Anne Capp

Prediction of Local Recurrence, Distant Metastases, and Death After Breast-Conserving Therapy in Early-Stage Invasive Breast Cancer Using a Five-Biomarker Panel

PURPOSE To determine the clinical utility of intrinsic molecular phenotype after breast-conserving therapy (BCT) with lumpectomy and whole-breast irradiation with or without a cavity boost. PATIENTS AND METHODS Four hundred ninety-eight patients with invasive breast cancer were enrolled into a randomized trial of BCT with or without a tumor bed radiation boost. Tumors were classified by intrinsic molecular phenotype as luminal A or B, HER-2, basal-like, or unclassified using a five-biomarker panel: estrogen receptor, progesterone receptor, HER-2, CK5/6, and epidermal growth factor receptor. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ipsilateral breast tumor recurrence (IBTR), locoregional recurrence (LRR), distant disease-free survival (DDFS), and death from breast cancer. RESULTS Median follow-up was 84 months. Three hundred ninety-four patients were classified as luminal A, 23 were luminal B, 52 were basal, 13 were HER-2, and 16 were unclassified. There were 24 IBTR (4.8%), 35 LRR (7%), 47 distant metastases (9.4%), and 37 breast cancer deaths (7.4%). The overall 5-year disease-free rates for the whole cohort were: IBTR 97.4%, LRR 95.6%, DDFS 92.9%, and breast cancer-specific death 96.3%. A significant difference was observed for survival between subtypes for LRR (P = .012), DDFS (P = .0035), and breast cancer-specific death (P = .0482), but not for IBTR (P = .346). CONCLUSION The 5-year and 10-year survival rates varied according to molecular subtype. Although this approach provides additional information to predict time to IBTR, LRR, DDFS, and death from breast cancer, its predictive power is less than that of traditional pathologic indices. This information may be useful in discussing outcomes and planning management with patients after BCT.

An Atlas-Based Electron Density Mapping Method for Magnetic Resonance Imaging (MRI)-Alone Treatment Planning and Adaptive MRI-Based Prostate Radiation Therapy

PURPOSE Prostate radiation therapy dose planning directly on magnetic resonance imaging (MRI) scans would reduce costs and uncertainties due to multimodality image registration. Adaptive planning using a combined MRI-linear accelerator approach will also require dose calculations to be performed using MRI data. The aim of this work was to develop an atlas-based method to map realistic electron densities to MRI scans for dose calculations and digitally reconstructed radiograph (DRR) generation. METHODS AND MATERIALS Whole-pelvis MRI and CT scan data were collected from 39 prostate patients. Scans from 2 patients showed significantly different anatomy from that of the remaining patient population, and these patients were excluded. A whole-pelvis MRI atlas was generated based on the manually delineated MRI scans. In addition, a conjugate electron-density atlas was generated from the coregistered computed tomography (CT)-MRI scans. Pseudo-CT scans for each patient were automatically generated by global and nonrigid registration of the MRI atlas to the patient MRI scan, followed by application of the same transformations to the electron-density atlas. Comparisons were made between organ segmentations by using the Dice similarity coefficient (DSC) and point dose calculations for 26 patients on planning CT and pseudo-CT scans. RESULTS The agreement between pseudo-CT and planning CT was quantified by differences in the point dose at isocenter and distance to agreement in corresponding voxels. Dose differences were found to be less than 2%. Chi-squared values indicated that the planning CT and pseudo-CT dose distributions were equivalent. No significant differences (p > 0.9) were found between CT and pseudo-CT Hounsfield units for organs of interest. Mean ± standard deviation DSC scores for the atlas-based segmentation of the pelvic bones were 0.79 ± 0.12, 0.70 ± 0.14 for the prostate, 0.64 ± 0.16 for the bladder, and 0.63 ± 0.16 for the rectum. CONCLUSIONS The electron-density atlas method provides the ability to automatically define organs and map realistic electron densities to MRI scans for radiotherapy dose planning and DRR generation. This method provides the necessary tools for MRI-alone treatment planning and adaptive MRI-based prostate radiation therapy.

