Breast-Conserving Therapy is Associated with Improved Survival Without an Increased Risk of Locoregional Recurrence Compared with Mastectomy in Both Clinically Node-Positive and Node-Negative Breast Cancer Patients.

INTRODUCTION: Randomized trials demonstrated equivalent survival between breast-conserving surgery combined with radiotherapy (BCT) and mastectomy alone. Contemporary retrospective studies using pathological stage have reported improved survival with BCT. However, pathological information is unknown before surgery. To mimic real-world surgical decision-making, this study assesses oncological outcomes by using clinical nodal status. METHODS: Female patients aged 18-69 years who were treated with upfront BCT or mastectomy between 2006 and 2016 for T1-3N0-3 breast cancer were identified by using prospective, provincial database. The patients were divided into clinically node-positive (cN+) and node-negative (cN0) strata. Multivariable logistic regression was used to assess the effect of local treatment type on overall survival (OS), breast cancer-specific survival (BCSS), and locoregional recurrence (LRR). RESULTS: Of 13,914 patients, 8228 had BCT and 5686 had mastectomy. Mastectomy patients had higher-risk clinicopathological factors: pathologically positive axillary staging was 21% in BCT and 38% in mastectomy groups. Most patients received adjuvant systemic therapy. For cN0 patients, 7743 had BCT and 4794 had mastectomy. On multivariable analysis, BCT was associated with improved OS (hazard ratio [HR] 1.37, p < 0.001) and BCSS (HR 1.32, p < 0.001), whereas LRR was not different between the groups (HR 0.84, p = 0.1). For cN+ patients, 485 had BCT and 892 had mastectomy. On multivariable analysis, BCT was associated with improved OS (HR 1.46, p = 0.002) and BCSS (HR 1.44, p = 0.008), whereas LRR was not different between the groups (HR 0.89, p = 0.7). CONCLUSIONS: In the era of contemporary systemic therapy, BCT was associated with better survival than mastectomy, without an increased risk of locoregional recurrence for both cN0 and cN+ presentations.

Intra-individual comparison of 18F-sodium fluoride PET-CT and 99mTc bone scintigraphy with SPECT in patients with prostate cancer or breast cancer at high risk for skeletal metastases (MITNEC-A1): a multicentre, phase 3 trial.

BACKGROUND: Detection of skeletal metastases in patients with prostate cancer or breast cancer remains a major clinical challenge. We aimed to compare the diagnostic performance of 99mTc-methylene diphosphonate (99mTc-MDP) single-photon emission CT (SPECT) and 18F-sodium fluoride (18F-NaF) PET-CT for the detection of osseous metastases in patients with high-risk prostate or breast cancer. METHODS: MITNEC-A1 was a prospective, multicentre, single-cohort, phase 3 trial conducted in ten hospitals across Canada. Patients aged 18 years or older with breast or prostate cancer with a WHO performance status of 0-2 and with high risk or clinical suspicion for bone metastasis, but without previously documented bone involvement, were eligible. 18F-NaF PET-CT and 99mTc-MDP SPECT were done within 14 days of each other for each participant. Two independent reviewers interpreted each modality without knowledge of other imaging findings. The primary endpoint was the overall accuracy of 99mTc-MDP SPECT and 18F-NaF PET-CT scans for the detection of bone metastases in the per-protocol population. A combination of histopathological, clinical, and imaging follow-up for up to 24 months was used as the reference standard to assess the imaging results. Safety was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT01930812, and is complete. FINDINGS: Between July 11, 2014, and March 3, 2017, 290 patients were screened, 288 of whom were enrolled (64 participants with breast cancer and 224 with prostate cancer). 261 participants underwent both 18F-NaF PET-CT and 99mTc-MDP SPECT and completed the required follow-up for statistical analysis. Median follow-up was 735 days (IQR 727-750). Based on the reference methods used, 109 (42%) of 261 patients had bone metastases. In the patient-based analysis, 18F-NaF PET-CT was more accurate than 99mTc-MDP SPECT (84·3% [95% CI 79·9-88·7] vs 77·4% [72·3-82·5], difference 6·9% [95% CI 1·3-12·5]; p=0·016). No adverse events were reported for the 288 patients recruited. INTERPRETATION: 18F-NaF has the potential to displace 99mTc-MDP as the bone imaging radiopharmaceutical of choice in patients with high-risk prostate or breast cancer. FUNDING: Canadian Institutes of Health Research.

