Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).

Long-term outcomes and effects of hypofractionated radiotherapy in microinvasive breast cancer: Analysis from a randomized trial.

PURPOSE: The natural history of microinvasive (T1mi) breast cancer is uncertain. The objective was to evaluate long-term local and distant recurrence rates following breast conserving surgery (BCS) in a prospective cohort of patients with T1mi compared to T1a-2 disease who received whole breast irradiation (WBI) in the context of a randomized trial of hypofractionation. METHODS: 1234 patients with T1-2 N0 breast cancer were randomized to receive adjuvant WBI of 42.5Gy in 16 daily fractions, or 50Gy in 25 daily fractions after BCS. An analysis of patients with T1mi tumors compared with T1a-2 disease was performed. Kaplan-Meier estimates of local recurrence (LR), distant recurrence, and overall survival (OS) were compared using the log-rank test. RESULTS: Median follow-up was 12 years. T1mi was found in 3% (n = 38) of patients. The 10-year LR rate was 22.6% in T1mi vs. 6.9% in T1a-2 breast cancer [hazard ratio (HR) = 3.73; 95% confidence interval (CI): 1.93, 7.19; p < 0.001]. The 10-year risk of distant recurrence was 5.1% for T1mi, and 12.1% for T1a-2 disease (HR = 0.56; 95% CI: 0.19, 1.84; p = 0.36). Ten-year OS was 91.5% in T1mi and 84.4% in T1a-2 disease, (HR = 0.48; 95% CI: 0.18, 1.30; p = 0.14). Rates of LR did not differ whether treated by hypofractionation or conventional fractionation (HR = 1.21; 95% CI: 0.35, 4.18; p = 0.77). CONCLUSIONS: The risk of LR was considerably higher in patients with T1mi compared to T1a-2 tumors, but OS remained very good. Future research should evaluate the utility of wider local excision and boost radiation to optimize local control for microinvasive breast cancer.

Same-Day Home Recovery for Benign Foregut Surgery.

Importance: Same-day home recovery (SHR) is now the standard of care for many major surgical procedures and has the potential to become standard practice for benign foregut procedures (eg, hiatal hernia repair, fundoplication, and Heller myotomy). Objective: To determine whether SHR for patients undergoing benign foregut surgery is feasible, safe, and effective. Design, Setting, and Participants: This prospective cohort study took place across 19 medical centers within an integrated health care system in northern California from January 2019 through September 2021. Participants included consecutive patients undergoing elective benign foregut surgery. Exposures: Standardized SHR program. Main Outcomes and Measures: The primary end point was the rate of SHR. The secondary end points were 7-day and 30-day rates of postoperative emergency department visits, hospital readmissions, and reoperations. Results: Of 1248 patients who underwent benign foregut surgery from January 2017 through September 2021, 558 were patients before implementation of the SHR program and 690 were patients postimplementation. The mean age of patients was 60 years, and 759 (59%) were female. The preimplementation SHR rate was 64 of 558 patients (11.5%) in 2018 and increased to 82 of 113 patients (72.6%) by 2021 (94/350 [26.9%] in 2019 and 112/227 [49.3%] in 2020; P < .001). There were no statistical differences in the 7-day and 30-day rates of postoperative emergency visits, hospital readmissions, and reoperations or 30-day mortality in the SHR vs non-SHR groups in the postimplementation era. Conclusions and Relevance: In this study, implementation of a regional SHR program among patients undergoing elective benign foregut surgery was feasible, safe, and effective. The changes in perioperative care require comprehensive patient education and full multidisciplinary support. An SHR program for benign foregut procedures has the potential to improve patient care and cost-effectiveness in care delivery.

Experiences and Perceptions of Older Adults with Lower-Risk Hormone Receptor-Positive Breast Cancer about Adjuvant Radiotherapy and Endocrine Therapy: A Patient Survey.

