Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.

BACKGROUND: A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. METHODS: IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. FINDINGS: Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). INTERPRETATION: In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. FUNDING: Cancer Research UK.

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.

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.

Improving the efficiency of breast radiotherapy treatment planning using a semi-automated approach.

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.

The feasibility of using Microsoft Kinect v2 sensors during radiotherapy delivery.

Consumer-grade distance sensors, such as the Microsoft Kinect devices (v1 and v2), have been investigated for use as marker-free motion monitoring systems for radiotherapy. The radiotherapy delivery environment is challenging for such sen-sors because of the proximity to electromagnetic interference (EMI) from the pulse forming network which fires the magnetron and electron gun of a linear accelerator (linac) during radiation delivery, as well as the requirement to operate them from the control area. This work investigated whether using Kinect v2 sensors as motion monitors was feasible during radiation delivery. Three sensors were used each with a 12 m USB 3.0 active cable which replaced the supplied 3 m USB 3.0 cable. Distance output data from the Kinect v2 sensors was recorded under four condi-tions of linac operation: (i) powered up only, (ii) pulse forming network operating with no radiation, (iii) pulse repetition frequency varied between 6 Hz and 400 Hz, (iv) dose rate varied between 50 and 1450 monitor units (MU) per minute. A solid water block was used as an object and imaged when static, moved in a set of steps from 0.6 m to 2.0 m from the sensor and moving dynamically in two sinusoidal-like trajectories. Few additional image artifacts were observed and there was no impact on the tracking of the motion patterns (root mean squared accuracy of 1.4 and 1.1mm, respectively). The sensors' distance accuracy varied by 2.0 to 3.8 mm (1.2 to 1.4 mm post distance calibration) across the range measured; the precision was 1 mm. There was minimal effect from the EMI on the distance calibration data: 0 mm or 1 mm reported distance change (2 mm maximum change at one position). Kinect v2 sensors operated with 12 m USB 3.0 active cables appear robust to the radiotherapy treatment environment.

Reproducibility in Radiomics: A Comparison of Feature Extraction Methods and Two Independent Datasets.

Radiomics involves the extraction of information from medical images that are not visible to the human eye. There is evidence that these features can be used for treatment stratification and outcome prediction. However, there is much discussion about the reproducibility of results between different studies. This paper studies the reproducibility of CT texture features used in radiomics, comparing two feature extraction implementations, namely the MATLAB toolkit and Pyradiomics, when applied to independent datasets of CT scans of patients: (i) the open access RIDER dataset containing a set of repeat CT scans taken 15 min apart for 31 patients (RIDER Scan 1 and Scan 2, respectively) treated for lung cancer; and (ii) the open access HN1 dataset containing 137 patients treated for head and neck cancer. Gross tumor volume (GTV), manually outlined by an experienced observer available on both datasets, was used. The 43 common radiomics features available in MATLAB and Pyradiomics were calculated using two intensity-level quantization methods with and without an intensity threshold. Cases were ranked for each feature for all combinations of quantization parameters, and the Spearman's rank coefficient, rs, calculated. Reproducibility was defined when a highly correlated feature in the RIDER dataset also correlated highly in the HN1 dataset, and vice versa. A total of 29 out of the 43 reported stable features were found to be highly reproducible between MATLAB and Pyradiomics implementations, having a consistently high correlation in rank ordering for RIDER Scan 1 and RIDER Scan 2 (rs > 0.8). 18/43 reported features were common in the RIDER and HN1 datasets, suggesting they may be agnostic to disease site. Useful radiomics features should be selected based on reproducibility. This study identified a set of features that meet this requirement and validated the methodology for evaluating reproducibility between datasets.

Influence of body habitus on dose parameters of nodal levels III to IV irradiation for breast cancer: comparison of 3 techniques.

This study aimed to investigate the effect of body habitus on supraclavicular (SC) dose-volume histogram (DVH) parameters among breast cancer patients according to 3 different techniques. Three SC irradiation plans were generated for 24 postoperative breast cancer patients: (1) direct antero-posterior field only (1fieldP), with dose prescribed to a 3-cm depth; (2) 3-cm depth plan (3cmP) using an antero-posterior field plus a posterior boost with the dose prescription defined to 3 cm; and (3) optimized plan (OptP) similar to 3cmP, with dose prescribed depending on the anatomy. The OptP plans had the least variation in DVH parameters with body habitus; 3cmP plans were the most varied. Conformity index among normal weight patients were 0.73, 0.78, and 0.87 (p = 0.02) and 0.61, 0.6, and 0.82 among overweight-obese patients for 1fieldP, 3cmP, and OptP, respectively (p < 0.001). V95% of the planning target volume among normal weight patients were 72.63%, 78.03%, and 87.18% for 1fieldP, 3cmP, and OptP, respectively (p = 0.02). The corresponding values among overweight-obese patients were 60.5%, 59.62%, and 81.62%, respectively (p = 0.001). Fixed depth dose prescriptions caused greater SC under dose than plans optimized according to patient's anatomy.