Impact of TAILORx on chemotherapy prescribing and 21-gene recurrence score-guided treatment costs in a population-based cohort of patients with breast cancer.

BACKGROUND: The trial assigning individualized options for treatment (Rx) (TAILORx) confirmed the predictive value of the 21-gene recurrence score (RS) assay in hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer and established thresholds for chemotherapy benefit in younger and older patients. Real-world chemotherapy use and RS-guided treatment costs in British Columbia post-TAILORx were examined. METHODS: The authors assembled 3 cohorts of HR-positive, HER2-negative, node-negative patients with breast cancer defined by diagnosis: before RS funding (cohort 1 [C1]: January 2013-December 2013), after introduction of public RS funding (cohort 2 [C2]: July 2015-June 2016), and after TAILORx results (cohort 3 [C3]: July 2018-June 2019). Chemotherapy use was compared between cohorts by age and RS. Budgetary impacts of RS testing on chemotherapy costs were evaluated pre- and post-TAILORx. RESULTS: Among the 2066 patients included, chemotherapy use declined by 19% after RS funding was introduced and by an additional 23% after TAILORx publication (P = .001). Reduction in chemotherapy use was significant for RS 11-20 tumors (C3 vs C2, P = .004). There was no significant change in chemotherapy use in patients >50 years old (C2:12% vs C3:10%, P = .22). RS testing was associated with higher cost savings post-TAILORx, except in patients 70 to 80 years old, where testing led to excess costs when adjusting for the low rate of RS-concordant chemotherapy prescribed. CONCLUSIONS: TAILORx has had population-based impacts on chemotherapy prescribing in intermediate RS tumors and patients ≤50 years old. The lower clinical use of RS and increased spending in patients 70-80 years old highlights the importance of careful selection of older candidates for high-cost genomic testing. LAY SUMMARY: The 21-gene recurrence score (RS) test helps predict whether patients with hormone-positive, HER2-negative, lymph node-negative breast cancer are likely to benefit from chemotherapy. The recent trial assigning individualized options for treatment (Rx) (TAILORx) found that patients with intermediate RS tumors did not benefit from chemotherapy. The authors assessed whether TAILORx results translated to real-world changes in chemotherapy prescribing patterns. In this study, chemotherapy use decreased by 23% after TAILORx, with the greatest reductions seen among intermediate RS tumors and younger patients. In contrast, RS testing had lower clinical value and increased treatment costs in elderly patients, which requires further study to ensure optimal care for this age group.

A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial. METHODS: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM). RESULTS: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model. CONCLUSIONS: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Sentinel Node Biopsy Should Not be Routine in Older Patients with ER-Positive HER2-Negative Breast Cancer Who Are Willing and Able to Take Hormone Therapy.

BACKGROUND: The SSO Choosing Wisely campaign recommended selective sentinel lymph node biopsy (SLNB) in clinically node-negative women aged ≥ 70 years with ER+ breast cancer. We sought to assess the association of SLNB positivity, adjuvant treatment, and survival in a population-based cohort. PATIENTS AND METHODS: Women aged ≥ 70 years treated for ER+ HER2- breast cancer between 2010 and 2016 were identified in our prospective provincial database. Overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Kaplan-Meier analysis. Multivariable logistic regression was used to assess the association of SLNB positivity with use of adjuvant treatments and survival outcomes. RESULTS: We identified 2662 patients who met study criteria. SLNB was positive in 25%. Increased use of chemotherapy (ChT), hormone therapy (HT), and radiotherapy (RT) was significantly associated with SLNB positivity. Five-year OS was 86%, and BCSS was 96% with median follow-up of 4.3 years. BCSS was worse with grade 3 disease (HR 4.1, 95% CI 2.1-8.1, p < 0.0001) and better with HT (HR 0.5 95% CI 0.3-0.9, p = 0.01). Patients with a positive SLNB treated without adjuvant therapy had lower BCSS (HR 3.2 95% CI 1.2-8.4, p = 0.017) than those with a negative SLNB, but patients with a positive SLNB treated with any combination of ChT, HT, and/or RT, had similar BCSS to those with a negative SLNB. CONCLUSIONS: BCSS in this population was excellent at 96%, and BCSS was similar with negative and positive SLNB when patients received HT. SLNB can be omitted in elderly patients willing to take HT.

Type and timing of systemic therapy use predict overall survival for patients with brain metastases treated with radiation therapy.