Older patients with lower-risk hormone receptor-positive (HR+) breast cancer are frequently offered both radiotherapy (RT) and endocrine therapy (ET) after breast-conserving surgery (BCS). A survey was performed to assess older patients' experiences and perceptions regarding RT and ET, and participation interest in de-escalation trials. Of the 130 patients approached, 102 eligible patients completed the survey (response rate 78%). The median age of respondents was 74 (interquartile range 71-76). Most participants (71%, 72/102) received both RT and ET. Patients felt the role of RT and ET, respectively, was to: reduce ipsilateral tumor recurrence (91%, 90/99 and 62%, 61/99) and improve survival (56%, 55/99 and 49%, 49/99). More patients had significant concerns regarding ET (66%, 65/99) than RT (39%, 37/95). When asked which treatment had the most negative effect on their quality of life, the results showed: ET (35%, 25/72), RT (14%, 10/72) or both (8%, 6/72). Participants would rather receive RT (57%, 41/72) than ET (43%, 31/72). Forty-four percent (44/100) of respondents were either, "not comfortable" or "not interested" in participating in potential de-escalation trials. Although most of the adjuvant therapy de-escalation trials evaluate the omission of RT, de-escalation studies of ET are warranted and patient centered.

De-escalating adjuvant therapies in older patients with lower risk estrogen receptor-positive breast cancer treated with breast-conserving surgery: A systematic review and meta-analysis.

PURPOSE: Radiation therapy (RT) and endocrine therapy (ET) are standard treatments for hormone receptor-positive (HR+) breast cancer after breast-conserving surgery (BCS). However, many older patients are at greater risk of treatment-related toxicities and non-cancer related death, and less likely to benefit from these standard treatments. A systematic review was performed evaluating outcomes of omitting RT or ET in older patients aged ≥50 treated with BCS for lower-risk breast cancer. METHODS: Medline, Embase, and the Cochrane Register of Controlled Trials were queried from 1980 to April 30th, 2020 for randomized controlled studies (RCTs) and prospective cohort studies (PCSs) evaluating omission of RT and/or ET compared to RT plus ET in patients. Meta-analysis was performed using random-effects models with findings reported as risk ratios (RR) with 95% confidence intervals (CI). RESULTS: From 3860 citations, 10 prospective studies met eligibility criteria. Omission of RT alone was evaluated in 7 RCTs (n = 4604) and one PCS (n = 667); omission of ET alone was assessed in 1 PCS (n = 271); and omission of either ET or RT was compared to ET plus RT in 1 RCT (n = 495). Adjuvant RT compared to no RT reduced 5- and 10-year in-breast tumor recurrence [5-year: RR 0.16, 95 %CI 0.09-0.27 l 10-year: 0.28, 95 %CI 0.16-0.5], but had no effect on survival [5-year: RR 0.94, 95 %CI 0.77-1.15; 10-year: 1.01, 95 %CI 0.9-1.12]. CONCLUSION: The current body of evidence suggests that RT can be omitted in older patients with lower-risk disease. However, more trials on the omission of ET are required to better inform treatment decisions.

Stereotactic radiosurgery optimization with hippocampal-sparing in patients treated for brain metastases.

BACKGROUND AND PURPOSE: Cranial irradiation is associated with significant neurocognitive sequelae, secondary to radiation-induced damage to hippocampal cells. It has been shown that hippocampal-sparing (HS) leads to modest benefit in neurocognitive function in patients with brain metastases, but further improvement is possible. We hypothesized that improved benefits could be seen using HS in patients treated with stereotactic radiation (HS-SRS). Our study evaluated whether the hippocampal dose could be significantly reduced in the treatment of brain metastases using SRS, while maintaining target coverage. MATERIALS AND METHODS: Sixty SRS plans were re-planned to minimize dose to the hippocampus while maintaining target coverage. Patients with metastases within 5 mm of the hippocampus were excluded. Minimum, mean, maximum and dose to 40% (mean equivalent dose in 2 Gy per fraction, EQD2 to the hippocampus) were compared between SRS and HS-SRS plans. Median number of brain metastases was two. RESULTS: Compared to baseline SRS plans, hippocampal-sparing plans demonstrated Dmin was reduced by 35%, from 0.4 Gy to 0.3 Gy (p-value 0.02). Similarly, Dmax was reduced by 55%, from 8.2 Gy to 3.6 Gy, Dmean by 52%, from 1.6 Gy to 0.5 Gy, and D40 by 50%, from 1.8 Gy to 0.9 Gy (p-values <0.001). CONCLUSIONS: Our study demonstrated that further reduction of hippocampal doses of more than 50% is possible in the treatment of brain metastases with SRS using dose optimization. This could result in significantly improved neurocognitive outcomes for patients treated for brain metastases.

Radiation-induced brain injury in patients with meningioma treated with proton or photon therapy.

