseline predictors were investigated. RESULTS: A total of 41 of 71 centers participated in the patient-reported outcome measures substudy; 1,265 (95%) of 1,333 patients consented, and 557 (58%) of 962 reported no moderate/marked AEs at 5 years. Breast appearance change was most prevalent and persisted over time (approximately 20% at each time point). Prevalence of breast hardness, pain, oversensitivity, edema, and skin changes reduced over time ( P < .001 for each), whereas breast shrinkage increased ( P < .001). Analysis by treatment group showed average number of AEs per person was lower in partial-breast (incidence rate ratio, 0.77; 95% CI, 0.71 to 0.84; P < .001) and reduced-dose (incidence rate ratio, 0.83; 95% CI, 0.76 to 0.90; P < .001) versus whole-breast group and decreased over time in all groups. Younger age, larger breast size/surgical deficit, lymph node positivity, and higher levels of anxiety/depression were baseline predictors of subsequent AE reporting. CONCLUSION: Most AEs reduced over time, with fewer AEs in the partial-breast and reduced-dose groups. Baseline predictors for AE reporting were identified. These findings will facilitate informed discussion and shared decision making for future patients receiving moderately hypofractionated breast radiotherapy..
Dunlop, A., Colgan, R., Kirby, A., Ranger, A. & Blasiak-Wal, I.
(2019). Evaluation of organ motion-based robust optimisation for VMAT planning for breast and internal mammary chain radiotherapy. Clin transl radiat oncol,
Aims: In patients undergoing locoregional radiotherapy (RT) for breast cancer including the internal mammary chain (IMC), VMAT has been shown to be superior to tangential-field radiotherapy in terms of target coverage and minimising dose to heart and lungs. In this study we describe and validate organ motion-based robust optimisation for generating breast and locoregional lymph node VMAT plans that are robust to inter-fractional changes. Materials and methods: In this retrospective study of five patients with left-sided breast cancer requiring locoregional breast radiotherapy including the IMC, non-robust plans were generated in the nominal scenario (planning-CT) and corresponding robust plans were created by optimising over a range of simulated CTs representing worst-case scenario shape changes to the breast. Both plans were re-calculated on CBCT images (n = 67) acquired prior to RT to generate estimates of delivered fractional dose. Plan robustness to inter-fractional changes was assessed in terms of the estimated target coverage and OAR dose. Results: Organ motion-based robust optimisation was able to generate clinically acceptable treatment plans in the nominal scenario on the planning CT with no significant differences to OAR dose between the robust and non-robust planning techniques. All plans (robust and non-robust) achieved the mandatory target coverage requirements. Estimates of delivered dose demonstrated a significant improvement in breast target coverage for the robust plans compared to non-robust plans. For the breast CTV, 92% of the robust plans achieved the optimal D98% > 95% clinical goal as compared to 71% of the non-robust plans (p < 0.01). 94% of robust plans achieved acceptable superficial breast coverage, as compared to 55% for the non-robust technique. Conclusions: Organ motion-based robust optimisation VMAT is able to produce clinically acceptable organ-at-risk sparing plans for locoregional breast radiotherapy (including the IMC) that are robust to inter-fractional changes, therefore reducing the likelihood of reactive adaptive re-planning..
Bhattacharya, I.S., Haviland, J.S., Hopwood, P., Coles, C.E., Yarnold, J.R., Bliss, J.M., Kirby, A.M. & IMPORT Trialists,
(2019). Can patient-reported outcomes be used instead of clinician-reported outcomes and photographs as primary endpoints of late normal tissue effects in breast radiotherapy trials? Results from the IMPORT LOW trial. Radiother oncol,
BACKGROUND: In an era of low local relapse rates after adjuvant breast radiotherapy, risks of late normal-tissue effects (NTE) need to be balanced against risk of relapse. NTE are assessed using patient-reported outcome measures (PROMs), clinician-reported outcomes (CRO) and photographs. This analysis investigates whether PROMs can be used as primary NTE endpoints in breast radiotherapy trials. METHODS: Analyses were conducted within IMPORT LOW (ISRCTN12852634) at 2 and 5 years. NTE were recorded by CRO, photographs and PROMs. Measures of agreement tested concordance, risk ratios for radiotherapy groups were compared, and influence of baseline characteristics on concordance investigated. RESULTS: In 1095 patients who consented to PROMS and photographs, PROMs were available at 2 and/or 5 years for 976 patients, of whom 909 had CRO and 844 had photographs. Few patients had moderate/marked NTE, irrespective of method used (eg. 19% patients and 9% clinicians reported breast shrinkage at year-5). Patients reported more NTE than assessed from CRO or photographs (p < 0.001 for most NTE). Concordance between assessments was poor on an individual patient level; eg. for year-5 breast shrinkage, % agreement = 48% and weighted kappa = 0.17. Risk ratios comparing radiotherapy schedules were consistent between PROMs and CRO or photographs. CONCLUSIONS: Few patients had moderate/marked NTE irrespective of method used. Patients reported more NTE than CRO and photographs, therefore NTE may be underestimated if PROMs are not used. Despite poor concordance between methods, effect sizes from PROMs were consistent with CRO and photographs, suggesting PROMs can be used as primary NTE endpoints in breast radiotherapy trials..
Bhattacharya, I.S., Haviland, J.S., Perotti, C., Eaton, D., Gulliford, S., Harris, E., Coles, C.E., Kirwan, C.C., Bliss, J.M., Kirby, A.M., et al.
(2019). Is breast seroma after tumour resection associated with patient-reported breast appearance change following radiotherapy? Results from the IMPORT HIGH (CRUK/06/003) trial. Radiother oncol,
BACKGROUND: Seroma describes a collection of serous fluid within a cavity, occurring following surgery. Seroma is associated with normal tissue effects (NTE) following breast radiotherapy, as reported by clinicians and on photographs. This study investigates the association between seroma and the NTE breast appearance change collected using patient-reported outcome measures (PROMs) in IMPORT HIGH, as well as investigating the association between breast appearance change and patient/tumour/treatment factors. METHODS: Case-control methodology was used for seroma analysis within IMPORT HIGH. Cases were patients reporting moderate/marked breast appearance change and controls reported none/mild changes at year-3. One control was selected at random for each case. Seromas were graded as not visible/subtle or visible/highly visible on CT radiotherapy planning scans. Logistic regression tested associations, adjusting for patient/tumour/treatment factors. RESULTS: 1078/1149 patients consented to PROMs, of whom 836 (78%) reported whether they had 3-year breast appearance change; 231 cases and 231 controls were identified. 304/462 (66%) patients received chemotherapy. Seroma prevalence was 20% (41/202) in cases and 16% (32/205) in controls, and less frequent in patients receiving adjuvant chemotherapy [10% (24/246) compared with 29% (40/138) without]. Visible seroma was not significantly associated with breast appearance change [OR 1.38 (95%CI 0.83-2.29), p = 0.219]. Larger tumour size, haematoma, current smoking and body image concerns at baseline were independent risk factors. CONCLUSIONS: Seroma was not associated with patient-reported breast appearance change, but haematoma and smoking were significant risk factors. Lack of association may be related to lower prevalence of seroma compared with previous reports, perhaps reflecting patients receiving adjuvant chemotherapy in whom seroma resolves prior to radiotherapy..
Bhattacharya, I.S., Kirby, A.M., Bliss, J.M. & Coles, C.E.
(2018). Can Interrogation of Tumour Characteristics Lead us to Safely Omit Adjuvant Radiotherapy in Patients with Early Breast Cancer?. Clin oncol (r coll radiol),
Adjuvant radiotherapy after breast-conserving surgery has been an important component of the standard of care for early breast cancer. Improvements in breast cancer care have resulted in a substantial reduction in local relapse rates over recent decades. Although the proportional benefits of adjuvant radiotherapy are similar for different prognostic risk groups of patients, the absolute benefits depend on the risk of relapse and therefore vary considerably between prognostic groups. Radiotherapy is not without risk and for some patients at very low risk of relapse the risks of radiotherapy may outweigh the benefit, leading to potential overtreatment. Randomised controlled trial (RCT) evidence shows that omission of radiotherapy in low risk early breast cancer does not reduce overall survival or increase breast cancer mortality and local recurrences are salvageable. Despite this there has not been a change in practice regarding omission of radiotherapy. The reasons for this may include challenges in patient selection. Recent advances in immunohistochemistry and genomic profiling may improve risk stratification and the development of biomarkers to directed therapies. Several RCTs have quantified the benefit of radiotherapy in reducing local relapse. Where a treatment benefit is known but is considered to be so small not to be clinically relevant then alternatives to RCTs may be considered to answer the question of need. This is because we can assess risk against a fixed 'absolute' boundary rather than needing a randomised comparator. The prospective cohort study is an alternative to the RCT design to answer the question of need for radiotherapy. The feasibility of recruitment into biomarker-directed de-escalation studies will become apparent as more studies open. The challenge is to determine if we are able to accurately risk stratify patients and avoid unnecessary toxicity, thereby tailoring the need for adjuvant breast radiotherapy on an individual patient basis..