INTRODUCTION: This study aimed to investigate whether systemic therapy (ST) use surrounding radiation therapy (RT) predicts overall survival (OS) after RT for patients with brain metastases (BMs). METHODS: Provincial RT and pharmacy databases were used to review all adult patients in British Columbia, Canada, who received a first course of RT for BMs between 2012 and 2016 (n = 3095). Multivariate analysis on a randomly selected subset was used to develop an OS nomogram. RESULTS: In comparison to the 2096 non-recipients of ST after RT, the median OS of the 999 recipients of ST after RT was 5.0 (95% Confidence interval (CI) 4.1-6.0) months longer (p < 0.0001). Some types of ST after RT were independently predictive of OS: targeted therapy (hazard ratio (HR) 0.42, CI 0.37-0.48), hormone therapy (HR 0.45, CI 0.36-0.55), cytotoxic chemotherapy (HR 0.71, CI 0.64-0.79), and immunotherapy (HR 0.64, CI 0.37-1.06). Patients who discontinued ST after RT had 0.9 (CI 0.3-1.4) months shorter median OS than patients who received no ST before or after RT (p < 0.0001). In the multivariate analysis of the 220-patient subset, established prognostic variables (extracranial disease, performance status, age, cancer diagnosis, and number of BMs), and the novel variables "ST before RT" and "Type of ST after RT" independently predicted OS. The nomogram predicted 6- and 12-month OS probability and median OS (bootstrap-corrected Harrell's Concordance Index = 0.70). CONCLUSIONS: The type and timing of ST use surrounding RT predict OS for patients with BMs.

The impact of new systemic therapies on survival and time on hormonal treatment in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: A population-based study in British Columbia from 2003 to 2013.

BACKGROUND: The purpose of this study was to determine whether new systemic therapy regimens have resulted in improved survival and increased time on first- and second-line hormonal treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) over time. METHODS: Patients diagnosed with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC were identified across 3 time cohorts (2003-2005, 2007-2009, and 2011-2013). Data were prospectively collected. Cases with previous, synchronous, or subsequent contralateral breast cancer were excluded. The types of first- and second-line therapies, the times on first- and second-line hormonal treatment, and the median survival times were compared across the cohorts. RESULTS: Within the time period analyzed, 9 new adjuvant systemic therapies (with or without neoadjuvant therapy) and 2 metastatic systemic therapies were approved at BC Cancer for the treatment of HR-positive, HER2-negative MBC. In the 3 time cohorts, 3953 patients diagnosed with MBC were identified. Among the 2432 patients (62%) who had HR-positive/HER2-negative disease, 2197 (90%) received at least 1 line of systemic therapy after the diagnosis of MBC, and 80% of these patients (1752 of 2197) received first- and/or second-line hormonal treatment. The median duration on hormonal treatment was 9.0 months for the first line and 6.1 months for the second line. The durations were similar across the time cohorts (range for the first line, 8.9-9.0 months; range for the second line, 6.0-6.1 months). The median survival for the entire study population was 2.0 years (95% confidence interval, 1.8-2.1 years), and there was no significant difference between the cohorts (range, 1.9-2.0 years). CONCLUSIONS: Even though more adjuvant and metastatic systemic therapies have been approved since 2003, population-level gains in survival and the time on hormonal treatment for patients with HR-positive, HER2-negative MBC have not been made over the course of a decade.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

LINAC based stereotactic radiosurgery for multiple brain metastases: guidance for clinical implementation.

Introduction: Stereotactic radiosurgery (SRS) is a promising treatment option for patients with multiple brain metastases (BM). Recent technical advances have made LINAC based SRS a patient friendly technique, allowing for accurate patient positioning and a short treatment time. Since SRS is increasingly being used for patients with multiple BM, it remains essential that SRS be performed with the highest achievable quality in order to prevent unnecessary complications such as radionecrosis. The purpose of this article is to provide guidance for high-quality LINAC based SRS for patients with BM, with a focus on single isocenter non-coplanar volumetric modulated arc therapy (VMAT). Methods: The article is based on a consensus statement by the study coordinators and medical physicists of four trials which investigated whether patients with multiple BM are better palliated with SRS instead of whole brain radiotherapy (WBRT): A European trial (NCT02353000), two American trials and a Canadian CCTG lead intergroup trial (CE.7). This manuscript summarizes the quality assurance measures concerning imaging, planning and delivery. Results: To optimize the treatment, the interval between the planning-MRI (gadolinium contrast-enhanced, maximum slice thickness of 1.5 mm) and treatment should be kept as short as possible (< two weeks). The BM are contoured based on the planning-MRI, fused with the planning-CT. GTV-PTV margins are minimized or even avoided when possible. To maximize efficiency, the preferable technique is single isocenter (non-)coplanar VMAT, which delivers high doses to the target with maximal sparing of the organs at risk. The use of flattening filter free photon beams ensures a lower peripheral dose and shortens the treatment time. To bench mark SRS treatment plan quality, it is advisable to compare treatment plans between hospitals. Conclusion: This paper provides guidance for quality assurance and optimization of treatment delivery for LINAC-based radiosurgery for patients with multiple BM.

