Change In Photographic Breast Appearance Research Articles

Prolongation of overall treatment time as a cause of treatment failure in early breast cancer: An analysis of the UK START (Standardisation of Breast Radiotherapy) trials of radiotherapy fractionation

BackgroundTests of tumour treatment time effect in patients prescribed post-operative radiotherapy for early breast cancer have focussed on time to start of radiotherapy rather than overall treatment time. The START randomised trials of radiotherapy fractionation provide an opportunity to directly estimate the effect of treatment acceleration. MethodsBetween 1986 and 2002, a total of 5861 women with early breast cancer were recruited into the UK START pilot (START-P), START-A and START-B randomised trials. START-P and START-A tested 13 fractions of 3.0–3.3Gy against 25 fractions of 2.0Gy with a fixed treatment duration of 5weeks for all schedules; START-B tested 15 fractions of 2.67Gy in 3weeks against 25 fractions of 2.0Gy over 5weeks. Estimates of the effect of length of treatment for local–regional relapse and for a measure of late normal tissue effects (change in photographic breast appearance, for patients following breast conserving surgery) were obtained from Cox proportional hazards regression analyses stratified according to trial. ResultsAt a median follow-up of 10years, 444/5831 (7.6%) patients with data available had a local–regional relapse, and 1135/3185 (35.6%) had mild or marked change in photographic breast appearance by 5years. Adjusting for prognostic factors, the estimate of the overall treatment time effect for local–regional relapse was 0.60Gy/day (95%CI 0.10 to 1.18Gy/day, p=0.02), and 0.14Gy/day (95%CI −0.09 to 0.34Gy/day, p=0.29) for change in photographic breast appearance. ConclusionsCombined analysis of the START trials generates the hypothesis that overall treatment time is a significant determinant of local cancer control after adjuvant whole breast radiotherapy, with approximately 0.6Gy per day ‘wasted’ in compensating for tumour cell proliferation.

Does breast composition influence late adverse effects in breast radiotherapy?

BackgroundLarge breast size is associated with increased risk of late adverse effects after surgery and radiotherapy for early breast cancer. It is hypothesised that effects of radiotherapy on adipose tissue are responsible for some of the effects seen. In this study, the association of breast composition with late effects was investigated along with other breast features such as fibroglandular tissue distribution, seroma and scar. MethodsThe patient dataset comprised of 18 cases with changes in breast appearance at 2 years follow-up post-radiotherapy and 36 controls with no changes, from patients entered into the FAST-Pilot and UK FAST trials at The Royal Marsden. Breast composition, fibroglandular tissue distribution, seroma and scar were assessed on planning CT scan images and compared using univariate analysis. The association of all features with late-adverse effect was tested using logistic regression (adjusting for confounding factors) and matched analysis was performed using conditional logistic regression. ResultsIn univariate analyses, no statistically significant differences were found between cases and controls in terms of breast features studied. A statistically significant association (p < 0.05) between amount of seroma and change in photographic breast appearance was found in unmatched and matched logistic regression analyses with odds ratio (95% CI) of 3.44 (1.28–9.21) and 2.57 (1.05–6.25), respectively. ConclusionsA significant association was found between seroma and late-adverse effects after radiotherapy although no significant associations were noted with breast composition in this study. Therefore, the cause for large breast size as a risk factor for late effects after surgery and optimally planned radiotherapy remains unresolved.

Changes in mast cell number and stem cell factor expression in human skin after radiotherapy for breast cancer

Background and purposeMast cells are involved in the pathogenesis of radiation fibrosis and may be a therapeutic target. The mechanism of increased mast cell number in relation to acute and late tissue responses in human skin was investigated. Materials and methodsPunch biopsies of skin 1 and 15–18months after breast radiotherapy and a contralateral control biopsy were collected. Mast cells were quantified by immunohistochemistry using the markers c-Kit and tryptase. Stem cell factor (SCF) and collagen-1 expression was analysed by qRT-PCR. Clinical photographic scores were performed at post-surgical baseline and 18months and 5years post-radiotherapy. Primary human dermal microvascular endothelial cell (HDMEC) cultures were exposed to 2Gy ionising radiation and p53 and SCF expression was analysed by Western blotting and ELISA. ResultsDermal mast cell numbers were increased at 1 (p=0.047) and 18months (p=0.040) using c-Kit, and at 18months (p=0.024) using tryptase immunostaining. Collagen-1 mRNA in skin was increased at 1month (p=0.047) and 18months (p=0.032) and SCF mRNA increased at 1month (p=0.003). None of 16 cases scored had a change in photographic appearance at 5years, compared to baseline. SCF expression was not increased in HDMECs irradiated in vitro. ConclusionsIncreased mast cell number was associated with up-regulated collagen-1 expression in human skin at early and late time points. This increase could be secondary to elevated SCF expression at 1month after radiotherapy. Although mast cells accumulate around blood vessels, no endothelial cell secretion of SCF was seen after in vitro irradiation. Modification of mast cell number and collagen-1 expression may be observed in skin at 1 and 18months after radiotherapy in breast cancer patients with no change in photographic breast appearance at 5years.