MRI-guided prostate radiation therapy planning: Investigation of dosimetric accuracy of MRI-based dose planning

BACKGROUND AND PURPOSE Dose planning requires a CT scan which provides the electron density distribution for dose calculation. MR provides superior soft tissue contrast compared to CT and the use of MR-alone for prostate planning would provide further benefits such as lower cost to the patient. This study compares the accuracy of MR-alone based dose calculations with bulk electron density assignment to CT-based dose calculations for prostate radiotherapy. MATERIALS AND METHODS CT and whole pelvis MR images were contoured for 39 prostate patients. Plans with uniform density and plans with bulk density values assigned to bone and tissue were compared to the patients gold standard full density CT plan. The optimal bulk density for bone was calculated using effective depth measurements. The plans were evaluated using ICRU point doses, dose volume histograms, and Chi comparisons. Differences in spatial uniformity were investigated for the CT and MR scans. RESULTS The calculated dose for CT bulk bone and tissue density plans was 0.1±0.6% (mean±1 SD) higher than the corresponding full density CT plan. MR bulk bone and tissue density plans were 1.3±0.8% lower than the full density CT plan. CT uniform density plans and MR uniform density plans were 1.4±0.9% and 2.6±0.9% lower, respectively. Paired t-tests performed on specific points on the DVH graphs showed that points on DVHs for all bulk electron density plans were equivalent with two exceptions. There was no significant difference between doses calculated on Pinnacle and Eclipse. The dose distributions of six patients produced Chi values outside the acceptable range of values when MR-based plans were compared to the full density plan. CONCLUSIONS MR-alone bulk density planning is feasible provided bone is assigned a density, however, manual segmentation of bone on MR images will have to be replaced with automatic methods. The major dose differences for MR bulk density plans are due to differences in patient external contours introduced by the MR couch-top and pelvic coil.

Does the planning dose–volume histogram represent treatment doses in image-guided prostate radiation therapy? Assessment with cone-beam computerised tomography scans

PURPOSE To assess the accuracy of the initial CT plan dose-volume histograms (DVHs) for prostate, rectum and bladder by comparison to delivered doses determined from cone beam CT (CBCT) scans acquired during image-guided treatment. MATERIALS AND METHODS Twelve prostate patients were treated using daily implanted fiducial guidance and following local protocol for bladder and rectal preparation. CBCT scans were acquired twice weekly and contoured for prostate, rectum and bladder. The planned beams were applied to all CBCT scans to determine the delivered doses. Prostate dose coverage was assessed by the proportion of the CTV fully encompassed by the 95% and 98% isodose lines. Rectal and bladder volumes receiving 40 Gy, 60 Gy and 70 Gy at treatment were compared to the initial plan, with significance determined using the one-sample t-test. RESULTS Four patients showed marginally compromised CTV coverage by the 95% isodose at all CBCT plans. For nine patients the initial plan rectal DVH was significantly outside the range of the treatment DVHs. CONCLUSIONS Dose coverage of the prostate was not achieved for all patients. Observed rectal and bladder doses were higher than predicted. The initial treatment plan cannot be assumed to represent accurate normal tissue doses.

Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53

Background:The aim of this study is to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 improves prognostication of oestrogen receptor-positive (ER+) breast cancer after breast-conserving therapy (BCT). In all, 498 patients with invasive breast cancer from a randomised trial of BCT with or without tumour bed radiation boost were assessed using IHC.Methods:The ER+ tumours were classified as ‘luminal A’ (LA): ER+ and/or PR+, Ki-67 low, p53−, HER2− or ‘luminal B’ (LB): ER+ and/or PR+and/or Ki-67 high and/or p53+ and/or HER2+. Kaplan–Meier and Cox proportional hazards methodology were used to ascertain relationships to ispilateral breast tumour recurrence (IBTR), locoregional recurrence (LRR), distant metastasis-free survival (DMFS) and breast cancer-specific survival (BCSS).Results:In all, 73 patients previously LA were re-classified as LB: a greater than four-fold increase (4.6–19.3%) compared with ER, PR, HER2 alone. In multivariate analysis, the LB signature independently predicted LRR (hazard ratio (HR) 3.612, 95% CI 1.555–8.340, P=0.003), DMFS (HR 3.023, 95% CI 1.501–6.087, P=0.002) and BCSS (HR 3.617, 95% CI 1.629–8.031, P=0.002) but not IBTR.Conclusion:The prognostic evaluation of ER+ breast cancer is improved using a marker panel, which includes Ki-67 and p53. This may help better define a group of poor prognosis ER+ patients with a greater probability of failure with endocrine therapy.