Mean heart dose variation over a course of breath-holding breast cancer radiotherapy.

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.

A multicentre study of the evidence for customized margins in photon breast boost radiotherapy.

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.

Initial patient imaging with an optimised radiotherapy beam for portal imaging.

BACKGROUND AND PURPOSE: To investigate the feasibility and the advantages of a portal-imaging mode on a medical accelerator, consisting of a thin low-Z bremsstrahlung target and a thin Gd2O2S/film detector, for patient imaging. PATIENTS AND METHODS: The international code of practice for high-energy photon dosimetry was used to calibrate dosimetry instruments for the imaging beam produced by 4.75 MeV electrons hitting a 6mm thick aluminium target. Images of the head and neck of a humanoid phantom were taken with a mammography film system and the dose in the phantom was measured with TLDs calibrated for this beam. The first head and neck patient images are compared with conventional images (taken with the treatment beam on a film radiotherapy verification detector). Visibility of structures for six patients was evaluated. RESULTS: Images of the head and neck of a humanoid phantom, taken with both imaging systems showed that the contrast increased dramatically for the new system while the dose required to form an image was less than 10(-2)Gy. The patient images taken with the new and the conventional systems showed that air-tissue interfaces were better defined in the new system image. Anatomical structures, visible on both films, are clearer with the new system. Additionally, bony structures, such as vertebrae, were clearly visible only with the new system. The system under evaluation was significantly better for all features in lateral images and most features in anterior images. CONCLUSIONS: This pilot study of the new portal imaging system showed the image quality is significantly improved.

Voluntary breath-holding for breast cancer radiotherapy is consistent and stable.

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.

The UK HeartSpare Study (Stage IB): randomised comparison of a voluntary breath-hold technique and prone radiotherapy after breast conserving surgery.

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.

Voluntary breath-hold technique for reducing heart dose in left breast radiotherapy.

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.

The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.

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.

How does imaging frequency and soft tissue motion affect the PTV margin size in partial breast and boost radiotherapy?

PURPOSE: This study investigates (i) the effect of verification protocols on treatment accuracy and PTV margins for partial breast and boost breast radiotherapy with short fractionation schema (15 fractions), (ii) the effect of deformation of the excision cavity (EC) on PTV margin size, (iii) the imaging dose required to achieve specific PTV margins. METHODS AND MATERIALS: Verification images using implanted EC markers were studied in 36 patients. Target motion was estimated for a 15 fraction partial breast regimen using imaging protocols based on on-line and off-line motion correction strategies (No Action Level (NAL) and the extended NAL (eNAL) protocols). Target motion was used to estimate a PTV margin for each protocol. To evaluate treatment errors due to deformation of the excision cavity, individual marker positions were obtained from 11 patients. The mean clip displacement and daily variation in clip position during radiotherapy were determined and the contribution of these errors to PTV margin calculated. Published imaging dose data were used to estimate total dose for each protocol. Finally the number of images required to obtain a specific PTV margin was evaluated and hence, the relationship between PTV margins and imaging dose was investigated. RESULTS: The PTV margin required to account for excision cavity motion, varied between 10.2 and 2.4mm depending on the correction strategy used. Average clip movement was 0.8mm and average variation in clip position during treatment was 0.4mm. The contribution to PTV margin from deformation was estimated to be small, less than 0.2mm for both off-line and on-line correction protocols. CONCLUSION: A boost or partial breast PTV margin of ∼10 mm, is possible with zero imaging dose and workload, however, patients receiving boost radiotherapy may benefit from a margin reduction of ∼4 mm with imaging doses from 0.4cGy to 25cGy using an eNAL protocol. PTV margin contributions from deformation errors are likely to be small in comparison to other sources of error, i.e., set up or delineation.

A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.

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.

Planning with intensity-modulated radiotherapy and tomotherapy to modulate dose across breast to reflect recurrence risk (IMPORT High trial).