(2018). Updated ASTRO guidelines on accelerated partial breast irradiation (APBI): to whom can we offer APBI outside a clinical trial?. Br j radiol,
The American Society of Radiation Oncology has recently updated its guidelines on the role of accelerated partial breast irradiation in the management of breast cancer. This commentary discusses the new recommendations and how we might advise patients in the light of existing data..
Edmunds, D.M., Gothard, L., Khabra, K., Kirby, A., Madhale, P., McNair, H., Roberts, D., Tang, K.K., Symonds-Tayler, R., Tahavori, F., et al.
(2018). Low-cost Kinect Version 2 imaging system for breath hold monitoring and gating: Proof of concept study for breast cancer VMAT radiotherapy. J appl clin med phys,
Voluntary inspiration breath hold (VIBH) for left breast cancer patients has been shown to be a safe and effective method of reducing radiation dose to the heart. Currently, VIBH protocol compliance is monitored visually. In this work, we establish whether it is possible to gate the delivery of radiation from an Elekta linac using the Microsoft Kinect version 2 (Kinect v2) depth sensor to measure a patient breathing signal. This would allow contactless monitoring during VMAT treatment, as an alternative to equipment-assisted methods such as active breathing control (ABC). Breathing traces were acquired from six left breast radiotherapy patients during VIBH. We developed a gating interface to an Elekta linac, using the depth signal from a Kinect v2 to control radiation delivery to a programmable motion platform following patient breathing patterns. Radiation dose to a moving phantom with gating was verified using point dose measurements and a Delta4 verification phantom. 60 breathing traces were obtained with an acquisition success rate of 100%. Point dose measurements for gated deliveries to a moving phantom agreed to within 0.5% of ungated delivery to a static phantom using both a conventional and VMAT treatment plan. Dose measurements with the verification phantom showed that there was a median dose difference of better than 0.5% and a mean (3% 3 mm) gamma index of 92.6% for gated deliveries when using static phantom data as a reference. It is possible to use a Kinect v2 device to monitor voluntary breath hold protocol compliance in a cohort of left breast radiotherapy patients. Furthermore, it is possible to use the signal from a Kinect v2 to gate an Elekta linac to deliver radiation only during the peak inhale VIBH phase..
Ranger, A., Dunlop, A., Hutchinson, K., Convery, H., Maclennan, M.K., Chantler, H., Twyman, N., Rose, C., McQuaid, D., Amos, R.A., et al.
(2018). A Dosimetric Comparison of Breast Radiotherapy Techniques to Treat Locoregional Lymph Nodes Including the Internal Mammary Chain. Clin oncol (r coll radiol),
AIMS: Radiotherapy target volumes in early breast cancer treatment increasingly include the internal mammary chain (IMC). In order to maximise survival benefits of IMC radiotherapy, doses to the heart and lung should be minimised. This dosimetry study compared the ability of three-dimensional conformal radiotherapy, arc therapy and proton beam therapy (PBT) techniques with and without breath-hold to achieve target volume constraints while minimising dose to organs at risk (OARs). MATERIALS AND METHODS: In 14 patients' datasets, seven IMC radiotherapy techniques were compared: wide tangent (WT) three-dimensional conformal radiotherapy, volumetric-modulated arc therapy (VMAT) and PBT, each in voluntary deep inspiratory breath-hold (vDIBH) and free breathing (FB), and tomotherapy in FB only. Target volume coverage and OAR doses were measured for each technique. These were compared using a one-way ANOVA with all pairwise comparisons tested using Bonferroni's multiple comparisons test, with adjusted P-values ≤ 0.05 indicating statistical significance. RESULTS: One hundred per cent of WT(vDIBH), 43% of WT(FB), 100% of VMAT(vDIBH), 86% of VMAT(FB), 100% of tomotherapy FB and 100% of PBT plans in vDIBH and FB passed all mandatory constraints. However, coverage of the IMC with 90% of the prescribed dose was significantly better than all other techniques using VMAT(vDIBH), PBT(vDIBH) and PBT(FB) (mean IMC coverage ± 1 standard deviation = 96.0% ± 4.3, 99.8% ± 0.3 and 99.0% ± 0.2, respectively). The mean heart dose was significantly reduced in vDIBH compared with FB for both the WT (P < 0.0001) and VMAT (P < 0.0001) techniques. There was no advantage in target volume coverage or OAR doses for PBT(vDIBH) compared with PBT(FB). CONCLUSIONS: Simple WT radiotherapy delivered in vDIBH achieves satisfactory coverage of the IMC while meeting heart and lung dose constraints. However, where higher isodose coverage is required, VMAT(vDIBH) is the optimal photon technique. The lowest OAR doses are achieved by PBT, in which the use of vDIBH does not improve dose statistics..
O'Connell, R.L., Di Micco, R., Khabra, K., Kirby, A.M., Harris, P.A., James, S.E., Power, K., Ramsey, K.W. & Rusby, J.E.
(2018). Comparison of Immediate versus Delayed DIEP Flap Reconstruction in Women Who Require Postmastectomy Radiotherapy. Plast reconstr surg,
BACKGROUND: The authors investigated aesthetic outcome and patient satisfaction in women who have undergone deep inferior epigastric artery perforator (DIEP) flap reconstruction in the setting of postmastectomy radiotherapy. Patients who underwent DIEP flap reconstruction without postmastectomy radiotherapy were the control group. METHODS: Participants who had undergone DIEP flap reconstruction between September 1, 2009, and September 1, 2014, were recruited, answered the BREAST-Q, and underwent three-dimensional surface-imaging. A panel assessed the aesthetic outcome by reviewing these images. RESULTS: One hundred sixty-seven women participated. Eighty women (48 percent) underwent immediate DIEP flap reconstruction and no postmastectomy radiotherapy; 28 (17 percent) underwent immediate DIEP flap reconstruction with postmastectomy radiotherapy; 38 (23 percent) underwent simple mastectomy, postmastectomy radiotherapy, and DIEP flap reconstruction; and 21 (13 percent) underwent mastectomy with temporizing implant, postmastectomy radiotherapy, and DIEP flap reconstruction. Median satisfaction scores were significantly different among the groups (p < 0.05). Post hoc comparison demonstrated that women who had an immediate DIEP flap reconstruction were significantly less satisfied if they had postmastectomy radiotherapy. In women requiring radiotherapy, those undergoing delayed reconstruction after a simple mastectomy were most satisfied, but there was no significant difference between the immediate DIEP flap and temporizing implant groups. Median panel scores differed among groups, being significantly higher if the immediate reconstruction was not subjected to radiotherapy. There was no significant difference in panel assessment among the three groups of women who had received radiotherapy. CONCLUSIONS: Patients who avoid having their immediate DIEP flap reconstruction irradiated are more satisfied and have better aesthetic outcome than those who undergo postmastectomy radiotherapy. In women requiring radiotherapy and who wish to have an immediate or "delayed-immediate" reconstruction, there were no significant differences in panel or patient satisfaction. Therefore, immediate DIEP flap reconstruction or mastectomy with temporizing implant then DIEP flap surgery are acceptable treatment pathways in the context of post-mastectomy radiotherapy..
Bagenal, J., Roche, N., Ross, G., Kirby, A. & Dodwell, D.
(2018). Should patients with ductal carcinoma in situ be treated with adjuvant whole breast radiotherapy after breast conservation surgery?. Bmj,
Mitchell, R.A., Wai, P., Colgan, R., Kirby, A.M. & Donovan, E.M.
