Whole Brain Radiotherapy Versus Stereotactic Radiosurgery in Poor-Prognosis Patients with One to 10 Brain Metastases: A Randomised Feasibility Study.

AIMS: A significant proportion of patients with brain metastases have a poor prognosis, with a life expectancy of 3-6 months. To determine the optimal radiotherapeutic strategy for brain metastases in this population, we conducted a randomised feasibility study of whole brain radiotherapy (WBRT) versus stereotactic radiosurgery (SRS). MATERIALS AND METHODS: Patients with a life expectancy of 3-6 months and between one and 10 brain metastases with a diameter ≤4 cm were enrolled at six Canadian cancer centres. Patients were randomly assigned (1:1) to receive either WBRT (20 Gy in five fractions) or SRS (15 Gy in one fraction). The primary end point was the rate of accrual per month. Secondary feasibility and clinical end points included the ratio of accrued subjects to screened subjects. This trial is registered with ClinicalTrials.gov (number NCT02220491). RESULTS: In total, 210 patients were screened to enrol 22 patients into the trial; 20 patients were randomised between the two arms. Two patients did not receive treatment because one patient died and another patient withdrew consent after being enrolled. Patients were accrued between January 2015 and November 2017; the accrual rate was 0.63 patients/month. The most common reasons for exclusion were anticipated median survival outside the required range (n = 40), baseline Karnofsky Performance Score below 70 (n = 28) and more than 10 brain metastases (n = 28). The median follow-up was 7.0 months and the median survival was 7.0 months for all patients in the trial. The median intracranial progression-free survival was 1.8 months in the SRS arm and 9.2 months in the WBRT arm. There were five grade 3+ toxicities in the SRS arm and one grade 3+ toxicity in the WBRT arm; no grade 5 toxicities were observed. The cumulative rates of retreatment were 40% in the SRS arm and 40% in the WBRT arm. CONCLUSIONS: A randomised trial evaluating WBRT versus SRS in patients with one to 10 metastases and a poor prognosis is feasible. A slower than expected accrual rate and difficulties with accurate prognostication were identified as issues in this feasibility study. A larger phase III randomised trial is planned to determine the optimal treatment in this patient population.

In the Era After the European Organisation for Research and Treatment of Cancer 'Boost' Study, is the Additional Radiotherapy to the Breast Tumour Bed Still Beneficial for Young Women?

AIMS: The European Organisation for Research and Treatment of Cancer (EORTC) 22,881-10,882 trial showed significant benefit of a radiotherapy boost (RTB) in women ≤40 years in a pre-hormone therapy (HT) era. We determined how the use of HT and RTB changed in response to clinical guidelines and whether the benefit of routine RTB was still observed in the HT era. MATERIALS AND METHODS: Between 1996 and 2004, a provincial database identified all women ≤40 years with breast cancer who met the inclusion criteria of the EORTC trial. In total, 411 patients were classified into three eras defined by the guidelines: era 1 (discretionary HT, discretionary RTB); era 2 (routine HT, discretionary RTB); era 3 (routine HT, routine RTB). HT use, RTB use and cumulative incidence of local recurrence were calculated and compared across eras. RESULTS: HT use increased after the first policy change from 13% to 75% for oestrogen receptor-positive patients (P < 0.01). RTB use also increased from 33% to 76% following the second policy change (P < 0.01). At 10 years, the cumulative incidence of local recurrence was 12% in era 1, 6% in era 2 and 6% in era 3 (era 2 versus era 3, P = 0.92). For patients in the routine HT era (eras 2 and 3 combined) there was no significant difference in local recurrence between RTB and 'no RTB' patients (6% versus 7%, P = 0.81). CONCLUSIONS: The routine use of HT and RTB increased significantly after new practice guidelines. Introduction of the HT guideline was associated with a 6% improvement in local recurrence at 10 years. No improvement in local recurrence was associated with the introduction of the RTB guideline in the HT era. The routine use of a boost in unselected young women with negative margins should be re-evaluated in the current HT era.

Impact of pathologic complete response on survival after neoadjuvant chemotherapy in early-stage breast cancer: a population-based analysis.

BACKGROUND: Achieving a pathologic complete response (pCR) has been associated with improved long-term outcomes in clinical trials. However, the benefit of achieving pCR across subtypes and its prognostic effect on real-world outcomes has not been well described. METHODS: A retrospective analysis of the Breast Cancer Outcomes Unit database was undertaken to identify patients with stage I-III breast cancer treated with neoadjuvant chemotherapy from 2005 to 2010 in British Columbia. Patients were separated into two groups: those with pCR and those with residual invasive disease in the breast/axillary lymph nodes (RD). The primary endpoint was relapse-free survival (RFS). Key secondary endpoints included breast cancer-specific survival (BCSS) and overall survival (OS). RESULTS: Of 267 patients identified, 74 patients (28%) achieved pCR and 193 patients (72%) had RD. Median follow-up was 7.5 years. The 5-year RFS was higher in the pCR group compared to the RD group (84% vs 70%; HR 0.45, p = 0.011). The 5-year BCSS was also higher in the pCR group than in the RD group (90% vs 77%; HR 0.39, p = 0.014). In multivariable analyses, pCR was associated with improved RFS (HR 0.39, p = 0.0077) and BCSS (HR 0.35, p = 0.015), whereas traditional pathological prognostic factors were not. Patients with TNBC who achieved pCR had improved RFS and BCSS compared to those with RD (HR 0.26, p = 0.020 and HR 0.35, p = 0.090, respectively). A similar but non-statistically significant trend was seen in the HER-2-positive and ER + subtypes. CONCLUSIONS: Achieving pCR after neoadjuvant chemotherapy was associated with clinically meaningful improvements in survival parameters in a real-world setting. The cumulative data support pCR as a valid surrogate endpoint in both clinical trials and population-based settings.

Using proliferative markers and Oncotype DX in therapeutic decision-making for breast cancer: the B.C. experience.

BACKGROUND: Proliferative scoring of breast tumours can guide treatment recommendations, particularly for estrogen receptor (er)-positive, her2-negative, T1-2, N0 disease. Our objectives were to □ estimate the proportion of such patients for whom proliferative indices [mitotic count (mc), Ki-67 immunostain, and Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.) recurrence score (rs)] were obtained.□ compare the indices preferred by oncologists with the indices available to them.□ correlate Nottingham grade (ng) and its subcomponents with Oncotype dx.□ assess interobserver variation. METHODS: All of the er-positive, her2-negative, T1-2, N0 breast cancers diagnosed from 2007 to 2011 (n = 5110) were linked to a dataset of all provincial breast cancers with a rs. A 5% random sample of the 5110 cancers was reviewed to estimate the proportion that had a mc, Ki-67 index, and rs. Correlation coefficients were calculated for the rs with ng subcomponent scores. Interobserver variation in histologic grading between outside and central review pathology reports was assessed using a weighted kappa test. RESULTS: During 2007-2011, most cancers were histologically graded and assigned a mc; few had a Ki-67 index or rs. The ng and mc were significantly positively correlated with rs. The level of agreement in histologic scoring between outside and central pathology reports was good or very good. Very few cases with a low mc had a high rs (1.8%). CONCLUSIONS: Patients with low ng and mc scores are unlikely to have a high rs, and thus are less likely to benefit from chemotherapy. In the context of limited resources, that finding can guide clinicians about when a rs adds the most value.