PURPOSE: To establish planning solutions for a concomitant three-level radiation dose distribution to the breast using linear accelerator- or tomotherapy-based intensity-modulated radiotherapy (IMRT), for the U.K. Intensity Modulated and Partial Organ (IMPORT) High trial. METHODS AND MATERIALS: Computed tomography data sets for 9 patients undergoing breast conservation surgery with implanted tumor bed gold markers were used to prepare three-level dose distributions encompassing the whole breast (36 Gy), partial breast (40 Gy), and tumor bed boost (48 or 53 Gy) treated concomitantly in 15 fractions within 3 weeks. Forward and inverse planned IMRT and tomotherapy were investigated as solutions. A standard electron field was compared with a photon field arrangement encompassing the tumor bed boost volume. The out-of-field doses were measured for all methods. RESULTS: Dose-volume constraints of volume >90% receiving 32.4 Gy and volume >95% receiving 50.4 Gy for the whole breast and tumor bed were achieved. The constraint of volume >90% receiving 36 Gy for the partial breast was fulfilled in the inverse IMRT and tomotherapy plans and in 7 of 9 cases of a forward planned IMRT distribution. An electron boost to the tumor bed was inadequate in 8 of 9 cases. The IMRT methods delivered a greater whole body dose than the standard breast tangents. A contralateral lung volume >2.5 Gy was increased in the inverse IMRT and tomotherapy plans, although it did not exceed the constraint. CONCLUSION: We have demonstrated a set of widely applicable solutions that fulfilled the stringent clinical trial requirements for the delivery of a concomitant three-level dose distribution to the breast.

Evaluation of implanted gold seeds for breast radiotherapy planning and on treatment verification: a feasibility study on behalf of the IMPORT trialists.

BACKGROUND AND PURPOSE: We describe a feasibility study testing the use of gold seeds for the identification of post-operative tumour bed after breast conservation surgery (BCS). MATERIALS AND METHODS: Fifty-three patients undergoing BCS for invasive cancer were recruited. Successful use was defined as all six seeds correctly positioned around the tumour bed during BCS, unique identification of all implanted seeds on CT planning scan and ≥ 3 seeds uniquely identified at verification to give couch displacement co-ordinates in 10/15 fractions. Planning target volume (PTV) margin size for four correction strategies were calculated from these data. Variability in tumour bed contouring was investigated with five radiation oncologists outlining five CT datasets. RESULTS: Success in inserting gold seeds, identifying them at CT planning and using them for on-treatment verification was recorded in 45/51 (88%), 37/38 (97%) and 42/43 (98%) of patients, respectively. The clinicians unfamiliar with CT breast planning consistently contoured larger volumes than those already trained. Margin size ranged from 10.1 to 1.4mm depending on correction strategy. CONCLUSION: It is feasible to implant tumour bed gold seeds during BCS. Whilst taking longer to insert than surgical clips, they have the advantage of visibility for outlining and verification regardless of the ionising radiation beam quality. Appropriate correction strategies enable margins of the order of 5mm as required by the IMPORT trials however, tackling clinician variability in contouring is important.

Prone versus supine positioning for whole and partial-breast radiotherapy: a comparison of non-target tissue dosimetry.

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.

Characterization of target volume changes during breast radiotherapy using implanted fiducial markers and portal imaging.

PURPOSE: To determine target volume changes by using volume and shape analysis for patients receiving radiotherapy after breast conservation surgery and to compare different methods of automatically identifying changes in target volume, position, size, and shape during radiotherapy for use in adaptive radiotherapy. METHODS AND MATERIALS: Eleven patients undergoing whole breast radiotherapy had fiducial markers sutured into the excision cavity at the time of surgery. Patients underwent imaging using computed tomography (for planning and at the end of treatment) and during treatment by using portal imaging. A marker volume (MV) was defined by using the measured marker positions. Changes in both individual marker positions and MVs were identified manually and using six automated similarity indices. Comparison of the two types of analysis (manual and automated) was undertaken to establish whether similarity indices can be used to automatically detect changes in target volumes. RESULTS: Manual analysis showed that 3 patients had significant MV reduction. This analysis also showed significant changes between planning computed tomography and the start of treatment for 9 patients, including single and multiple marker movement, deformation (shape change), and rotation. Four of the six similarity indices were shown to be sensitive to the observed changes. CONCLUSIONS: Significant changes in size, shape, and position occur to the fiducial marker-defined volume. Four similarity indices can be used to identify these changes, and a protocol for their use in adaptive radiotherapy is suggested.