(2017). Improving the efficiency of breast radiotherapy treatment planning using a semi-automated approach. J appl clin med phys,
OBJECTIVES: To reduce treatment planning times while maintaining plan quality through the introduction of semi-automated planning techniques for breast radiotherapy. METHODS: Automatic critical structure delineation was examined using the Smart Probabilistic Image Contouring Engine (SPICE) commercial autosegmentation software (Philips Radiation Oncology Systems, Fitchburg, WI) for a cohort of ten patients. Semiautomated planning was investigated by employing scripting in the treatment planning system to automate segment creation for breast step-and-shoot planning and create objectives for segment weight optimization; considerations were made for three different multileaf collimator (MLC) configurations. Forty patients were retrospectively planned using the script and a planning time comparison performed. RESULTS: The SPICE heart and lung outlines agreed closely with clinician-defined outlines (median Dice Similarity Coefficient > 0.9); median difference in mean heart dose was 0.0 cGy (range -10.8 to 5.4 cGy). Scripted treatment plans demonstrated equivalence with their clinical counterparts. No statistically significant differences were found for target parameters. Minimal ipsilateral lung dose increases were also observed. Statistically significant (P < 0.01) time reductions were achievable for MLCi and Agility MLC (Elekta Ltd, Crawley, UK) plans (median 4.9 and 5.9 min, respectively). CONCLUSIONS: The use of commercial autosegmentation software enables breast plan adjustment based on doses to organs at risk. Semi-automated techniques for breast radiotherapy planning offer modest reductions in planning times. However, in the context of a typical department's breast radiotherapy workload, minor savings per plan translate into greater efficiencies overall..
O'Leary, B., Alarcon, L., Mallon, E. & Kirby, A.
(2017). Radiotherapy-associated Pemphigus - a Rare Cause of Grade 4 Skin Toxicity. Clin oncol (r coll radiol),
Bartlett, F.R., Donovan, E.M., McNair, H.A., Corsini, L.A., Colgan, R.M., Evans, P.M., Maynard, L., Griffin, C., Haviland, J.S., Yarnold, J.R., et al.
(2017). The UK HeartSpare Study (Stage II): Multicentre Evaluation of a Voluntary Breath-hold Technique in Patients Receiving Breast Radiotherapy. Clin oncol (r coll radiol),
AIMS: To evaluate the feasibility and heart-sparing ability of the voluntary breath-hold (VBH) technique in a multicentre setting. MATERIALS AND METHODS: Patients were recruited from 10 UK centres. Following surgery for early left breast cancer, patients with any heart inside the 50% isodose from a standard free-breathing tangential field treatment plan underwent a second planning computed tomography (CT) scan using the VBH technique. A separate treatment plan was prepared on the VBH CT scan and used for treatment. The mean heart, left anterior descending coronary artery (LAD) and lung doses were calculated. Daily electronic portal imaging (EPI) was carried out and scanning/treatment times were recorded. The primary end point was the percentage of patients achieving a reduction in mean heart dose with VBH. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. RESULTS: In total, 101 patients were recruited during 2014. Primary end point data were available for 93 patients, 88 (95%) of whom achieved a reduction in mean heart dose with VBH. Mean cardiac doses (Gy) for free-breathing and VBH techniques, respectively, were: heart 1.8 and 1.1, LAD 12.1 and 5.4, maximum LAD 35.4 and 24.1 (all P<0.001). Population EPI-based displacement data showed Σ =+1.3-1.9 mm and σ=1.4-1.8 mm. Median CT and treatment session times were 21 and 22 min, respectively. CONCLUSIONS: The VBH technique is confirmed as effective in sparing heart tissue and is feasible in a multicentre setting..
O'Connell, R.L., Di Micco, R., Khabra, K., Wolf, L., deSouza, N., Roche, N., Barry, P.A., Kirby, A.M. & Rusby, J.E.
(2017). The potential role of three-dimensional surface imaging as a tool to evaluate aesthetic outcome after Breast Conserving Therapy (BCT). Breast cancer research and treatment,
O'Connell, R.L., Di Micco, R., Khabra, K., Wolf, L., deSouza, N., Roche, N., Barry, P.A., Kirby, A.M. & Rusby, J.E.
(2017). The potential role of three-dimensional surface imaging as a tool to evaluate aesthetic outcome after Breast Conserving Therapy (BCT). Breast cancer res treat,
PURPOSE: To establish whether objective measurements of symmetry of volume and shape using three-dimensional surface imaging (3D-SI) can be used as surrogate markers of aesthetic outcome in patients who have undergone breast conserving therapy (BCT). METHODS: Women who had undergone unilateral BCT in the preceding 1-6 years were invited to participate. Participants completed a satisfaction questionnaire (BREAST-Q) and underwent 3D-SI. Volume and surface symmetry were measured on the images. Assessment of aesthetic outcome was undertaken by a panel of clinicians. The Kruskal-Wallis test was used to assess the relationship between volume and shape symmetry measurements with the panel score. Spearman's rho correlations were used to assess the relationship between the measurements and patient satisfaction. RESULTS: 200 women participated. Median volume symmetry was 87% (IQR 78-93) and shape symmetry was 5.9 mm (IQR 4.2-8.0). The participants were grouped according to panel assessment of aesthetic outcome (poor, fair, good, excellent) and the median volume and shape symmetry was calculated for each group. Volume symmetry significantly differed between the groups. Post hoc pairwise comparisons demonstrated that these differences existed between panel scores of fair versus good and good versus excellent. Median shape symmetry also differed according to patient panel groups with four significant pairwise comparisons between poor versus good, poor versus excellent, fair versus good and fair versus excellent. There was a significant but weak correlation of both volume symmetry and surface asymmetry with BREAST-Q scores (correlation coefficients 0.187 and -0.229, respectively). CONCLUSION: Breast volume and shape symmetry are both associated with panel assessment scores and patient satisfaction. The objective volume and shape symmetry measures were strongly associated with panel assessment scores, such that a 3D-SI tool could replace panel assessment as a faster and more objective method of evaluating aesthetic outcomes..
Coles, C.E., Griffin, C.L., Kirby, A.M., Titley, J., Agrawal, R.K., Alhasso, A., Bhattacharya, I.S., Brunt, A.M., Ciurlionis, L., Chan, C., et al.
(2017). Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet,
BACKGROUND: Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. METHODS: IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634. FINDINGS: Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7-83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5-2·3) of patients in the control group, 0·2% (0·02-1·2) in the reduced-dose group, and 0·5% (0·2-1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0·73% (-0·99 to 0·22) for the reduced-dose and -0·38% (-0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy. INTERPRETATION: We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. FUNDING: Cancer Research UK..
O'Connell, R.L., DiMicco, R., Khabra, K., O'Flynn, E.A., deSouza, N., Roche, N., Barry, P.A., Kirby, A.M. & Rusby, J.E.
(2016). Initial experience of the BREAST-Q breast-conserving therapy module. Breast cancer res treat,
PURPOSE: The most recently developed module of the BREAST-Q, a validated patient outcome measure, is for patients who have undergone breast-conserving therapy (BCT) for cancer. This aim of this study was to assess patient satisfaction and quality of life after BCT using BREAST-Q, investigate clinical risk factors for lower satisfaction and explore the relationship between patient satisfaction with the appearance of their breasts and the other domains of the BREAST-Q. METHODS: Women who had undergone unilateral BCT in the preceding 1-6 years were invited to participate at the time of their annual surveillance mammogram. Clinicopathological data were collected from an electronic database. Linear regression was used to evaluate risk factors for lower satisfaction. Spearman's rho correlation coefficients were calculated to evaluate the relationship between domains. RESULTS: 200 women completed the questionnaire. Mean age was 60 years (SD 11.1). Time from surgery was 35.5 months (SD 17.8). Median score for 'Satisfaction with breasts' was 68 (interquartile range 55-80). Lowest scores were for 'sexual wellbeing' (57, IQR 45-66). On multivariate analysis, BMI at the time of surgery (p = 0.002), delayed wound healing (p = 0.001) and axillary surgery (p = 0.003) were independent risk factors for lower satisfaction. There was significant correlation between 'Satisfaction with breasts' and all other BREAST-Q domains. CONCLUSION: High BMI, delayed wound healing and axillary surgery are risk factors for lower patient satisfaction. This first publication reporting the whole dataset for the BREAST-Q BCT will serve as a benchmark for future studies of patient satisfaction following BCT..
Dunkerley, N., Bartlett, F.R., Kirby, A.M., Evans, P.M. & Donovan, E.M.