Randomized, paired comparison of No-Sting Barrier Film versus sorbolene cream (10% glycerine) skin care during postmastectomy irradiation

PURPOSE Postmastectomy irradiation provides an excellent model for irradiated skin care practices because of the relatively uniform surface and radiation compared with other situations in which radiation-induced moist desquamation is common. We designed a study to test the effect of prophylactic 3M Cavilon No-Sting Barrier Film (No-Sting) on the rates of moist desquamation compared with sorbolene cream (with 10% glycerin). METHODS AND MATERIALS The irradiated chest wall was divided into medial and lateral halves. Sixty-one women were randomized to have No-Sting applied to either the medial or lateral half, with the alternate half treated with sorbolene. RESULTS For all patients, the skin toxicity, calculated as the area under the curve, mean No-Sting and sorbolene score was 8.1 vs. 9.2, respectively (p = 0.005, Wilcoxon signed rank test). The total number of weeks of moist desquamation for the 61 patients was 40 vs. 45, equating to a mean of 0.65 week vs. 0.74 week per patient in the No-Sting and sorbolene-treated areas, respectively. The rates of moist desquamation were 33% vs. 46% (p = 0.096, McNemars Exact test). For 58 fully assessable patients (minimum of 7 weekly observations), the area under the curve and rates of moist desquamation were significantly different statistically (p = 0.002 and 0.049, respectively). No statistically significant differences were noted in the pain scores. The pruritus scores were significantly reduced in the No-Sting area (area under the curve, p = 0.011). CONCLUSION No-Sting reduces the duration and frequency of radiation-induced moist desquamation.

Treatment-Related Morbidity in Prostate Cancer: A Comparison of 3-Dimensional Conformal Radiation Therapy With and Without Image Guidance Using Implanted Fiducial Markers

PURPOSE To estimate the prevalence of rectal and urinary dysfunctional symptoms using image guided radiation therapy (IGRT) with fiducials and magnetic resonance planning for prostate cancer. METHODS AND MATERIALS During the implementation stages of IGRT between September 2008 and March 2010, 367 consecutive patients were treated with prostatic irradiation using 3-dimensional conformal radiation therapy with and without IGRT (non-IGRT). In November 2010, these men were asked to report their bowel and bladder symptoms using a postal questionnaire. The proportions of patients with moderate to severe symptoms in these groups were compared using logistic regression models adjusted for tumor and treatment characteristic variables. RESULTS Of the 282 respondents, the 154 selected for IGRT had higher stage tumors, received higher prescribed doses, and had larger volumes of rectum receiving high dosage than did the 128 selected for non-IGRT. The follow-up duration was 8 to 26 months. Compared with the non-IGRT group, improvement was noted in all dysfunctional rectal symptoms using IGRT. In multivariable analyses, IGRT improved rectal pain (odds ratio [OR] 0.07 [0.009-0.7], P=.02), urgency (OR 0.27 [0.11-0.63], P=<.01), diarrhea (OR 0.009 [0.02-0.35], P<.01), and change in bowel habits (OR 0.18 [0.06-0.52], P<.010). No correlation was observed between rectal symptom levels and dose-volume histogram data. Urinary dysfunctional symptoms were similar in both treatment groups. CONCLUSIONS In comparison with men selected for non-IGRT, a significant reduction of bowel dysfunctional symptoms was confirmed in men selected for IGRT, even though they had larger volumes of rectum treated to higher doses.

Infections after fiducial marker implantation for prostate radiotherapy: are we underestimating the risks?