Abstract S4-1: The UK START (Standardisation of Breast Radiotherapy) Trials: 10-year follow-up results

Abstract Background International standard adjuvant radiotherapy regimens following primary surgery for early breast cancer have historically delivered a high total dose (50Gy) in 25 small daily doses (fractions) over 5 weeks, however randomised trials, including START, indicate that a lower total dose delivered in fewer, larger fractions (Fr) is likely to be at least as safe and effective (START Trialists' Group, Lancet 2008 &amp; Lancet Oncol 2008). With patients remaining at risk of local relapse for many years, information on long-term outcomes is needed to provide confidence in clinical practice. Here, we report 10-year follow-up of the UK START Trials testing 13- and 15-Fr regimens in terms of local cancer control and late adverse effects. Methods Between 1999 and 2002, 4451 women with completely excised invasive breast cancer (T1-3, N0-1, M0) were randomised after primary surgery to comparisons of 50Gy in 25Fr over 5 weeks vs 41·6Gy or 39Gy in 13Fr over 5 weeks (START A), or 50Gy in 25Fr over 5 weeks vs 40Gy in 15Fr over 3 weeks (START B). Women were eligible if aged over 18 years and did not have an immediate surgical reconstruction. Protocol-specified principal endpoints were local-regional (LR) tumour relapse and late normal tissue effects. Analysis was by intention to treat. Findings Median follow-up in survivors is now 9.3 years in START A and 9.9 years in START B, with 139 LR relapses in START A and 95 in START B. In START A, the 10-year rate of LR relapse was 7.4% (95%CI 5.5–10.0) after 50Gy, 6.3% (95%CI 4.7–8.5) after 41·6Gy and 8.8% (95%CI 6.7–11.4) after 39Gy. In START B, the 10-year rate of LR relapse was 5.5% (95%CI 4.2–7.2) after 50Gy and 4.3% (95%CI 3.2–5.9) after 40Gy. Clinician assessments suggested lower 10-year rates of any moderate/marked late normal tissue effects after 39Gy (43.9%; 95%CI 39.3–48.7) and similar rates after 41.6Gy (49.5%; 95%CI 44.9–54.3) compared with 50Gy (50.4%; 95%CI 45.8–55.3) in START A and lower rates after 40Gy in START B (37.9%; 95%CI 34.5–41.5) compared with 50Gy (45.3%; 95%CI 41.7–49.0). From a planned meta-analysis of START A and the START pilot trial (Owen et al, Lancet Oncol 2006), the adjusted estimate of α/β value for tumour control was 3.5Gy (95% CI 1.2–5.7) and for late change in photographic breast appearance was 3.1Gy (95% CI 2.0–4.2). Interpretation Long-term follow-up confirms that breast cancer and the surrounding dose-limiting healthy tissues respond similarly to radiotherapy fraction size and thus that appropriately-dosed hypofractionated radiotherapy is safe and effective in treatment of patients with early breast cancer. 41·6Gy in 13Fr and 40Gy in 15Fr each appear comparable to 50Gy in 25Fr in terms of local-regional tumour control and late normal tissue effects. These results support the continued use of 40Gy in 15Fr as standard of care (UK NICE Guidance 2009) for women requiring adjuvant radiotherapy for early breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-1.