INTRODUCTION: Radiation therapy is often used to treat meningioma with adverse features or when unresectable. Proton therapy has advantages over photon therapy in reducing integral dose to the brain. This study compared the incidence of radiological and clinical adverse events after photon versus proton therapy in the treatment of meningioma. METHODS: A retrospective review was conducted on patients with meningioma treated with proton or photon therapy at two high-volume tertiary cancer centers. Patients with a history of prior radiation therapy (RT) or less than 3 months of follow-up were excluded. Post-RT imaging changes were categorized into abnormal T2 signal intensities (T2 changes) or abnormal T1 post-contrast and T2 signal intensities (T1c+T2 changes) on magnetic resonance imaging (MRI). Clinical outcomes of adverse events and survival were compared between the proton and photon therapies. RESULTS: Among the total of 77 patients, 38 patients received proton therapy and 39 patients received photon therapy. The median age at diagnosis was 55 years and median follow-up was 2.2 years. No significant differences in symptomatic adverse events were observed between the two groups: grade ≥ 2 adverse events were seen in 4 (10.5%) patients in the proton group and 3 (7.7%) patients in the photon group (p = 0.67). The 2-year cumulative incidences of T2 changes were 38.3% after proton therapy and 47.7% after photon therapy (p = 0.53) and the 2-year cumulative incidences of T1c+T2 changes were 26.8% after proton therapy and 5.3% after photon therapy (p = 0.02). One patient experienced grade ≥ 4 adverse event in each group (p = 0.99). Estimated 2-year progression-free survival was 79.5% (proton therapy 76.0% vs. photon therapy 81.3%, p = 0.66) and 2-year overall survival was 89.7% (proton therapy 86.6% vs. photon therapy 89.3%, p = 0.65). CONCLUSIONS: Following RT, high rates of T2 changes were seen in meningioma patients regardless of treatment modality. Proton therapy was associated with significantly higher rates of T1c+T2 changes compared with photon therapy, but severe adverse events were uncommon in both groups and survival outcomes were comparable between the two groups. Future studies will aim at correlating the MRI changes with models that can be incorporated into RT planning to avoid toxicity.

Can we rely on surgical clips placed during oncoplastic breast surgery to accurately delineate the tumor bed for targeted breast radiotherapy?

PURPOSE: Oncoplastic breast surgery (OBS) is gaining popularity among surgeons for breast-conserving surgery treatments. OBS relies on complex relocation and deformation of breast tissue involving the tumor bed (TB). In this study, we investigate the validity of using surgical clips with OBS for accurate TB delineation in adjuvant, targeted breast radiotherapy. METHODS: Different OBS techniques were simulated on realistic breast phantoms. Surgical clips were used to demarcate the TB. Following tumor resection and closure, the true TB (TBTrue) was extracted. Each phantom was CT imaged at several phases of surgery in order to record pre- and post-OBS closure surgical clip displacements. Two senior radiation oncologists (ROs) were asked to delineate TBs on CTs by relying on surgical clips placed as per standard protocol, and by referring to operative notes. Their original contours, as well as those expanded using 5-15 mm margins, were compared with the accurate TBTrue using the dice similarity coefficient (DSC), Hausdorff Distance (HD), and over- and under-contoured volumes. Inter- and intra-RO contour agreements were also evaluated. RESULTS: Post-OBS surgical clips were significantly displaced outside the original breast quadrant. Inter- and Intra-RO TB contours were consistent, yet systematically differed from TBTrue (DSC values range = 0.38 to 0.69, and maximum HD range = 17.8 mm to 38.0 mm). Using expansion margins did not improve contour congruence and caused significant over-contoured volumes. CONCLUSION: Following OBS, surgical clips alone are not reliable radiographic surrogates of TB locations and accurate TB delineation is challenging. For complex OBS cases, indication of any type of partial breast irradiation is very questionable.

Management Strategies for Older Patients with Low-Risk Early-Stage Breast Cancer: A Physician Survey.