(2016). Mean heart dose variation over a course of breath-holding breast cancer radiotherapy. Br j radiol,
OBJECTIVE: The purpose of the work was to estimate the dose received by the heart throughout a course of breath-holding breast radiotherapy. METHODS: 113 cone-beam CT (CBCT) scans were acquired for 20 patients treated within the HeartSpare 1A study, in which both an active breathing control (ABC) device and a voluntary breath-hold (VBH) method were used. Predicted mean heart doses were obtained from treatment plans. CBCT scans were imported into a treatment planning system, heart outlines defined, images registered to the CT planning scan and mean heart dose recorded. Two observers outlined two cases three times each to assess interobserver and intraobserver variation. RESULTS: There were no statistically significant differences between ABC and VBH heart dose data from CT planning scans, or in the CBCT-based estimates of heart dose, and no effect from the order of the breath-hold method. Variation in mean heart dose per fraction over the three imaged fractions was <6 cGy without setup correction, decreasing to 3.3 cGy with setup correction. If scaled to 15 fractions, all differences between predicted and estimated mean heart doses were <0.5 Gy and in 80% of cases, they were <0.25 Gy. CONCLUSION: Variation in mean heart dose was at an acceptable level over the duration of breath-holding radiotherapy and was well predicted by the planning system. Advances in knowledge: Mean heart dose was not adversely affected by fraction-to-fraction variations throughout a course of heart-sparing radiotherapy using two well-established breath-holding methods..
Landeg, S.J., Kirby, A.M., Lee, S.F., Bartlett, F., Titmarsh, K., Donovan, E., Griffin, C.L., Gothard, L., Locke, I. & McNair, H.A., et al.
(2016). A randomized control trial evaluating fluorescent ink versus dark ink tattoos for breast radiotherapy. Br j radiol,
OBJECTIVE: The purpose of this UK study was to evaluate interfraction reproducibility and body image score when using ultraviolet (UV) tattoos (not visible in ambient lighting) for external references during breast/chest wall radiotherapy and compare with conventional dark ink. METHODS: In this non-blinded, single-centre, parallel group, randomized control trial, patients were allocated to receive either conventional dark ink or UV ink tattoos using computer-generated random blocks. Participant assignment was not masked. Systematic (∑) and random (σ) setup errors were determined using electronic portal images. Body image questionnaires were completed at pre-treatment, 1 month and 6 months to determine the impact of tattoo type on body image. The primary end point was to determine that UV tattoo random error (σsetup) was no less accurate than with conventional dark ink tattoos, i.e. <2.8 mm. RESULTS: 46 patients were randomized to receive conventional dark or UV ink tattoos. 45 patients completed treatment (UV: n = 23, dark: n = 22). σsetup for the UV tattoo group was <2.8 mm in the u and v directions (p = 0.001 and p = 0.009, respectively). A larger proportion of patients reported improvement in body image score in the UV tattoo group compared with the dark ink group at 1 month [56% (13/23) vs 14% (3/22), respectively] and 6 months [52% (11/21) vs 38% (8/21), respectively]. CONCLUSION: UV tattoos were associated with interfraction setup reproducibility comparable with conventional dark ink. Patients reported a more favourable change in body image score up to 6 months following treatment. Advances in knowledge: This study is the first to evaluate UV tattoo external references in a randomized control trial..
Harris, E.J., Mukesh, M.B., Donovan, E.M., Kirby, A.M., Haviland, J.S., Jena, R., Yarnold, J., Baker, A., Dean, J., Eagle, S., et al.
(2016). A multicentre study of the evidence for customized margins in photon breast boost radiotherapy. Br j radiol,
OBJECTIVE: To determine if subsets of patients may benefit from smaller or larger margins when using laser setup and bony anatomy verification of breast tumour bed (TB) boost radiotherapy (RT). METHODS: Verification imaging data acquired using cone-beam CT, megavoltage CT or two-dimensional kilovoltage imaging on 218 patients were used (1574 images). TB setup errors for laser-only setup (dlaser) and for bony anatomy verification (dbone) were determined using clips implanted into the TB as a gold standard for the TB position. Cases were grouped by centre-, patient- and treatment-related factors, including breast volume, TB position, seroma visibility and surgical technique. Systematic (Σ) and random (σ) TB setup errors were compared between groups, and TB planning target volume margins (MTB) were calculated. RESULTS: For the study population, Σlaser was between 2.8 and 3.4 mm, and Σbone was between 2.2 and 2.6 mm, respectively. Females with larger breasts (p = 0.03), easily visible seroma (p ≤ 0.02) and open surgical technique (p ≤ 0.04) had larger Σlaser. Σbone was larger for females with larger breasts (p = 0.02) and lateral tumours (p = 0.04). Females with medial tumours (p < 0.01) had smaller Σbone. CONCLUSION: If clips are not used, margins should be 8 and 10 mm for bony anatomy verification and laser setup, respectively. Individualization of TB margins may be considered based on breast volume, TB and seroma visibility. ADVANCES IN KNOWLEDGE: Setup accuracy using lasers and bony anatomy is influenced by patient and treatment factors. Some patients may benefit from clip-based image guidance more than others..
Kirby, A., Hanna, G., Wilcox, M. & MacKenzie, M.
(2015). In Regard to Vaidya et al. Int j radiat oncol biol phys,
Bartlett, F.R., Colgan, R.M., Donovan, E.M., McNair, H.A., Carr, K., Evans, P.M., Griffin, C., Locke, I., Haviland, J.S., Yarnold, J.R., et al.
(2015). The UK HeartSpare Study (Stage IB): randomised comparison of a voluntary breath-hold technique and prone radiotherapy after breast conserving surgery. Radiother oncol,
PURPOSE: To compare mean heart and left anterior descending coronary artery (LAD) doses (NTDmean) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold (VBH) and free-breathing prone techniques. MATERIALS AND METHODS: Following surgery for early breast cancer, patients with estimated breast volumes >750 cm(3) underwent planning-CT scans in supine VBH and free-breathing prone positions. Radiotherapy treatment plans were prepared, and mean heart and LAD doses were calculated. Patients were randomised to receive one technique for fractions 1-7, before switching techniques for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging and alternate-day cone-beam CT (CBCT) imaging were performed. The primary endpoint was the difference in mean LAD NTDmean between techniques. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. RESULTS: 34 patients were recruited, with complete dosimetric data available for 28. Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 (p<0.001) and 2.9 and 7.8 (p<0.001). Clip-based CBCT errors for VBH and prone respectively were ⩽3.0 mm and ⩽6.5 mm (Σ) and ⩽3.5 mm and ⩽5.4 mm (σ). CONCLUSIONS: In larger-breasted women, supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position..
Hanna, G.G. & Kirby, A.M.
(2015). Intraoperative radiotherapy in early stage breast cancer: potential indications and evidence to date. Br j radiol,
Following early results of recent studies of intraoperative radiotherapy (IORT) in the adjuvant treatment of patients with early breast cancer, the clinical utility of IORT is a subject of much recent debate within the breast oncology community. This review describes the intraoperative techniques available, the potential indications and the evidence to date pertaining to local control and toxicity. We also discuss any implications for current practice and future research. .
Colgan, R., James, M., Bartlett, F.R., Kirby, A.M. & Donovan, E.M.
(2015). Voluntary breath-holding for breast cancer radiotherapy is consistent and stable. Br j radiol,
OBJECTIVE: To evaluate breath-hold stability and constancy for a voluntary breath-hold (VBH) technique in a retrospective analysis. METHODS: Movie loop sequences of electronic portal image data from multiple breath holds in a cohort of 19 patients were used to assess within and between breath-hold stability. In vivo dosimetry data based on electronic portal imaging (EPI) were analysed for 31 VBH patients plus a cohort of free-breathing (FB) patients to provide a reference. A phantom experiment simulated the impact on dose of FB, breath hold and unplanned release of breath hold. RESULTS: 165/174 (93%) movie loop data sets had no detectable displacement. For the remaining 12, median displacement = 1.5 mm and maximum displacement = 3 mm (one patient on one fraction). In vivo dosimetry data analysis showed a median dose difference measured to planned of -0.2% (VBH) and -0.1% (FB). Dose distribution evaluation (γ) pass rates were 84% (VBH) and 91% (FB) including the lung region; 93% and 96% with a lung override. Unplanned release of phantom breath-hold position changed median dose by ≤1% and degraded γ pass rates to 79-62%. Failing regions were mostly in the periphery of the treated volume. CONCLUSION: The data confirmed that multiple VBHs using visual monitoring are stable; in vivo dose verification via EPI was within expected and acceptable levels. ADVANCES IN KNOWLEDGE: These data provide further reassurance that VBH is a safe technique for cardiac sparing breast radiotherapy and support its rapid, widespread implementation..
