Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments. METHODS: Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated. RESULTS: Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. CONCLUSION: Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies

DCE MRI and DW Imaging for response prediction and measurement of locally advanced mamma carcinoma treated by neoadjuvant chemotherapy; results of patients treated in Deventer Hospital from 2006 to 2012.

Introduction: Neoadjuvant chemotherapy (NAC) is being used in increased extent for treatment of breast carcinoma. The success of NAC is highly dependent on reliable assessment of tumor response to NAC. The current method for response assessment using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1 criteria) has limitations. Diffusion-Weighted Imaging (DW Imaging), a very promising new magnetic resonance imaging (MRI) modality, is not considered in the criteria. Also, phase of imaging for dynamic contrast enhanced magnetic resonance imaging (DCE MRI) is not specified. Purpose: The study’s purpose was to find solutions for the shortcoming the RECIST 1.1 criteria still have. Parameters provided by DCE MRI and DW Imaging have been studied to find the best MRI method for all three MRI’s made during the course of NAC. Methods: In this retrospective study, 89 patients (90 tumors) with invasive breast cancer were included. DCE MRI and DW Imaging were performed before NAC, after 3 cycles of NAC and before surgery. If possible, tumor diameter was measured using RECIST 1.1 criteria of the early and late enhancement area as well as the washout area. The apparent diffusion coefficient (ADC) was derived as well. These parameters were correlated with the golden standard; final histopathology. Final histopathology was categorized in 2 ways. It was divided in pathologic complete response (pCR) and non-pathologic complete response (non-pCR). Secondly, it was categorized in the Miller and Payne grading system. Results: Pretreatment ADC values significantly differed for the pCR and non-pCR groups (mean ± SD, 15.46 ± 0.71 x 10-2 mm2/s versus, 12.72 ± 0.30 x 10-2 mm2/s, p = 0.002). Best cut-off value of ADC for the prediction of pCR was 11.95 x 10-2 mm2/s yielding a sensitivity of 100% and specificity of 43%. The aggressive HER2 enriched and triple negative subtype had higher pretreatment ADC values than the hormone positive tumors; (mean ± SD, 14.522 ± 2.534 x 10-2 mm2/s, 14.143 ± 2.862 x 10-2 mm2/s versus 12.357 ± 2.332 x 10-2 mm2/s). For early response measurements, the change of largest diameter of the late enhancement area was best in predicting pathologic outcome. An odds ratio of 1,038 (CI 95% 1.013-1.063), p = 0.003 to predict pCR and 1.028 (CI 95% 1.008-1.048) , p = 0.005 to predict Miller and Payne grades per per cent tumor diameter decrease was found. Percentage increase of ADC was not suitable for prediction of pCR or Miller and Payne grades (p = 0.465 and 0.676). DCE MRI at preoperative MRI had a sensitivity of 97% and a specificity of 100% for prediction of pCR if measurements at late enhancement and washout were combined. Residual tumor diameter measurements by measuring washout area had highest correlation with pathological tumor size with Pearson’s correlation of 0.644 and regression coefficient of 0.784 (CI 95% 0.271-1.297). Conclusion: Best MRI method is different for the three MRI’s made during the course of NAC for breast cancer. For the pretreatment MRI, DW imaging’s parameter ADC proves to be a surrogate marker for detection of aggressive breast tumors and prediction of pCR. For early response measurements, DCE MRI is superior to DW Imaging. Measurement of percentage change of late enhancement area is best for response measurement and prediction of reaching pCR. At preoperative MRI, DCE MRI was very accurate, with a sensitivity of 100% and a specificity of 97%, for prediction of pCR if measurements at late enhancement and washout were combined. If residual tumor is present, diameter measurements of washout area is best in estimation of size.

Endovascular treatment versus no endovascular treatment after 6–24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands:a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial

Background: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6–24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). Methods: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. Findings: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2–5] vs 4 [2–6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20–2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44–1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49–14·10]). Interpretation: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6–24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow. Funding: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences &amp; Health, and the Netherlands Brain Foundation.</p