The impact of dose heterogeneity on late normal tissue complication risk after hypofractionated whole breast radiotherapy

Background and purposeLinear quadratic models predict that hypofractionation increases the biological effect of physical dose inhomogeneity. The clinical significance of this effect was tested retrospectively in a trial of adjuvant breast hypofractionation. MethodsThe UK FAST trial randomised 915 women after breast conservation surgery between standard fractionation and two dose levels of a 5-fraction regimen delivering 5.7 or 6.0Gy fractions in 5weeks, using 3D dosimetry. Logistic regression tested for association between the absolute volumes receiving different isodose level >100% of prescribed dose (hotspots) and the risk of change in 2-year photographic breast appearance. The strength of this association was compared between control and hypofractionated groups. ResultsThree hundred and ninety datasets from 11 participating centres were available for analysis. At 2years post-randomisation, 81 (20.8%) had mild change and 24 (6.2%) had marked change in photographic breast appearance. After adjusting for breast size and surgical deficit, there was no statistically significant association between the risk of 2-year change in breast appearance and dose inhomogeneity in either the control or hypofractionated schedules, according to the various definitions of hotspots analysed. The magnitude of the effect of dosimetry on 2-year change in breast appearance did not vary significantly between control and hypofractionated schedules for any of the dosimetry parameters (p>0.05 for all heterogeneity tests). ConclusionDose inhomogeneity had no greater impact on the risk of 2-year change in photographic breast appearance after hypofractionated breast radiotherapy than after standard fractionation.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015)

Background and purposeRandomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. Materials and methodsWomen aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. ResultsNine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26–2.29, p<0.001) for 30Gy and 1.15 (0.82–1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3–22.3%, p<0.001) for 30Gy and 11.1% (7.9–15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5–13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. ConclusionsAt 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Large breast size as a risk factor for late adverse effects of breast radiotherapy: Is residual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation?

Background and PurposeLarge breast size is associated with an increased risk of late adverse effects after breast conservation surgery and radiotherapy, even when 3D dosimetry is used. The purpose of this study is to test the hypothesis that residual dose inhomogeneity is sufficient to explain the association. MethodsPatients previously treated after breast conservation surgery with whole breast radiotherapy using 3D dosimetry and followed up in the UK FAST hypofractionation trial were selected for this analysis. The residual level of dose inhomogeneity across the whole breast treatment volume was used to test for association between residual dosimetry and post-treatment change in breast appearance at 2years post-radiotherapy. ResultsAt 2years, 201/279 (72%) of women had no change in photographic breast appearance, 61 (22%) had mild change and 17 (6%) had marked change. Breast size and dosimetry were both significantly associated with late effects in univariate analyses, but only breast size remained an independent significant risk factor for change in breast appearance when included in a multiple regression model together with other prognostic factors (p=0.006 for trend). ConclusionLarge-breasted women are more likely to suffer change in breast size and shape after whole breast radiotherapy delivered using 3D dosimetry, but residual dose inhomogeneity is insufficient to explain the association.

Acute Toxicity and 2-year Adverse Effects of 30 Gy in Five Fractions over 15 Days to Whole Breast after Local Excision of Early Breast Cancer

Aims A pilot study was undertaken with the aim of documenting acute skin reactions and 2-year late adverse effects of a five-fraction course of adjuvant whole breast radiotherapy delivered over 15 days after local tumour excision of early breast cancer. Materials and methods Thirty women with early invasive breast cancer aged ≥50 years with a pathological tumour size <3 cm, complete microscopic resection, negative axillary node status and no requirement for cytotoxic therapy were prescribed 30 Gy in five fractions over 15 days to the whole breast using tangential 6–10 MV X-ray beams and three-dimensional dose compensation with written informed consent. Post-surgical baseline photographs of the breasts were taken, and acute skin erythema and moist desquamation were each scored weekly for 7 weeks using four-point graded scales (grade 0 = none, 1 = mild, 2 = moderate, 3 = severe). This was followed by an annual clinical assessment, including repeat photographs at 2 years. Results Nine patients (30%, 95% confidence interval 14.7–49.4%) developed grade 2 erythema, with the remaining 21 patients developing milder degrees of reaction. Four (13.3%, 95% confidence interval 3.7–30.7) patients developed moist desquamation, grade 1 in three women and grade 2 in the fourth. At 2 years after treatment, 23/30 (77%) patients scored no change in photographic breast appearance compared with the pre-treatment baseline; seven (23%, 95% confidence interval 9.9–42.3) scored a mild change in breast appearance, and none developed a marked change. After a mean follow-up of 3.1 years (standard deviation 0.37, range 2.1–3.9 years) there have been no ipsilateral local tumour relapses. Conclusions Further evaluation of a five-fraction regimen of adjuvant whole breast radiotherapy in a phase III randomised trial is justified, including a regimen delivered in a total of 5 days.