Taylor, C.W. & Kirby, A.M.
(2015). Cardiac Side-effects From Breast Cancer Radiotherapy. Clin oncol (r coll radiol),
Breast cancer radiotherapy reduces the risk of cancer recurrence and death. However, it usually involves some radiation exposure of the heart and analyses of randomised trials have shown that it can increase the risk of heart disease. Estimates of the absolute risks of radiation-related heart disease are needed to help oncologists plan each individual woman's treatment. The risk for an individual woman varies according to her estimated cardiac radiation dose and her background risk of ischaemic heart disease in the absence of radiotherapy. When it is known, this risk can then be compared with the absolute benefit of the radiotherapy. At present, many UK cancer centres are already giving radiotherapy with mean heart doses of less than 3 Gy and for most women the benefits of the radiotherapy will probably far outweigh the risks. Technical approaches to minimising heart dose in breast cancer radiotherapy include optimisation of beam angles, use of multileaf collimator shielding, intensity-modulated radiotherapy, treatment in a prone position, treatment in deep inspiration (including the use of breath-hold and gating techniques), proton therapy and partial breast irradiation. The multileaf collimator is suitable for many women with upper pole left breast cancers, but for women with central or lower pole cancers, breath-holding techniques are now recommended in national UK guidelines. Ongoing work aims to identify ways of irradiating pan-regional lymph nodes that are effective, involve minimal exposure of organs at risk and are feasible to plan, deliver and verify. These will probably include wide tangent-based field-in-field intensity-modulated radiotherapy or arc radiotherapy techniques in combination with deep inspiratory breath-hold, and proton beam irradiation for women who have a high predicted heart dose from intensity-modulated radiotherapy..
Tsang, Y., Ciurlionis, L., Kirby, A.M., Locke, I., Venables, K., Yarnold, J.R., Titley, J., Bliss, J., Coles, C.E. & IMPORT Trial Management Group, , et al.
(2015). Clinical impact of IMPORT HIGH trial (CRUK/06/003) on breast radiotherapy practices in the United Kingdom. Br j radiol,
OBJECTIVE: IMPORT HIGH is a multicentre randomized UK trial testing dose-escalated intensity-modulated radiotherapy (IMRT) after tumour excision in females with early breast cancer and higher than average local recurrence risk. A survey was carried out to investigate the impact of this trial on the adoption of advanced breast radiotherapy (RT) techniques in the UK. METHODS: A questionnaire was sent to all 26 IMPORT HIGH recruiting RT centres to determine whether the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. In order to compare the clinical practice of breast RT between IMPORT HIGH and non-IMPORT HIGH centres, parts of the Royal College of Radiologists (RCR) breast RT audit result were used in this study. RESULTS: 26/26 participating centres completed the questionnaire. After joining the trial, the number of centres routinely using tumour bed clips to guide whole-breast RT rose from 5 (19%) to 21 (81%). 20/26 (77%) centres now contour target volumes and organs at risk (OARs) in some or all patients compared with 14 (54%) before the trial. 14/26 (54%) centres offer inverse-planned IMRT for selected non-trial patients with breast cancer, and 10/14 (71%) have adopted the IMPORT HIGH trial protocol for target volume and OARs dose constraints. Only 2/26 (8%) centres used clip information routinely for breast treatment verification prior to IMPORT HIGH, a minority that has since risen to 7/26 (27%). Data on 1386 patients was included from the RCR audit. This suggested that more cases from IMPORT HIGH centres had surgical clips implanted (83 vs 67%), were treated using CT guided planning with full three-dimensional dose compensation (100 vs 75%), and were treated with photon boost RT (30 vs 8%). CONCLUSION: The study suggests that participation in the IMPORT HIGH trial has played an important part in providing the guidance and support networks needed for the safe integration of advanced RT techniques, where appropriate, as a standard of care for breast cancer patients treated at participating cancer centres. ADVANCES IN KNOWLEDGE: We investigated the impact of the IMPORT HIGH trial on the adoption of advanced breast RT techniques in the UK and the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification..
Bartlett, F.R., Yarnold, J.R. & Kirby, A.M.
(2014). Response to D Woolf and M Keshtgar's reply to: breast radiotherapy and heart disease - where are we now?. Clin oncol (r coll radiol),
Bartlett, F.R., Colgan, R.M., Donovan, E.M., Carr, K., Landeg, S., Clements, N., McNair, H.A., Locke, I., Evans, P.M., Haviland, J.S., et al.
(2014). Voluntary breath-hold technique for reducing heart dose in left breast radiotherapy. J vis exp,
Breath-holding techniques reduce the amount of radiation received by cardiac structures during tangential-field left breast radiotherapy. With these techniques, patients hold their breath while radiotherapy is delivered, pushing the heart down and away from the radiotherapy field. Despite clear dosimetric benefits, these techniques are not yet in widespread use. One reason for this is that commercially available solutions require specialist equipment, necessitating not only significant capital investment, but often also incurring ongoing costs such as a need for daily disposable mouthpieces. The voluntary breath-hold technique described here does not require any additional specialist equipment. All breath-holding techniques require a surrogate to monitor breath-hold consistency and whether breath-hold is maintained. Voluntary breath-hold uses the distance moved by the anterior and lateral reference marks (tattoos) away from the treatment room lasers in breath-hold to monitor consistency at CT-planning and treatment setup. Light fields are then used to monitor breath-hold consistency prior to and during radiotherapy delivery. .
Phillips, I., Locke, I., Kirby, A. & Rahman, F.
(2014). Palliative External Beam Radiotherapy for Painful Bone Metastases. Clinical oncology,
Kirby, A.N., Jena, R., Harris, E.J., Evans, P.M., Crowley, C., Gregory, D.L. & Coles, C.E.
(2013). Tumour bed delineation for partial breast/breast boost radiotherapy: what is the optimal number of implanted markers?. Radiother oncol,
PURPOSE: International consensus has not been reached regarding the optimal number of implanted tumour bed (TB) markers for partial breast/breast boost radiotherapy target volume delineation. Four common methods are: insertion of 6 clips (4 radial, 1 deep and 1 superficial), 5 clips (4 radial and 1 deep), 1 clip at the chest wall, and no clips. We compared TB volumes delineated using 6, 5, 1 and 0 clips in women who have undergone wide-local excision (WLE) of breast cancer (BC) with full-thickness closure of the excision cavity, in order to determine the additional margin required for breast boost or partial breast irradiation (PBI) when fewer than 6 clips are used. METHODS: Ten patients with invasive ductal BC who had undergone WLE followed by implantation of six fiducial markers (titanium clips) each underwent CT imaging for radiotherapy planning purposes. Retrospective processing of the DICOM image datasets was performed to remove markers and associated imaging artefacts, using an in-house software algorithm. Four observers outlined TB volumes on four different datasets for each case: (1) all markers present (CT6M); (2) the superficial marker removed (CT(5M)); (3) all but the chest wall marker removed (CTCW); (4) all markers removed (CT(0M)). For each observer, the additional margin required around each of TB(0M), TBCW, and TB(5M) in order to encompass TB(6M) was calculated. The conformity level index (CLI) and differences in centre-of-mass (COM) between observers were quantified for CT(0M), CTCW, CT(5M), CT(6M). RESULTS: The overall median additional margins required to encompass TB(6M) were 8mm (range 0-28 mm) for TB(0M), 5mm (range 1-13 mm) for TBCW, and 2mm (range 0-7 mm) for TB(5M). CLI were higher for TB volumes delineated using CT(6M) (0.31) CT(5M) (0.32) than for CTCW (0.19) and CT(0M) (0.15). CONCLUSIONS: In women who have undergone WLE of breast cancer with full-thickness closure of the excision cavity and who are proceeding to PBI or breast boost RT, target volume delineation based on 0 or 1 implanted markers is not recommended as large additional margins are required to account for uncertainty over true TB location. Five implanted markers (one deep and four radial) are likely to be adequate assuming the addition of a standard 10-15 mm TB-CTV margin. Low CLI values for all TB volumes reflect the sensitivity of low volumes to small differences in delineation and are unlikely to be clinically significant for TB(5M) and TB(6M) in the context of adequate TB-CTV margins..
