Anna M. Kirby

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.

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.

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.

Target volume definition for external beam partial breast radiotherapy: Clinical, pathological and technical studies informing current approaches

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.

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

Summary 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.

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?

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.

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.

Tumour bed delineation for partial breast/breast boost radiotherapy: What is the optimal number of implanted markers?

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.

The role of ipsilateral breast radiotherapy in management of occult primary breast cancer presenting as axillary lymphadenopathy

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.

Risk Factors for Regional Nodal Relapse in Breast Cancer Patients With One to Three Positive Axillary Nodes

PURPOSE In many centers, supraclavicular fossa radiotherapy (SCF RT) is not routinely offered to breast cancer patients with one to three positive lymph nodes. We aimed to identify a subgroup of these patients who are at high risk of supra or infraclavicular fossa relapse (SCFR) such that they can be offered SCFRT at the time of diagnosis to improve long term locoregional control. METHODS AND MATERIALS We performed a retrospective analysis of the pathological features of 1,065 cases of invasive breast cancer with one to three positive axillary lymph nodes. Patients underwent radical breast conserving surgery or mastectomy. A total of 45% of patients received adjuvant chest wall/breast RT. No patients received adjuvant SCFRT. The primary outcome was SCFR. Secondary outcomes were chest wall/breast recurrence, distant metastasis, all death, and breast-cancer specific death. Kaplan-Meier estimates were used to calculate actuarial event rates and survival functions compared using log-rank tests. Multivariate analyses (MVA) of factors associated with outcome were conducted using Cox proportional hazards models. RESULTS Median follow-up was 9.7 years. SCFR rate was 9.2%. Median time from primary diagnosis to SCFR was 3.4 years (range, 0.7-14.4 years). SCFR was associated with significantly lower 10-year survival (18% vs. 65%; p < 0.001). Higher grade and number of positive lymph nodes were the most significant predictors of SCFR on MVA (p < 0.001). 10 year SCFR rates were less than 1% in all patients with Grade 1 cancers compared with 30% in those having Grade 3 cancers with three positive lymph nodes. Additional factors associated with SCFR on univariate analysis but not on MVA included larger nodal deposits (p = 0.002) and proportion of positive nodes (p = 0.003). CONCLUSIONS Breast cancer patients with one to three positive lymph nodes have a heterogenous risk of SCFR. Patients with two to three positive axillary nodes and/or high-grade disease may warrant consideration of SCFRT.