Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is ...widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis.
In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12–20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774.
Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1–18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months 95% CI 3·45–5·06, 93 events) than in patients assigned to WBRT (median 3·0 months 2·86–3·25, 93 events; hazard ratio HR 0·47 95% CI 0·35–0·63; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 52% of 54 evaluable patients assigned to SRS vs 41 85% of 48 evaluable patients assigned to WBRT; difference −33·6% 95% CI −45·3 to −21·8, p<0·00031). Median overall survival was 12·2 months (95% CI 9·7–16·0, 69 deaths) for SRS and 11·6 months (9·9–18·0, 67 deaths) for WBRT (HR 1·07 95% CI 0·76–1·50; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three 3% of 93 patients in the SRS group vs eight 9% of 92 patients in the WBRT group) and cognitive disturbance (three 3% vs five 5%). There were no treatment-related deaths.
Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population.
National Cancer Institute.
Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the ...treatment of patients with brain metastases remains controversial.
To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT.
At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013.
The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone.
The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival.
There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients 63.5%) than when combined with WBRT (44/48 patients 91.7%; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 45.5% vs 16/17 94.1%; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 60% vs 17/18 94.4%; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04).
Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy.
clinicaltrials.gov Identifier: NCT00377156.
The American College of Surgeons Oncology Group Z1071 trial reported a false-negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting ...with node-positive breast cancer. One proposed method to decrease the FNR is clip placement in the positive node at initial diagnosis with confirmation of clipped node resection at surgery.
Z1071 was a multi-institutional trial wherein women with clinical T0-T4,N1-N2,M0 breast cancer underwent SLN surgery and axillary dissection (ALND) after neoadjuvant chemotherapy. In cases with a clip placed in the node, the clip location at surgery (SLN or ALND) was evaluated.
A clip was placed at initial node biopsy in 203 patients. In the 170 (83.7%) patients with cN1 disease and at least 2 SLNs resected, clip location was confirmed in 141 cases. In 107 (75.9%) patients where the clipped node was within the SLN specimen, the FNR was 6.8% (confidence interval CI: 1.9%-16.5%). In 34 (24.1%) cases where the clipped node was in the ALND specimen, the FNR was 19.0% (CI: 5.4%-41.9%). In cases without a clip placed (n = 355) and in those where clipped node location was not confirmed at surgery (n = 29), the FNR was 13.4% and 14.3%, respectively.
Clip placement at diagnosis of node-positive disease with removal of the clipped node during SLN surgery reduces the FNR of SLN surgery after neoadjuvant chemotherapy. Clip placement in the biopsy-proven node at diagnosis and evaluation of resected specimens for the clipped node should be considered when conducting SLN surgery in this setting.
Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a ...prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC.
Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%.
Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189;
= .002).
The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.
Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival.
To determine the effects of ...complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer.
The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected.
All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician.
Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point.
Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval CI, 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.
clinicaltrials.gov Identifier: NCT00003855.
This study sought to identify the risk of sudden cardiac death (SCD) associated with obstructive sleep apnea (OSA).
Risk stratification for SCD, a major cause of mortality, is difficult. OSA is ...linked to cardiovascular disease and arrhythmias and has been shown to increase the risk of nocturnal SCD. It is unknown if OSA independently increases the risk of SCD.
We included 10,701 consecutive adults undergoing their first diagnostic polysomnogram between July 1987 and July 2003. During follow-up up to 15 years, we assessed incident resuscitated or fatal SCD in relation to the presence of OSA, physiological data including the apnea-hypopnea index (AHI), and nocturnal oxygen saturation (O2sat) parameters, and relevant comorbidities.
During an average follow-up of 5.3 years, 142 patients had resuscitated or fatal SCD (annual rate 0.27%). In multivariate analysis, independent risk factors for SCD were age, hypertension, coronary artery disease, cardiomyopathy or heart failure, ventricular ectopy or nonsustained ventricular tachycardia, and lowest nocturnal O2sat (per 10% decrease, hazard ratio HR: 1.14; p = 0.029). SCD was best predicted by age >60 years (HR: 5.53), apnea-hypopnea index >20 (HR: 1.60), mean nocturnal O2sat <93% (HR: 2.93), and lowest nocturnal O2sat <78% (HR: 2.60; all p < 0.0001).
In a population of 10,701 adults referred for polysomnography, OSA predicted incident SCD, and the magnitude of risk was predicted by multiple parameters characterizing OSA severity. Nocturnal hypoxemia, an important pathophysiological feature of OSA, strongly predicted SCD independently of well-established risk factors. These findings implicate OSA, a prevalent condition, as a novel risk factor for SCD.
Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma ...(MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL.
To determine the impact of tumor biology on rates of breast-conserving surgery and pathologic complete response (pCR) after neoadjuvant chemotherapy.
The impact of tumor biology on the rate of ...breast-conserving surgery after neoadjuvant chemotherapy has not been well studied.
We used data from ACOSOG Z1071, a prospective, multicenter study assessing sentinel lymph node surgery after neoadjuvant chemotherapy in patients presenting with node-positive breast cancer from 2009 through 2011, to determine rates of breast-conserving surgery and pCR after chemotherapy by approximated biologic subtype.
Of the 756 patients enrolled on Z1071, 694 had findings available from pathologic review of breast and axillary specimens from surgery after chemotherapy. Approximated subtype was triple-negative in 170 (24.5%), human epidermal growth factor receptor 2 (HER2)-positive in 207 (29.8%), and hormone-receptor-positive, HER2-negative in 317 (45.7%) patients. Patient age, clinical tumor and nodal stage at presentation did not differ across subtypes. Rates of breast-conserving surgery were significantly higher in patients with triple-negative (46.8%) and HER2-positive tumors (43.0%) than in those with hormone-receptor-positive, HER2-negative tumors (34.5%) (P = 0.019). Rates of pCR in both the breast and axilla were 38.2% in triple-negative, 45.4% in HER2-positive, and 11.4% in hormone-receptor-positive, HER2-negative disease (P < 0.0001). Rates of pCR in the breast only and the axilla only exhibited similar differences across tumor subtypes.
Patients with triple-negative and HER2-positive breast cancers have the highest rates of breast-conserving surgery and pCR after neoadjuvant chemotherapy. Patients with these subtypes are most likely to be candidates for less invasive surgical approaches after chemotherapy.
Background Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series ...contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. Study Design We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. Results Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio HR 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. Conclusions Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥ 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years.
Summary Background Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived ...growth factor receptor α proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. Methods We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov , number NCT00041197. Findings All randomised patients were included in the analysis. At median follow-up of 19·7 months (minimum–maximum 0–56·4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% 95% CI 96–100 vs 83% 78–88 at 1 year; hazard ratio HR 0·35 0·22–0·53; one-sided p<0·0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 3% vs 0), abdominal pain (12 3% vs six 1%), and diarrhoea (ten 2% vs five 1%) in the imatinib group and hyperglycaemia (two <1% vs seven 2%) in the placebo group. Interpretation Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. Funding US National Institutes of Health and Novartis Pharmaceuticals.
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