The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5–96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive ...chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.
MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18–70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0–1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical–pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005–002625–31. Recruitment is complete and further long-term follow-up is ongoing.
Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8–9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1–96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6–93·8) for chemotherapy versus 89·4% (86·8–91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48–0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 90.7% of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3–96·3) with chemotherapy versus 88·6% (83·5–92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points SE 2·8, 95% CI −0·5 to 10·4) and 90·2% (86·8–92·7) versus 90·0% (86·6–92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points 2·1, −4·0 to 4·4). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1–94·3) with chemotherapy and 89·2% (85·2–92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points SE 2·3, 95% CI −2·1 to 7·2) and 91·2% (87·2–94·0) versus 89·9% (85·8–92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points 2·4, −3·5 to 6·1).
With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.
European Commission Sixth Framework Programme.
Anastomotic leakage is a severe complication after low anterior resection for rectal cancer. With a global increase in registration initiatives, adapting uniform definitions and grading systems is ...highly relevant.
This study aimed to provide clinical parameters to categorize anastomotic leakage into subcategories according to the International Study Group of Rectal Cancer.
All of the patients who underwent a low anterior resection in the Netherlands with primary anastomosis were included using the population-based Dutch Surgical Colorectal Audit.
Data were derived from the Dutch Surgical Colorectal Audit.
The development of grade B anastomotic leakage (requiring invasive treatment but no surgery) versus grade C anastomotic leakage (requiring reoperation) was measured.
Overall, 4287 patients underwent low anterior resection with primary anastomosis. A total of 159 patients (4%) were diagnosed with grade B anastomotic leakage versus 259 (6%) with grade C. Hospital stay and intensive care unit visits were significantly higher in patients with grade C anastomotic leakage compared with patients with grade B leakage. Mortality in patients with grade C leakage was higher compared with grade B leakage, although nonsignificant (5.8% vs 2.5%; p = 0.12). Multivariate analysis showed that patients with diverting stomas (n = 2866) had a decreased risk of developing grade C leakage compared with grade B (OR = 0.17 (95% CI, 0.10-0.29)). Male patients had an increased risk of developing grade C anastomotic leakage, and patients receiving neoadjuvant treatment before surgery had an increased risk of developing grade B anastomotic leakage.
Some possibly relevant variables, such as smoking and nutritional status, were not recorded in the database.
Anastomotic leakage after low anterior resection for rectal cancer was a frequent observed complication in this cohort. Differences in clinical outcome suggest that grade B and C leakage should be considered separate entities in future registrations. In patients with a diverting stoma, the chances of experiencing grade C anastomotic leakage were reduced. See Video Abstract at http://links.lww.com/DCR/A315.
Objectives
To compare four previously published methods for rectal tumor response evaluation after chemoradiotherapy on MRI.
Methods
Twenty-two radiologists (5 rectal MRI experts, 17 ...general/abdominal radiologists) retrospectively reviewed the post-chemoradiotherapy MRIs of 90 patients, scanned at 10 centers (with non-standardized protocols). They applied four response methods; two based on T2W-MRI only (MRI tumor regression grade (mrTRG); split-scar sign), and two based on T2W-MRI+DWI (modified-mrTRG; DWI-patterns). Image quality was graded using a 0–6-point score (including slice thickness and in-plane resolution; sequence angulation; DWI b-values, signal-to-noise, and artefacts); scores < 4 were classified below average. Mixed model linear regression was used to calculate average sensitivity/specificity/accuracy to predict a complete response (versus residual tumor) and assess the impact of reader experience and image quality. Group interobserver agreement (IOA) was calculated using Krippendorff’s alpha. Readers were asked to indicate their preferred scoring method(s).
Results
Average sensitivity/specificity/accuracy was 57%/64%/62% (mrTRG), 36%/79%/66% (split-scar), 40%/79%/67% (modified-mrTRG), and 37%/82%/68% (DWI-patterns); mrTRG showed higher sensitivity but lower specificity and accuracy (
p
< 0.001) compared to the other methods. IOA was lower for the split scar method (0.18 vs. 0.39–0.43). Higher reader experience had a significant positive effect on diagnostic performance and IOA (except for the split scar sign); below-average imaging quality had a significant negative effect on diagnostic performance. DWI pattern was selected as the preferred method by 73% of readers.