Hypofractionation for early breast cancer: First results of the UK standardization of breast radiotherapy (START) trials

LBA518 Background: The START Trials (ST-A and ST-B) test the hypothesis that breast cancer is as sensitive to fraction (Fr) size as late reacting normal tissues, with an a/β value of about 4Gy. Methods: The phase III randomised START Trials tested hypofractionated post-operative RT in women with completely excised invasive breast cancer (T1–3, N0–1, M0). Centres opted for either ST-A or ST-B. ST-A tested 50Gy in 25Fr (5 wks) vs 41.6Gy vs 39Gy, both in 13Fr (5 wks). ST-B tested 50Gy in 25Fr (5 wks) vs 40Gy in 15Fr (3 wks). Stratification was by centre, surgery and boost. The primary endpoint was local-regional (LR) relapse. Late normal tissue effects (NTE) were assessed by breast photographs, clinical examination and quality of life (QL) questionnaires. Survival analysis methods were used to estimate rates of relapse and NTEs, and hazard ratios (HR) (with 95%CI). Smoothed estimates of absolute differences in relapse rates were obtained from the rates in the 50Gy control arms and the HR. Results: 2236 (ST-A) and 2215 (ST-B) patients were recruited from 35 UK centres during 1999–2002. Median follow-up is 5.1 years (ST-A) and 6.0 years (ST-B). There were 93 LR relapses in ST-A (4.1% at 5 years, 3.2- 5.0%), with absolute differences in LR relapse rates at 5 years compared with 50Gy of 0.2% (−1.3%−2.6%) for 41.6Gy and 0.9% (−0.8%−3.7%) for 39Gy. The a/β estimate for tumour control was 5.0Gy (−2.7–12.7). In ST-B, there were 65 LR relapses (2.8% at 5 years, 2.1–3.5%), with an absolute difference in LR relapse rates at 5 years of −0.6% (−1.7%−0.9%) for 40Gy vs 50Gy. In ST-A the rate of mild/marked change in photographic breast appearance was lower in 39Gy vs 50Gy (HR 0.69, 0.52–0.91), and similarly for 40Gy vs 50Gy in ST-B (HR 0.83, 0.66–1.04). The a/β estimate for change in breast appearance was 3.1Gy (1.6–4.6). Rates of induration, telangiectasia and breast oedema were lower in 39Gy (ST-A) and 40Gy (ST-B) compared with the 50Gy arms. QL results were consistent with the clinical findings. Conclusions: The fractionation sensitivity of breast cancer is comparable to that of late reacting normal tissues, confirming the results of a recent pilot trial. These results support the use of hypofractionated RT schedules for early breast cancer. No significant financial relationships to disclose.

Double-blind, placebo-controlled, randomised phase II trial of IH636 grape seed proanthocyanidin extract (GSPE) in patients with radiation-induced breast induration

Background and purposeTissue hardness (induration), pain and tenderness are common late adverse effects of curative radiotherapy for early breast cancer. The purpose of this study was to test the efficacy of IH636 grape seed proanthocyanidin extract (GSPE) in patients with tissue induration after high-dose radiotherapy for early breast cancer in a double-blind placebo-controlled randomised phase II trial. Patients and methodsSixty-six eligible research volunteers with moderate or marked breast induration at a mean 10.8 years since radiotherapy for early breast cancer were randomised to active drug (n=44) or placebo (n=22). All patients were given grape seed proanthocyanidin extract (GSPE) 100mg three times a day orally, or corresponding placebo capsules, for 6 months. The primary endpoint was percentage change in surface area (cm2) of palpable breast induration measured at the skin surface 12 months after randomisation. Secondary endpoints included change in photographic breast appearance and patient self-assessment of breast hardness, pain and tenderness. ResultsAt 12 months post-randomisation, ≥50% reduction in surface area (cm2) of breast induration was recorded in13/44 (29.5%) GSPE and 6/22 (27%) placebo group patients (NS). At 12 months post-randomisation, there was no significant difference between treatment and control groups in terms of external assessments of tissue hardness, breast appearance or patient self-assessments of breast hardness, pain or tenderness. ConclusionsThe study failed to show efficacy of orally-adminstered GSPE in patients with breast induration following radiotherapy for breast cancer.