Bartlett, F.R., Colgan, R.M., Carr, K., Donovan, E.M., McNair, H.A., Locke, I., Evans, P.M., Haviland, J.S., Yarnold, J.R. & Kirby, A.M., et al.
(2013). The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy. Radiother oncol,
PURPOSE: To determine whether voluntary deep-inspiratory breath-hold (v_DIBH) and deep-inspiratory breath-hold with the active breathing coordinator™ (ABC_DIBH) in patients undergoing left breast radiotherapy are comparable in terms of normal-tissue sparing, positional reproducibility and feasibility of delivery. METHODS: Following surgery for early breast cancer, patients underwent planning-CT scans in v_DIBH and ABC_DIBH. Patients were randomised to receive one technique for fractions 1-7 and the second technique for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging (EPI) was performed and matched to digitally-reconstructed radiographs. Cone-beam CT (CBCT) images were acquired for 6/15 fractions and matched to planning-CT data. Population systematic (Σ) and random errors (σ) were estimated. Heart, left-anterior-descending coronary artery, and lung doses were calculated. Patient comfort, radiographer satisfaction and scanning/treatment times were recorded. Within-patient comparisons between the two techniques used the paired t-test or Wilcoxon signed-rank test. RESULTS: Twenty-three patients were recruited. All completed treatment with both techniques. EPI-derived Σ were ≤ 1.8mm (v_DIBH) and ≤ 2.0mm (ABC_DIBH) and σ ≤ 2.5mm (v_DIBH) and ≤ 2.2mm (ABC_DIBH) (all p non-significant). CBCT-derived Σ were ≤ 3.9 mm (v_DIBH) and ≤ 4.9 mm (ABC_DIBH) and σ ≤ 4.1mm (v_DIBH) and ≤ 3.8mm (ABC_DIBH). There was no significant difference between techniques in terms of normal-tissue doses (all p non-significant). Patients and radiographers preferred v_DIBH (p=0.007, p=0.03, respectively). Scanning/treatment setup times were shorter for v_DIBH (p=0.02, p=0.04, respectively). CONCLUSIONS: v_DIBH and ABC_DIBH are comparable in terms of positional reproducibility and normal tissue sparing. v_DIBH is preferred by patients and radiographers, takes less time to deliver, and is cheaper than ABC_DIBH..
Bartlett, F.R., Yarnold, J.R., Donovan, E.M., Evans, P.M., Locke, I. & Kirby, A.M.
(2013). Multileaf collimation cardiac shielding in breast radiotherapy: Cardiac doses are reduced, but at what cost?. Clin oncol (r coll radiol),
AIMS: To measure cardiac tissue doses in left-sided breast cancer patients receiving supine tangential field radiotherapy with multileaf collimation (MLC) cardiac shielding of the heart and to assess the effect on target volume coverage. MATERIALS AND METHODS: Sixty-seven consecutive patients who underwent adjuvant radiotherapy to the left breast (n = 48) or chest wall (n = 19) in 2009/2010 were analysed. The heart, left anterior descending coronary artery (LAD), whole breast and partial breast clinical target volumes (WBCTV and PBCTV) were outlined retrospectively (the latter only in patients who had undergone breast-conserving surgery [BCS]). The mean heart and LAD NTDmean and maximum LAD doses (LADmax) were calculated for all patients (NTDmean is a biologically weighted mean dose normalised to 2 Gy fractions using a standard linear quadratic model). Coverage of WBCTV and PBCTV by the 95% isodose was assessed (BCS patients only). RESULTS: The mean heart NTDmean (standard deviation) was 0.8 (0.3) Gy, the mean LAD NTDmean 6.7 (4.3) Gy and the mean LADmax 40.3 (10.1) Gy. Coverage of the WBCTV by 95% isodose was <90% in one in three patients and PBCTV coverage <95% (range 78-94%) in one in 10 BCS patients. CONCLUSION: The use of MLC cardiac shielding reduces doses to cardiac tissues at the expense of target tissue coverage. Formal target volume delineation in combination with an assessment of the likelihood of local relapse is recommended in order to aid decisions regarding field and MLC placement..
Bartlett, F.R., Yarnold, J.R. & Kirby, A.M.
(2013). Breast radiotherapy and heart disease - where are we now?. Clin oncol (r coll radiol),
Juneja, P., Harris, E.J., Kirby, A.M. & Evans, P.M.
(2012). Adaptive breast radiation therapy using modeling of tissue mechanics: a breast tissue segmentation study. Int j radiat oncol biol phys,
PURPOSE: To validate and compare the accuracy of breast tissue segmentation methods applied to computed tomography (CT) scans used for radiation therapy planning and to study the effect of tissue distribution on the segmentation accuracy for the purpose of developing models for use in adaptive breast radiation therapy. METHODS AND MATERIALS: Twenty-four patients receiving postlumpectomy radiation therapy for breast cancer underwent CT imaging in prone and supine positions. The whole-breast clinical target volume was outlined. Clinical target volumes were segmented into fibroglandular and fatty tissue using the following algorithms: physical density thresholding; interactive thresholding; fuzzy c-means with 3 classes (FCM3) and 4 classes (FCM4); and k-means. The segmentation algorithms were evaluated in 2 stages: first, an approach based on the assumption that the breast composition should be the same in both prone and supine position; and second, comparison of segmentation with tissue outlines from 3 experts using the Dice similarity coefficient (DSC). Breast datasets were grouped into nonsparse and sparse fibroglandular tissue distributions according to expert assessment and used to assess the accuracy of the segmentation methods and the agreement between experts. RESULTS: Prone and supine breast composition analysis showed differences between the methods. Validation against expert outlines found significant differences (P<.001) between FCM3 and FCM4. Fuzzy c-means with 3 classes generated segmentation results (mean DSC = 0.70) closest to the experts' outlines. There was good agreement (mean DSC = 0.85) among experts for breast tissue outlining. Segmentation accuracy and expert agreement was significantly higher (P<.005) in the nonsparse group than in the sparse group. CONCLUSIONS: The FCM3 gave the most accurate segmentation of breast tissues on CT data and could therefore be used in adaptive radiation therapy-based on tissue modeling. Breast tissue segmentation methods should be used with caution in patients with sparse fibroglandular tissue distribution..
Yates, L., Kirby, A., Crichton, S., Gillett, C., Cane, P., Fentiman, I. & Sawyer, E.
(2012). RISK FACTORS FOR REGIONAL NODAL RELAPSE IN BREAST CANCER PATIENTS WITH ONE TO THREE POSITIVE AXILLARY NODES. International journal of radiation oncology biology physics,
Kirby, A.M., Evans, P.M., Helyer, S.J., Donovan, E.M., Convery, H.M. & Yarnold, J.R.
(2011). A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion. Radiother oncol,
PURPOSE: To test a prone position against the international-standard supine position in women undergoing whole-breast-radiotherapy (WBRT) after wide-local-excision (WLE) of early breast cancer (BC) in terms of feasibility, set-up errors, and respiratory motion. METHODS: Following WLE of BC with insertion of tumour-bed clips, patients underwent 4D-CT for WBRT-planning in supine and prone positions (the latter using an in-house-designed platform). Patients were randomised to undergo WBRT fractions 1-7 in one position, switching to the alternate position for fractions 8-15 (40Gy/15-fractions total). Cone-beam CT-images (CBCT) were acquired prior to fractions 1, 4, 7, 8, 11 and 14. CBCT data were matched to planning-CT data using (i) chest-wall and (ii) clips. Systematic and random errors were calculated. Maximal displacement of chest-wall and clips with respiration was measured on 4D-CT. Clinical- to planning-target-volume (CTV-PTV) margins were calculated. Patient-comfort-scores and treatment-times were evaluated. RESULTS: Twenty-five patients were randomized. 192/192 (100%) planned supine fractions and 173/192 (90%) prone fractions were completed. 3D population systematic errors were 1.3-1.9mm (supine) and 3.1-4.3mm (prone) (p=0.02) and random errors 2.6-3.2mm (supine) and 3.8-5.4mm (prone) (p=0.02). Prone positioning reduced chest-wall and clip motion (0.5±0.2mm (prone) versus 2.7±0.5mm (supine) (p<0.001)) with respiration. Calculated CTV-PTV margins were greater for prone (12-16mm) than for supine treatment (10mm). Patient-comfort-scores and treatment times were comparable (p=0.06). CONCLUSIONS: Set-up errors were greater using our prone technique than for our standard supine technique, resulting in the need for larger CTV-PTV margins in the prone position. Further work is required to optimize the prone treatment-platform and technique before it can become a standard treatment option at our institution..