Visual Outcomes and Local Control After Fractionated Stereotactic Radiotherapy for Optic Nerve Sheath Meningioma.

PURPOSE: To review the outcomes of patients with optic nerve sheath meningiomas (ONSM) treated with fractionated stereotactic radiotherapy. METHODS: Patient characteristics, treatment, and outcomes were analyzed for all patients with primary and secondary ONSM treated from 2001 to 2012. Clinically significant visual acuity change was defined as a 2-line change on the Snellen eye chart from pre-fractionated stereotactic radiotherapy. RESULTS: Forty-one patients were treated: 23 patients with primary ONSM and 18 patients with secondary ONSM. The median age at diagnosis was 56 years. The median visual follow up was 3.8 years and the median radiologic follow up was 4.4 years. At diagnosis, 36% had normal vision (20/20-20/40), 10% had mild impairment (<20/40-20/60), 20% had moderate visual impairment (<20/60-20/200), 27% had severe impairment (<20/200), and 7% had no light perception. Common acute side effects were headache (32%) and nausea (15%); 15% of patients required corticosteroids during stereotactic radiotherapy. Chronic toxicities included retinopathy (7%), pituitary dysfunction (13%), chronic ocular pain (5%), and cataracts (2%). Visual acuity was stable in 65%, improved in 27%, and decreased in 8% of patients. Visual fields were stable in 70%, improved in 21%, and reduced in 9%. Actuarial 5-year local control rates were 100% for primary ONSM and 88% for secondary ONSM. Actuarial 5-year visual preservation rates were 100% for primary ONSM and 86% for secondary ONSM. CONCLUSIONS: Fractionated stereotactic radiotherapy for primary and secondary ONSM was well tolerated and provides excellent local control and visual preservation. Longer follow up is required to determine the risk of late ocular and pituitary sequelae.

Provincial development of a patient-reported outcome initiative to guide patient care, quality improvement, and research.

The BC Cancer Agency Radiotherapy (RT) program started the Prospective Outcomes and Support Initiative (POSI) at all six centres to utilize patient-reported outcomes for immediate clinical care, quality improvement, and research. Patient-reported outcomes were collected at time of computed tomography simulation via tablet and 2 to 4 weeks post-RT via either tablet or over the phone by a registered nurse. From 2013 to 2016, patients were approached on 20,150 attempts by POSI for patients treated with RT for bone metastases (52%), brain metastases (11%), lung cancer (17%), gynecological cancer (16%), head and neck cancer (2%), and other pilots (2%). The accrual rate for all encounters was 85% (n = 17,101), with the accrual rate varying between the lowest and the highest accruing centre from 78% to 89% ( P < .001) and varying by tumour site ( P < .001). Using the POSI database, we have performed research and quality improvement initiatives that have changed practice.

Miliary metastases are associated with epidermal growth factor receptor mutations in non-small cell lung cancer: a population-based study.

BACKGROUND: Miliary metastases are characterized by metastatic nodules that are diffuse, innumerable and small. The purpose of this study was to examine the incidence, prognostic significance and impact of epidermal growth factor receptor (EGFR) mutations for miliary metastases from non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients were identified from a Provincial cancer registry (British Columbia, Canada) for the period 2010-2012. Inclusion criteria were stage IV NSCLC at presentation and conclusive EGFR mutation testing. Miliary metastases were defined by subjective and objective radiographic criteria. The primary endpoint was the incidence of miliary lung, brain and liver metastases. Secondary endpoints were survival and the prognostic implication for each site of miliary metastases. RESULTS: For 543 patients, the total number of brain, lung and liver metastases were 165 (30.4%), 290 (53.4%) and 67 (12.3%), respectively. The EGFR mutation positive (EGFR+) subgroup had a significantly higher 3-year cumulative incidence of miliary brain (4.1 vs. 0.5%, p = .015) and miliary lung (11.6 vs. 3.3%, p < .001) metastases compared to EGFR wild type (WT). A greater proportion of metastases from EGFR + cancers were miliary for brain (8.5 vs. 1.7%, p = .035) and lung (18.9 vs. 6.9%, p = .003) sites. Only non-miliary brain (HR = 1.45) and liver (HR = 1.70) metastases predicted for poor overall survival. CONCLUSIONS: Mutations in EGFR were associated with a higher rate of miliary brain and lung metastases. The presence of miliary metastases did not predict for poor overall survival.