When managing older patients with lower-risk hormone-receptor-positive (HR+), HER2 negative (HER2-) early-stage breast cancer (EBC), the harms and benefits of adjuvant therapies should be taken into consideration. A survey was conducted among Canadian oncologists on the definitions of "low risk" and "older", practice patterns, and future trial designs. We contacted 254 physicians and 21% completed the survey (50/242). Most respondents (68%, 34/50) agreed with the definition of "low risk" HR+/HER2- EBC being node-negative and either: ≤3 cm and low histological grade, ≤2 cm and intermediate grade, or ≤1 cm and high grade. The most popular chronological and biological age definition for older patients was ≥70 (45%, 22/49; 45% 21/47). In patients ≥ 70 with low risk EBC, most radiation and medical oncologists would recommend post-lumpectomy radiotherapy (RT) and endocrine therapy (ET). Seventy-eight percent (38/49) felt that trials are needed to evaluate RT and ET's role in patients ≥ 70. The favored design was ET alone, vs. RT plus ET (39%, 15/38). The preferred primary and secondary endpoints were disease-free survival and quality of life, respectively. Although oncologists recommended both RT and ET, there is interest in performing de-escalation trials in patients ≥ 70.

Exploring the nausea experience among female patients with breast cancer; A pilot interview study.

INTRODUCTION: Nausea is a difficult symptom to report and measure in clinical trials. We conducted a pilot interview study to improve our understanding of the nausea experience. MATERIALS AND METHODS: Female patients with breast cancer that had experienced nausea during radiation therapy and/or chemotherapy underwent semi-structured interviews that focused on patient-defined and standard definitions, preferences for nausea grading scales, and nausea sub-features: intensity, location, timing/duration, character, associated symptoms, precipitating/alleviating factors, impact on quality of life. RESULTS: 10 patients were interviewed. Patients defined nausea more variably than vomiting and retching/dry heaving. An ordinal grading scale with a 0-10 intensity range was preferred over visual-analogue and qualitative scales. Patients had experienced different intensities of nausea and deemed reporting their worst, average and least intensities feasible. High-intensity episodes were deemed more problematic than low-intensity episodes regardless of their duration. The duration and character of nausea were difficult to describe. A range of associated symptoms, precipitating and alleviating factors were documented. Nausea had a detrimental impact on quality of life. CONCLUSIONS: Nausea has a range of subjective and objective features. Our pilot study provided valuable information that will inform the design of a planned larger survey study. Creating an operational clinical trial definition for nausea appears feasible.

Characterization of lymphatic malformations using primary cells and tissue transcriptomes.

Lymphatic malformations (LMs) are disfiguring congenital anomalies characterized by aberrant growth of lymphatic vessels. They are broadly categorized histopathologically as macrocystic and microcystic. Although sclerotherapy has shown some success in the treatment of macrocystic malformations, there has been less progress with developing treatment strategies for microcystic malformations. In this study, we characterized lymphatic endothelial cells isolated from lymphatic and lymphaticovenous malformations. When compared to cells from normal lymphatic vessels, we found that the primary cultured malformed cells are morphologically different and also exhibited differences in binding, proliferation, migration and tube formation. Transcriptome analysis identified several genes whose expression was substantially higher in malformed compared to normal lymphatic endothelium, including DIRAS3 and FOXF1. Further analysis of LM tissue samples revealed distinguishing gene expression patterns that could pave the way to understanding the molecular pathogenesis of LMs. Based on gene expression signatures, we propose a new hypothesis that the subtype of localized LMs could be formed because of disruptions in lymph node development.

Hypofractionation Is an Acceptable Alternative to Conventional Fractionation in the Treatment of Postlumpectomy Ductal Carcinoma In Situ With Radiotherapy.

PURPOSE: The standard dose of postlumpectomy radiotherapy (RT) for ductal carcinoma in situ (DCIS) is 50 Gy in 25 fractions using conventional fractionation (CF). However, in invasive carcinoma, hypofractionation (HF) with 40 to 42.6 Gy in 15 to 16 fractions has largely become a standard of care. The purpose of this study was to review the management of postlumpectomy DCIS in terms of RT dose-fractionation and its impact on local recurrence (LR), in one of the largest Canadian academic centers. METHODS AND MATERIALS: Between 2003 and 2008, a total of 348 women with DCIS were treated with postlumpectomy RT. Patient characteristics, histopathology, dose-fractionation, use of endocrine therapy, local, regional, contralateral breast recurrences, and cause of death were collected. Local recurrence-free survival was determined. Univariate and multivariate analyses were performed to identify risk factors for LR. RESULTS: The median age of the cohort was 59 years. Two hundred two (58%) patients received CF and 146 (42%) HF. Initially, the yearly proportion of HF was 34%, but increased up to 68% since 2007. Estrogen receptor was positive in 195 patients, and 43% of those received endocrine therapy. With a median follow-up of 64.8 months, 36 LRs were detected. The 5-year local recurrence-free survival rate was 94% for the HF group versus 91% for the CF group (P = .80). On multivariate analysis, only the use of endocrine therapy showed a trend towards decreasing LR (hazard ratio, 0.44; 95% confidence interval, 0.18-1.08; P = .07). CONCLUSIONS: The utilization of HF for DCIS postlumpectomy has increased over time and is a valid option as it results in similar rates of local control.