Barton, S.R., Smith, I.E., Kirby, A.M., Ashley, S., Walsh, G. & Parton, M.
(2011). The role of ipsilateral breast radiotherapy in management of occult primary breast cancer presenting as axillary lymphadenopathy. Eur j cancer,
AIM: To assess the role of ipsilateral breast radiotherapy (IBR) in women with occult primary breast cancer presenting with axillary metastases (OPBC). METHODS: Patients with axillary nodal metastases and histological diagnosis of breast cancer without palpable, mammographic or ultrasonographic evidence of a breast primary were identified from a prospectively maintained single institution database. Imaging, surgery, radiotherapy, recurrence and survival data were collected. Patients whose breast cancer primary was detected on MRI (but occult on clinical examination and other imaging) were excluded from the analyses of IBR and outcome, but were included in other exploratory analyses. RESULTS: Fifty-five patients were included between 1975 and 2009. Median follow up was 68 months. Twenty patients had breast magnetic resonance imaging (MRI) in addition to other imaging. A primary breast cancer was detected in 7 of these 20. 48/55 patients had no detectable breast primary. 35/48 patients (73%) were treated with radiotherapy to the conserved breast, and 13/48 (27%) with observation. Patients who had IBR had better 5 year local recurrence free survival (LRFS) (84% versus 34%, p<0.001), and relapse free survival (RFS) (64% versus 34%, p=0.05), but no difference in overall survival (OS) (84% versus 85%, p=0.2). There was no difference in 5 year LRFS (80% versus 90%: p=0.3) between patients who received radiation of 50 Gy in 25 fractions versus ≥60 Gy. CONCLUSION: Patients with OPBC should be managed with IBR and breast conservation, or mastectomy. Our data suggest it is not necessary to irradiate the breast to more than 50 Gy in 25 fractions..
Kirby, A.M., Evans, P.M., Nerurkar, A.Y., Desai, S.S., Krupa, J., Devalia, H., della Rovere, G.Q., Harris, E.J., Kyriakidou, J. & Yarnold, J.R., et al.
(2010). How does knowledge of three-dimensional excision margins following breast conservation surgery impact upon clinical target volume definition for partial-breast radiotherapy?. Radiother oncol,
BACKGROUND AND PURPOSE: To compare partial-breast clinical target volumes generated using a standard 15 mm margin (CTV(standard)) with those generated using three-dimensional surgical excision margins (CTV(tailored 30)) in women who have undergone wide local excision (WLE) for breast cancer. MATERIAL AND METHODS: Thirty-five women underwent WLE with placement of clips in the anterior, deep and coronal excision cavity walls. Distances from tumour to each of six margins were measured microscopically. Tumour bed was defined on kV-CT images using clips. CTV(standard) was generated by adding a uniform three-dimensional 15 mm margin, and CTV(tailored 30) was generated by adding 30 mm minus the excision margin in three-dimensions. Concordance between CTV(standard) and CTV(tailored 30) was quantified using conformity (CoI), geographical-miss (GMI) and normal-tissue (NTI) indices. An external-beam partial-breast irradiation (PBI) plan was generated to cover 95% of CTV(standard) with the 95% isodose. Percentage-volume coverage of CTV(tailored 30) by the 95% isodose was measured. RESULTS: Median (range) coronal, superficial and deep excision margins were 15.0 (0.5-76.0)mm, 4.0 (0.0-60.0)mm and 4.0 (0.5-35.0)mm, respectively. Median CoI, GMI and NTI were 0.62, 0.16 and 0.20, respectively. Median coverage of CTV(tailored 30) by the PBI-plan was 97.7% (range 84.9-100.0%). CTV(tailored 30) was inadequately covered by the 95% isodose in 4/29 cases. In three cases, the excision margin in the direction of inadequate coverage was
Kirby, A.M., Coles, C.E. & Yarnold, J.R.
(2010). Target volume definition for external beam partial breast radiotherapy: clinical, pathological and technical studies informing current approaches. Radiother oncol,
Partial breast irradiation (PBI) is currently under investigation in several phase III trials and, following a recent consensus statement, its use off-study may increase despite ongoing uncertainty regarding optimal target volume definition. We review the clinical, pathological and technical evidence for target volume definition in external beam partial breast irradiation (EB-PBI). The optimal method of tumour bed (TB) delineation requires X-ray CT imaging of implanted excision cavity wall markers. The definition of clinical target volume (CTV) as TB plus concentric 15 mm margins is based on the anatomical distribution of multifocal and multicentric disease around the primary tumour in mastectomy specimens, and the clinical locations of local tumour relapse (LR) after breast conservation surgery. If the majority of LR originate from foci of residual invasive and/or intraduct disease in the vicinity of the TB after complete microscopic resection, CTV margin logically takes account of the position of primary tumour within the surgical resection specimen. The uncertain significance of independent primary tumours as sources of preventable LR, and of wound healing responses in stimulating LR, increases the difficulties in defining optimal CTV. These uncertainties may resolve after long-term follow-up of current PBI trials. By contrast, a commonly used 10mm clinical to planning target volume (PTV) margin has a stronger evidence base, although departmental set-up errors need to be confirmed locally. A CTV-PTV margin >10mm may be required in women with larger breasts and/or large seromas, whilst the role of image-guided radiotherapy with or without TB markers in reducing CTV-PTV margins needs to be explored..
Kirby, A.M., Evans, P.M., Donovan, E.M., Convery, H.M., Haviland, J.S. & Yarnold, J.R.
(2010). Prone versus supine positioning for whole and partial-breast radiotherapy: a comparison of non-target tissue dosimetry. Radiother oncol,
PURPOSE: To compare non-target tissue (including left-anterior-descending coronary-artery (LAD)) dosimetry of prone versus supine whole (WBI) and partial-breast irradiation (PBI). METHODS AND MATERIALS: Sixty-five post-lumpectomy breast cancer patients underwent CT-imaging supine and prone. On each dataset, the whole-breast clinical-target-volume (WB-CTV), partial-breast CTV (tumour-bed + 15 mm), ipsilateral-lung and chest-wall were outlined. Heart and LAD were outlined in left-sided cases (n=30). Tangential-field WBI and PBI plans were generated for each position. Mean LAD, heart, and ipsilateral-lung doses (x(mean)), maximum LAD (LAD(max)) doses, and the volume of chest-wall receiving 50 Gy (V(50Gy)) were compared. RESULTS: Two-hundred and sixty plans were generated. Prone positioning reduced heart and LAD doses in 19/30 WBI cases (median reduction in LAD(mean)=6.2 Gy) and 7/30 PBI cases (median reduction in LAD(max)=29.3 Gy) (no difference in 4/30 cases). However, prone positioning increased cardiac doses in 8/30 WBI (median increase in LAD(mean)=9.5 Gy) and 19/30 PBI cases (median increase in LAD(max)=22.9 Gy) (no difference in 3/30 cases). WB-CTV>1000cm(3) was associated with improved cardiac dosimetry in the prone position for WBI (p=0.04) and PBI (p=0.04). Prone positioning reduced ipsilateral-lung(mean) in 65/65 WBI and 61/65 PBI cases, and chest-wall V(50Gy) in all WBI cases. PBI reduced normal-tissue doses compared to WBI in all cases, regardless of the treatment position. CONCLUSIONS: In the context of tangential-field WBI and PBI, prone positioning is likely to benefit left-breast-affected women of larger breast volume, but to be detrimental in left-breast-affected women of smaller breast volume. Right-breast-affected women are likely to benefit from prone positioning regardless of breast volume..
Kirby, A.M., deSouza, N.M., Evans, P.M. & Yarnold, J.R.
(2009). MRI Delineation of Tumour Bed for Partial Breast Irradiation: Fusion/Comparison with CT/Titanium Clip-based Method. Clin oncol-uk,
Kirby, A.M., Evans, P.M., Haviland, J. & Yarnold, J.R.
(2009). Left Anterior Descending Coronary Artery (LAD) Doses from Breast Radiotherapy: is Prone Treatment Beneficial?. Clin oncol-uk,
Kirby, A.M., Yarnold, J.R., Evans, P.M., Morgan, V.A., Schmidt, M.A., Scurr, E.D. & desouza, N.M.