A Cross-Sectional Cohort Study of Cerebrovascular Disease and Late Effects After Radiation Therapy for Craniopharyngioma.

BACKGROUND: The study objective was to describe radiation-induced vascular abnormalities, stroke prevalence, and stroke risk factors in survivors of childhood craniopharyngioma. PROCEDURE: Twenty survivors of childhood craniopharyngioma who received radiotherapy (RT) were included in the study. A clinical history, quality of life assessment, cognitive functioning assessment, magnetic resonance angiogram or computed tomography angiogram, fasting lipid profile, and fasting glucose or hemoglobin A1c test were obtained. RESULTS: Median age at diagnosis was 10.3 years and median age at time of study was 29.0 years. Vascular abnormalities were detected in six (32%) of 19 patients' angiograms (vascular stenosis, decreased artery size, aneurysm, cavernoma, and small vessel disease). Five (25%) of 20 patients experienced a stroke after RT. Median time since RT was 27.8 versus 9.1 years in patients with versus without vascular abnormalities (P = 0.02). A low level of high-density lipoproteiin (HDL) was present in 100% (5/5) of patients who had a post-RT stroke as compared with 13% (2/15) of patients who did not have any post-RT stroke (P = 0.02). Previous stroke had occurred in 0% (0/5) of patients receiving growth hormone (GH) replacement at the time of study, compared to 40% (6/15) of patients who were not receiving GH replacement (P = 0.09). CONCLUSIONS: Patients with craniopharyngioma treated with RT have a high prevalence of stroke and vascular abnormalities, particularly those with low HDL and longer duration of time since RT. There is a trend to suggest that continual GH replacement may reduce the risk of stroke. These patients should undergo careful monitoring and aggressive modification of stroke risk factors.

Stereotactic Radiosurgery for Metastases in Eloquent Central Brain Locations.

BACKGROUND: To examine stereotactic radiosurgery (SRS) following whole brain radiotherapy for metastases in eloquent, central brain locations: brainstem, thalamus, and basal ganglia. METHODS: We conducted a retrospective review of patients with metastases in eloquent, central brain locations who were treated with SRS between January 2000 and April 2012. All patients had whole brain radiotherapy. Patients eligible for SRS had one to three brain metastases, metastasis size ≤4 cm, and Karnofsky performance status ≥70. Local progression-free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS: For 24 patients, the median age was 50 years (range, 36-73). Metastases by location were: 11 brainstem, 9 thalamus, and 5 basal ganglia. The median metastasis size was 15 mm (range, 2-33) and the median SRS dose prescription was 15 Gy (range, 12-24). The median local progression-free survival was 13.7 months and median overall survival was 16.4 months. Compared with a cohort of 188 patients with noneloquent brain metastases receiving a median dose of 24 Gy, overall survival of 10.8 months was not significantly different (p=0.16). The only symptomatic complication was grade 2 headache in 8.3%. Asymptomatic adverse radiologic events were radionecrosis in two (8.3%), peritumoural edema in four (16.7%), and hemorrhage in one patient (4.2%). CONCLUSIONS: Lower SRS marginal doses do not appear to compromise survival in patients with eloquently located brain metastases compared with higher doses for other brain metastases, with minimal symptomatic complications.

Machine Learning to Predict the Need for Postmastectomy Radiotherapy after Immediate Breast Reconstruction.