Conclusions
Methods incorporating DWI showed the most favorable results when combining diagnostic performance, IOA, and reader preference. Reader experience and image quality clearly impacted diagnostic performance emphasizing the need for state-of-the-art imaging and dedicated radiologist training.
Key Points
•
In a multireader study comparing 4 MRI methods for rectal tumor response evaluation, those incorporating DWI showed the best results when combining diagnostic performance, IOA, and reader preference.
•
The most preferred method (by 73% of readers) was the “DWI patterns” approach with an accuracy of 68%, high specificity of 82%, and group IOA of 0.43.
• Reader experience level and MRI quality had an evident effect on diagnostic performance and IOA.
The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical ...utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy.
In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher.
A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease.
Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).
Summary Background Mechanical bowel preparation is a common practice before elective colorectal surgery. We aimed to compare the rate of anastomotic leakage after elective colorectal resections and ...primary anastomoses between patients who did or did not have mechanical bowel preparation. Methods We did a multicentre randomised non-inferiority study at 13 hospitals. We randomly assigned 1431 patients who were going to have elective colorectal surgery to either receive mechanical bowel preparation or not. Patients who did not have mechanical bowel preparation had a normal meal on the day before the operation. Those who did were given a fluid diet, and mechanical bowel preparation with either polyethylene glycol or sodium phosphate. The primary endpoint was anastomotic leakage, and the study was designed to test the hypothesis that patients who are given mechanical bowel preparation before colorectal surgery do not have a lower risk of anastomotic leakage than those who are not. The median follow-up was 24 days (IQR 17–34). We analysed patients who were treated as per protocol. This study is registered with ClinicalTrials.gov , number NCT00288496. Findings 77 patients were excluded: 46 who did not have a bowel resection; 21 because of missing outcome data; and 10 who withdrew, cancelled, or were excluded for other reasons. The rate of anastomotic leakage did not differ between both groups: 32/670 (4·8%) patients who had mechanical bowel preparation and 37/684 (5·4%) in those who did not (difference 0·6%, 95% CI −1·7% to 2·9%, p=0·69). Patients who had mechanical bowel preparation had fewer abscesses after anastomotic leakage than those who did not (2/670 0·3% vs 17/684 2·5%, p=0·001). Other septic complications, fascia dehiscence, and mortality did not differ between groups. Interpretation We advise that mechanical bowel preparation before elective colorectal surgery can safely be abandoned.
Objectives
To investigate sources of variation in a multicenter rectal cancer MRI dataset focusing on hardware and image acquisition, segmentation methodology, and radiomics feature extraction ...software.
Methods
T2W and DWI/ADC MRIs from 649 rectal cancer patients were retrospectively acquired in 9 centers. Fifty-two imaging features (14 first-order/6 shape/32 higher-order) were extracted from each scan using whole-volume (expert/non-expert) and single-slice segmentations using two different software packages (PyRadiomics/CapTk). Influence of hardware, acquisition, and patient-intrinsic factors (age/gender/cTN-stage) on ADC was assessed using linear regression. Feature reproducibility was assessed between segmentation methods and software packages using the intraclass correlation coefficient.
Results
Image features differed significantly (
p
< 0.001) between centers with more substantial variations in ADC compared to T2W-MRI. In total, 64.3% of the variation in mean ADC was explained by differences in hardware and acquisition, compared to 0.4% by patient-intrinsic factors. Feature reproducibility between expert and non-expert segmentations was good to excellent (median ICC 0.89–0.90). Reproducibility for single-slice versus whole-volume segmentations was substantially poorer (median ICC 0.40–0.58). Between software packages, reproducibility was good to excellent (median ICC 0.99) for most features (first-order/shape/GLCM/GLRLM) but poor for higher-order (GLSZM/NGTDM) features (median ICC 0.00–0.41).
Conclusions
Significant variations are present in multicenter MRI data, particularly related to differences in hardware and acquisition, which will likely negatively influence subsequent analysis if not corrected for. Segmentation variations had a minor impact when using whole volume segmentations. Between software packages, higher-order features were less reproducible and caution is warranted when implementing these in prediction models.
Key Points
• Features derived from T2W-MRI and in particular ADC differ significantly between centers when performing multicenter data analysis.
• Variations in ADC are mainly (> 60%) caused by hardware and image acquisition differences and less so (< 1%) by patient- or tumor-intrinsic variations.