(2009). Tumor bed delineation for partial breast and breast boost radiotherapy planned in the prone position: what does MRI add to X-ray CT localization of titanium clips placed in the excision cavity wall?. Int j radiat oncol biol phys,
PURPOSE: To compare tumor bed (TB) volumes delineated using magnetic resonance imaging plus computed tomography and clips (MRCT) with those delineated using CT and clips (CT/clips) alone in postlumpectomy breast cancer patients positioned prone and to determine the value of MRCT for planning partial breast irradiation (PBI). METHODS AND MATERIALS: Thirty women with breast cancer each had 6 to 12 titanium clips secured in the excision cavity walls at lumpectomy. Patients underwent CT imaging in the prone position, followed by MRI (T(1)-weighted [standard and fat-suppressed] and T(2)-weighted sequences) in the prone position. TB volumes were delineated separately on CT and on fused MRCT datasets. Clinical target volumes (CTV) (where CTV = TB + 15 mm) and planning target volumes (PTV) (where PTV = CTV + 10 mm) were generated. Conformity indices between CT- and MRCT-defined target volumes were calculated (ratio of the volume of agreement to total delineated volume). Discordance was expressed as a geographical miss index (GMI) (where the GMI = the fraction of total delineated volume not defined by CT) and a normal tissue index (the fraction of total delineated volume designated as normal tissue on MRCT). PBI dose distributions were generated to cover CT-defined CTV (CTV(CT)) with >or=95% of the reference dose. The percentage of MRCT-defined CTV (CTV(MRCT)) receiving >or=95% of the reference dose was measured. RESULTS: Mean conformity indices were 0.54 (TB), 0.84 (CTV), and 0.89 (PTV). For TB volumes, the GMI was 0.37, and the NTI was 0.09. Median percentage volume coverage of CTV(CT) was 97.1% (range, 95.3%-100.0%) and of CTV(MRCT) was 96.5% (range, 89.0%-100.0%). CONCLUSIONS: Addition of MR to CT/clip data generated TB volumes that were discordant with those based on CT/clips alone. However, clinically satisfactory coverage of CTV(MRCT) by CTV(CT)-based tangential PBI fields provides support for CT/clip-based TB delineation remaining the method of choice for PBI/breast boost radiotherapy planned using tangential fields..
Kirby, A.M. & Mikhaeel, N.G.
(2007). The role of FDG PET in the management of lymphoma: what is the evidence base?. Nucl med commun,
[18F]Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is playing an increasing role in the management of both Hodgkin and non-Hodgkin lymphoma, offering potential advantages in the accuracy of disease assessment at a number of points in the management pathway. This review evaluates the current level of confidence in the use of PET technology in (1) initial staging, (2) the assessment of early response to chemotherapy, (3) the assessment of residual masses at completion of initial treatment, (4) follow-up, and (5) radiotherapy planning..
Kirby, A.M. & George Mikhaeel, N.
(2007). The role of FDG PET in the management of lymphoma: practical guidelines. Nucl med commun,
Practical guidelines for the use of FDG PET in the management of lymphoma are given, based on the evidence presented in the previous article. A statement and recommendations are given where appropriate. The recommendations are summarized at the end of the paper..
Kirby, A.M., A'Hern, R.P., D'Ambrosio, C., Tanay, M., Syrigos, K.N., Rogers, S.J., Box, C., Eccles, S.A., Nutting, C.M. & Harrington, K.J., et al.
(2006). Gefitinib (ZD1839, Iressa(TM)) as palliative treatment in recurrent or metastatic head and neck cancer. Brit j cancer,
To assess the level of activity and toxicity of gefitinib ( ZD1839, Iressa((TM))) in a population of patients with locally recurrent and/ or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single- agent gefitinib at a dose of 500 mg day (-1). Clinical, symptomatic and radiological response, time to progression ( TTP), survival and toxicity were recorded. A total of 47 patients were enrolled ( 35 male and 12 female) with a median age of 62 years ( range 18 - 93 years). The observed clinical response rate was 8% with a disease control rate ( complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed ( 76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type ( all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one- third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study..
Edmunds, D., Gothard, L., Khabra, K., Kirby, A., Madhale, P., McNair, H., Roberts, D., Symonds-Tayler, R. & Donovan, E.
Low-cost Kinect Version 2 imaging system for breath hold monitoring and gating: Proof of concept study for breast cancer VMAT radiotherapy. Journal of applied clinical medical physics,
Coles, C., Griffin, C., Kirby, A., Titley, J., Agrawal, R., Alhasso, A., Bhattacharya, I., Brunt, M., Ciurlionis, L., Chan, C., et al.
Partial breast radiotherapy after breast conservation surgery for early breast cancer: 5-year outcomes from the IMPORT LOW (CRUK/06/003) phase III randomised controlled trial. The lancet,
Harris, E.J., Mukesh, M., Jena, R., Baker, A., Bartelink, H., Brooks, C., Dean, J., Donovan, E.M., Collette, S., Eagle, S., et al.
A multicentre observational study evaluating image-guided radiotherapy for more accurate partial-breast intensity-modulated radiotherapy: comparison with standard imaging technique. Efficacy and mechanism evaluation,
Whole-breast radiotherapy (WBRT) is the standard treatment for breast cancer following breast-conserving surgery. Evidence shows that tumour recurrences occur near the original cancer: the tumour bed. New treatment developments include increasing dose to the tumour bed during WBRT (synchronous integrated boost) and irradiating only the region around the tumour bed, for patients at high and low risk of tumour recurrence, respectively. Currently, standard imaging uses bony anatomy to ensure accurate delivery of WBRT. It is debatable whether or not more targeted treatments such as synchronous integrated boost and partial-breast radiotherapy require image-guided radiotherapy (IGRT) focusing on implanted tumour bed clips (clip-based IGRT).Objectives
Primary – to compare accuracy of patient set-up using standard imaging compared with clip-based IGRT. Secondary – comparison of imaging techniques using (1) tumour bed radiotherapy safety margins, (2) volume of breast tissue irradiated around tumour bed, (3) estimated breast toxicity following development of a normal tissue control probability model and (4) time taken.Design
Multicentre observational study embedded within a national randomised trial: IMPORT-HIGH (Intensity Modulated and Partial Organ Radiotherapy – HIGHer-risk patient group) testing synchronous integrated boost and using clip-based IGRT.Setting
Five radiotherapy departments, participating in IMPORT-HIGH.Participants
Two-hundred and eighteen patients receiving breast radiotherapy within IMPORT-HIGH.Interventions
There was no direct intervention in patients’ treatment. Experimental and control intervention were clip-based IGRT and standard imaging, respectively. IMPORT-HIGH patients received clip-based IGRT as routine; standard imaging data were obtained from clip-based IGRT images.Main outcome measures
Difference in (1) set-up errors, (2) safety margins, (3) volume of breast tissue irradiated, (4) breast toxicity and (5) time, between clip-based IGRT and standard imaging.Results
The primary outcome of overall mean difference in clip-based IGRT and standard imaging using daily set-up errors was 2–2.6 mm (p < 0.001). Heterogeneity testing between centres found a statistically significant difference in set-up errors at one centre. For four centres (179 patients), clip-based IGRT gave a mean decrease in the systematic set-up error of between 1 mm and 2 mm compared with standard imaging. Secondary outcomes were as follows: clip-based IGRT and standard imaging safety margins were less than 5 mm and 8 mm, respectively. Using clip-based IGRT, the median volume of tissue receiving 95% of prescribed boost dose decreased by 29 cm3(range 11–193 cm3) compared with standard imaging. Difference in median time required to perform clip-based IGRT compared with standard imaging was X-ray imaging technique dependent (range 8–76 seconds). It was not possible to estimate differences in breast toxicity, the normal tissue control probability model indicated that for breast fibrosis maximum radiotherapy dose is more important than volume of tissue irradiated.Conclusions and implications for clinical practice
Margins of less than 8 mm cannot be used safely without clip-based IGRT for patients receiving concomitant tumour bed boost, as there is a risk of geographical miss of the tumour bed being treated. In principle, smaller but accurately placed margins may influence local control and toxicity rates, but this needs to be evaluated from mature clinical trial data in the future.Funding
The National Institute for Health Research Efficacy and Mechanism Evaluation programme..