Salvage low-dose-rate (125)I partial prostate brachytherapy after dose-escalated external beam radiotherapy.

PURPOSE: To report outcomes on 5 patients treated with salvage partial low-dose-rate (LDR) 125-iodine ((125)I) permanent prostate seed brachytherapy (BT) for biopsy-proven locally persistent prostate cancer, following failure of dose-escalated external beam radiotherapy (EBRT). MATERIAL AND METHODS: A retrospective review of the Fox Chase Cancer Center prostate cancer database identified five patients treated with salvage partial LDR (125)I seed implant for locally persistent disease following dose-escalated EBRT to 76-84 Gy in 2 Gy per fraction equivalent. All patients had post-EBRT biopsies confirming unilateral locally persistent prostate cancer. Pre-treatment, EBRT and BT details, as well as post-treatment characteristics were documented and assessed. RESULTS: The median follow-up post-implant was 41 months. All five patients exhibited low acute genitourinary and gastrointestinal toxicities. Increased erectile dysfunction was noted in three patients. There were no biochemical failures following salvage LDR (125)I seed BT to date, with a median post-salvage PSA of 0.4 ng/mL. CONCLUSIONS: In carefully selected patients with local persistence of disease, partial LDR (125)I permanent prostate seed implant appears to be a feasible option for salvage local therapy with an acceptable toxicity profile. Further study is needed to determine long-term results of this approach.

Closed meloplication percutaneous cable suture technique.

The aging midface is caused by a complex process of soft tissue volume loss, gravitational changes, and attenuation of the ligaments involved. This process results in a skeletonized appearance and elongation of the eyelid cheek complex and a medial and inferior descent of the malar fat pads. Standard facelifting techniques have been unsuccessful in addressing these issues. The authors describe the technical aspects of the closed meloplication percutaneous cable suture technique in detail, evaluate 55 cases as a retrospective chart review over a 5-year period, and address the complication rate.

High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival.

Aberrant activation of Notch receptors has been shown to cause mammary tumors in mice. We therefore used in situ hybridization to analyze expression of Notch ligands and receptors in human breast cancer. High levels of JAG1 and NOTCH1 were noted in a subset of tumors with poor prognosis pathologic features (P < 0.05). We therefore used tissue microarrays to analyze the expression of these genes in a collection of breast cancers from patients representing a wide spectrum of clinical stages, and from whom associated follow-up survival data was available (n = 184). Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes [5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1(Hi vs. Lo) (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1(Hi vs. Lo) (P = 0.02)]. Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003). These data (a) identify novel prognostic markers for breast cancer, (b) suggest a mechanism whereby Notch is activated in aggressive breast tumors, and (c) may identify a signaling pathway activated in poor prognosis breast cancer which can be therapeutically targeted.

Dose-dependent response of FGF-2 for lymphangiogenesis.

Spatio-temporal studies on the growth of capillary blood vessels and capillary lymphatic vessels in tissue remodeling have suggested that lymphangiogenesis is angiogenesis-dependent. We revisited this concept by using fibroblast growth factor 2 (FGF-2) (80 ng) to stimulate the growth of both vessel types in the mouse cornea. When we lowered the dose of FGF-2 in the cornea 6.4-fold (12.5 ng), the primary response was lymphangiogenic. Further investigation revealed that vascular endothelial growth factor-C and -D are required for this apparent lymphangiogenic property of FGF-2, and when the small amount of accompanying angiogenesis was completely suppressed, lymphangiogenesis remained unaffected. Our findings demonstrate that there is a dose-dependent response of FGF-2 for lymphangiogenesis, and lymphangiogenesis can occur in the absence of a preexisting or developing vascular bed, i.e., in the absence of angiogenesis, in the mouse cornea.

Lymphangiogenesis new mechanisms.

A mouse model has been developed to study lymphangiogenesis dissociated from angiogenesis. bFGF implanted in a mouse cornea at a concentration below the threshold to induce angiogenesis potently induces lymphangiogenesis. This model has permitted a study of cellular and molecular mechanisms of lymphangiogenesis.