• Features derived using different image segmentations (expert/non-expert) were reproducible, provided that whole-volume segmentations were used. When using different feature extraction software packages with similar settings, higher-order features were less reproducible.
Several factors are included in decision making for treatment of patients with locally advanced rectal cancer, including a trade-off between risks and gains of both clinical and functional outcomes. ...However, it is largely unknown which outcomes are most important to patients and whether this differs between patients and clinicians.
Both clinicians and patients treated for locally advanced rectal cancer were invited to fill out an online questionnaire, including a choice-based conjoint experiment. Participants were presented 14 comparisons of two hypothetical case presentations, characterized by different treatments and outcomes of care (6 attributes) and were asked to select the case with the best outcome at that moment. Hierarchical Bayes Estimation was used to calculate the relative importance (RI) of each of the six attributes.
In total, 94 patients and 128 clinicians completed the questionnaire. For patients, avoiding surgery with permanent stoma was most important (RI 24.4, 95%CI 21.88–26.87) and a 2-year difference in disease-free survival was least important (RI 5.6, 95%CI 4.9–6.2). Clinicians assigned highest importance to avoiding severe and daily worries about cancer recurrence (RI 30.7, 95%CI 29.1–32.4), while this was ranked 4th by patients (RI 17.9, 95%CI 16.5–19.4, p < 0.001).
When confronted with different outcomes within one case description, patients find the duration of disease free survival the least important. In addition, considerable differences were found between the importance assigned by patients and clinicians to clinical and functional outcomes, most notably in avoiding surgery with permanent stoma and worries about recurrence.
Objectives
To develop and validate a multiparametric model to predict neoadjuvant treatment response in rectal cancer at baseline using a heterogeneous multicenter MRI dataset.
Methods
Baseline ...staging MRIs (T2W (T2-weighted)-MRI, diffusion-weighted imaging (DWI) / apparent diffusion coefficient (ADC)) of 509 patients (9 centres) treated with neoadjuvant chemoradiotherapy (CRT) were collected. Response was defined as (1) complete versus incomplete response, or (2) good (Mandard tumor regression grade (TRG) 1–2) versus poor response (TRG3-5). Prediction models were developed using combinations of the following variable groups:
(1) Non-imaging: age/sex/tumor-location/tumor-morphology/CRT-surgery interval
(2) Basic staging: cT-stage/cN-stage/mesorectal fascia involvement, derived from (2a) original staging reports, or (2b) expert re-evaluation
(3) Advanced staging: variables from 2b combined with cTN-substaging/invasion depth/extramural vascular invasion/tumor length
(4) Quantitative imaging: tumour volume + first-order histogram features (from T2W-MRI and DWI/ADC)
Models were developed with data from 6 centers (
n
= 412) using logistic regression with the Least Absolute Shrinkage and Selector Operator (LASSO) feature selection, internally validated using repeated (
n
= 100) random hold-out validation, and externally validated using data from 3 centers (
n
= 97).
Results
After external validation, the best model (including non-imaging and advanced staging variables) achieved an area under the curve of 0.60 (95%CI=0.48–0.72) to predict complete response and 0.65 (95%CI=0.53–0.76) to predict a good response. Quantitative variables did not improve model performance. Basic staging variables consistently achieved lower performance compared to advanced staging variables.
Conclusions
Overall model performance was moderate. Best results were obtained using advanced staging variables, highlighting the importance of good-quality staging according to current guidelines. Quantitative imaging features had no added value (in this heterogeneous dataset).
Clinical relevance statement
Predicting tumour response at baseline could aid in tailoring neoadjuvant therapies for rectal cancer. This study shows that image-based prediction models are promising, though are negatively affected by variations in staging quality and MRI acquisition, urging the need for harmonization.
Key Points
This multicenter study combining clinical information and features derived from MRI rendered disappointing performance to predict response to neoadjuvant treatment in rectal cancer.
Best results were obtained with the combination of clinical baseline information and state-of-the-art image-based staging variables, highlighting the importance of good quality staging according to current guidelines and staging templates.
No added value was found for quantitative imaging features in this multicenter retrospective study. This is likely related to acquisition variations, which is a major problem for feature reproducibility and thus model generalizability.
In this pilot study, we investigated the feasibility of response prediction using digital 18 FFDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant ...chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial.
Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and 18 FFDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P ≤ 0.2, promising predictive features for response were selected.
Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy, early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features.
Both multiparametric MRI and 18 FFDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT.
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