BackgroundThe use of gold fiducial markers (FM) for prostate image-guided radiotherapy (IGRT) is standard practice. Published literature suggests low rates of serious infection following this procedure of 0-1.3%, but this may be an underestimate. We aim to report on the infection incidence and severity associated with the use of transrectally implanted intraprostatic gold FM.MethodsThree hundred and fifty-nine patients who underwent transrectal FM insertion between January 2012 and December 2013 were assessed retrospectively via a self-reported questionnaire. All had standard oral fluoroquinolone antibiotic prophylaxis. The patients were asked about infective symptoms and the treatment received including antibiotics and/or related hospital admissions. Potential infective events were confirmed through medical records.Results285 patients (79.4%) completed the questionnaire. 77 (27.0%) patients experienced increased urinary frequency and dysuria, and 33 patients (11.6%) reported episodes of chills and fevers after the procedure. 22 patients (7.7%) reported receiving antibiotics for urinary infection and eight patients (2.8%) reported hospital admission for urosepsis related to the procedure.ConclusionThe overall rate of symptomatic infection with FM implantation in this study is 7.7%, with one third requiring hospital admission. This exceeds the reported rates in other FM implantation series, but is in keeping with the larger prostate biopsy literature. Given the higher than expected complication rate, a risk-adaptive approach may be helpful. Where higher accuracy is important such as stereotactic prostate radiotherapy, the benefits of FM may still outweigh the risks. For others, a non-invasive approach for prostate IGRT such as cone-beam CT could be considered.

Patients' and clinicians' preferences for adjuvant chemotherapy in endometrial cancer: an ANZGOG substudy of the PORTEC-3 intergroup randomised trial.

Background:To determine the minimum survival benefits that patients, and their clinicians, judged sufficient to make adjuvant chemotherapy (ACT) worthwhile, in addition to pelvic radiotherapy, for women with high risk and advanced stage endometrial cancer.Methods:Eighty-three participants in the PORTEC-3 trial completed a time trade-off questionnaire before and after adjuvant therapy; 44 of their clinicians completed it once only. The questionnaire used four hypothetical scenarios including baseline survival times without ACT of 5 and 8 years, and baseline survival rates at 5 years without ACT of 50 and 65%.Results:Over 50% of patients judged an extra 1 year of survival time or an extra 5% in survival rate sufficient to make ACT worthwhile. Over 50% of clinicians judged an extra 1 year of survival time, or an extra 10% in survival rate, sufficient to make ACT worthwhile. Compared with patients, clinicians required similar survival time benefits (medians both 1 year, P=0.4), but larger survival rate benefits (medians 8.5% vs 5%, P=0.03), and clinicians’ preferences varied less (IQR 0.5–1.5 years vs 0.4–2 years, P=0.0007; 5–10% vs 1–13%, P=0.004). Patients’ preferences changed over time for the survival rate scenarios depending on whether they had ACT or not (change in median benefit - 3 months vs 2.5 months respectively, P=0.028). There were no strong predictors of patients’ or clinicians’ preferences.Conclusions:Patients and clinicians judged moderate survival benefits sufficient to make ACT worthwhile after pelvic radiotherapy for endometrial cancer. These benefits are larger than those judged sufficient by patients with breast or colon cancers, but similar to those judged sufficient by patients with lung or ovarian cancers.

Optimal single 3T MR imaging sequence for HDR brachytherapy of cervical cancer

Purpose The superior image quality of 3 tesla (3T) magnetic resonance (MR) imaging in cervical cancer offers the potential to use a single image set for brachytherapy. This study aimed to determine a suitable single sequence for contouring tumour and organs at risk, applicator reconstruction, and treatment planning. Material and methods A 3T (Skyra, Siemens Healthcare AG, Germany) MR imaging system with an 18 channel body matrix coil generated HDR cervical cancer brachytherapy planning images on 20 cases using plastic-based treatment applicators. Seven different T2-weighted Turbo Spin Echo (TSE) sequences including both 3D and contiguous 2D scans based on sagittal, axial (transverse), and oblique planes were analysed. Each image set was assessed for total scanning time and usefulness in tumour localization via inter- and intra-observer analysis of high-risk clinical target volume (HR CTV) contouring. Applicator reconstruction in the treatment planning system was also considered. Results The intra-observer difference in HR CTV volumes between 2D and 3D axial-based image sets was low with an average difference of 3.1% for each observer. 2D and 3D sagittal image sets had the highest intra- and inter observer differences (over 15%). A 2D axial ‘double oblique’ sequence was found to produce the best intra- (average difference of 0.6%) and inter-observer (mean SD of 9.2%) consistency and greatest conformity (average 0.80). Conclusions There was little difference between 2D and 3D-based scanning sequences; however the increased scanning time of 3D sequences have potential to introduce greater patient motion artifacts. A contiguous 2D sequence based on an axial T2-weighted turbo-spin-echo (TSE) sequence orientated in all planes of the treatment applicator provided consistent tumour delineation whilst allowing applicator reconstruction and treatment planning.