Background: Post mastectomy radiotherapy (PMRT) is an independent predictor of reconstructive complications. PMRT may alter the timing and type of reconstruction recommended. This study aimed to create a machine learning model to predict the probability of requiring PMRT after immediate breast reconstruction (IBR). Methods: In this retrospective study, breast cancer patients who underwent IBR from January 2017 to December 2020 were reviewed and data were collected on 81 preoperative characteristics. Primary outcome was recommendation for PMRT. Four algorithms were compared to maximize performance and clinical utility: logistic regression, elastic net (EN), logistic lasso, and random forest (RF). The cohort was split into a development dataset (75% of cohort for training-validation) and 25% used for the test set. Model performance was evaluated using area under the receiver operating characteristic curve (AUC), precision-recall curves, and calibration plots. Results: In a total of 800 patients, 325 (40.6%) patients were recommended to undergo PMRT. With the training-validation dataset (n = 600), model performance was logistic regression 0.73 AUC [95% confidence interval (CI) 0.65-0.80]; RF 0.77 AUC (95% CI, 0.74-0.81); EN 0.77 AUC (95% CI, 0.73-0.81); logistic lasso 0.76 AUC (95% CI, 0.72-0.80). Without significantly sacrificing performance, 81 predictive factors were reduced to 12 for prediction with the EN method. With the test dataset (n = 200), performance of the EN prediction model was confirmed [0.794 AUC (95% CI, 0.730-0.858)]. Conclusion: A parsimonious accurate machine learning model for predicting PMRT after IBR was developed, tested, and translated into a clinically applicable online calculator for providers and patients.

Toward a Skin Dose-Area Metric Predictive of Moist Desquamation Using In Vivo Skin Dosimetry and Skin Assessments.

Purpose: Moist desquamation (MD) is a concerning acute side effect of radiation therapy for breast cancer, often seen in skin folds for patients having large or pendulous breasts. In vivo skin dosimetry, clinical assessments, and patient-reported skin reactions were used to determine a relationship between dose-area metrics and the development of MD, to lend insight into skin tolerances and possibly guide future treatment planning dose constraints. Methods and Materials: Skin dose was measured using GafChromic film on the inner surface of an early prototype carbon-fiber accessory for breast support to remove the inframammary fold in 20 patients at high risk of developing MD undergoing adjuvant whole breast radiation therapy. Prescribed doses were 42.5 Gray (Gy) in 16 fractions or 50 Gy in 25 fractions using 6 to 15 MV x-rays. To account for fraction size differences, analysis was performed using the equivalent dose in 2 Gy fractions using α/ß = 11 (EQD211). MD was assessed out to 2 weeks post radiation therapy by trained therapists and by a patient-reported outcome questionnaire. Results: Statistically significant differences in areas receiving 30 to 48 Gy (EQD211) were observed between patients who did and did not develop MD in the inframammary area. Patients receiving EQD211 maximum dose ≤ 46 Gy and ≥ 38 Gy to ≤ 50 cm2 of their breast skin did not develop MD. Conclusions: The findings of this study offer insight into the relationship between skin toxicity and areas of skin irradiated to doses up to 50 Gy. Potential skin dose constraints to test in future studies to prevent MD are suggested.

Breast conserving surgery combined with radiation therapy offers improved survival over mastectomy in early-stage breast cancer.

INTRODUCTION: Landmark trials established equivalent survival regardless of extent of breast surgery in early-stage breast cancer. However, recent studies suggest a survival advantage for breast conserving surgery (BCS) with radiotherapy (BCT). This study assesses the impact of type of surgery on overall survival (OS), breast cancer specific survival (BCSS) and local recurrence (LR) in a modern population-based cohort. METHODS: Female patients aged ≥18, pT1-2pN0, who had surgery between 2006 and 2016 were identified from Breast Cancer Outcome Unit prospective database. Neoadjuvant chemotherapy patients were excluded. Multivariable Cox regression was used to assess the effect of surgical procedure on OS, BCSS, and LR on cohort with complete data. RESULTS: BCT was performed in 8422 patients and TM in 4034 patients. The baseline characteristics differed between the groups. Mean follow up was 8.3 years. BCT was associated with increased OS HR 1.37, p < 0.001, BCSS survival HR 1.49, p < 0.001, and similar LR HR 1.00, p > 0.90. CONCLUSION: This study supports that in early-stage breast cancer, BCT has improved BCSS compared to TM without an increased risk of LR.

Protocol for a systematic review with prospective individual patient data meta-analysis in EGFR-mutant NSCLC with brain metastases to assess the effect of SRS+osimertinib compared to osimertinib alone: the STARLET Collaboration.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice. METHODS: Randomised controlled trials will be eligible if they include participants with BM arising from EGFR-mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform's Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups. ETHICS AND DISSEMINATION: Approved by each trial's ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION: CRD42022330532.