Progression Of Non-target Lesions Research Articles

Perivascular fat attenuation index value and plaque volume increased in non-target lesions of coronary arteries after stenting.

Progression of non-target lesions (NTLs) after stenting has been reported and is associated with the triggering of an inflammatory response. The perivascular fat attenuation index (FAI) may be used as a novel imaging biomarker for the direct quantification of coronary inflammation. To investigate whether FAI values can help identify changes in inflammation status in patients undergoing stent implantation, especially in NTLs. Patients who underwent pre- and post-stenting coronary computed tomography angiography (CCTA) examination between January 2015 and February 2021 were consecutively enrolled. The pre- and post-stenting FAIs of the full coronary arteries were compared in both the non- and stent-implanted coronary arteries. Moreover, local FAI values were measured and compared between the NTLs and target lesions in the stent implantations. We also compared changes in plaque type and volume in NTLs before and after stenting. A total of 89 patients (mean age 61 years; male 59) were enrolled. The perivascular FAI values in the full coronary arteries decreased after stenting in both the non- and stent-implanted coronary arteries, similar to those in the target lesions. Conversely, the perivascular FAI values in the NTLs increased after stenting (p < 0.05). In addition, the plaque volumes significantly increased in the NTLs after stenting, regardless of whether they were non-calcified, mixed, or calcified (p < 0.05). Perivascular FAI values and plaque volumes increased in the NTLs after stenting. Perivascular FAI can be a promising imaging biomarker for monitoring coronary inflammation after stenting and facilitate long-term monitoring in clinical settings. Perivascular fat attenuation index, a non-invasive imaging biomarker, may help identify coronary arteries with high inflammation in non-target lesions and facilitate long-term monitoring, potentially providing an opportunity for more targeted treatment. • Perivascular fat attenuation index (FAI) values and plaque volumes increased in the non-target lesions (NTLs) after stenting, suggesting potential focal inflammation progression after stenting. However, stenting along with anti-inflammatory treatment ameliorated inflammation in the full coronary arteries. • Perivascular FAI, a non-invasive imaging biomarker, may help identify coronary arteries with high inflammation in NTLs and facilitate long-term monitoring, potentially providing an opportunity for more targeted treatment.

Association Between Stent Implantation and Progression of Nontarget Lesions in a Rabbit Model of Atherosclerosis.

Progression of nontarget lesions (NTLs) after percutaneous coronary intervention (PCI) has been reported. However, it remains unknown whether progression of NTLs was causally related to stenting. This study was undertaken to test the hypothesis that stent implantation triggers acute phase response and systemic inflammation which may be associated with progression of NTLs. Thirty New Zealand rabbits receiving endothelial denudation and atherogenic diet were randomly divided into stenting, sham, and control groups. Angiography and intravascular ultrasonography were performed in the stenting and sham groups, and stent implantation performed only in the stenting group. Histopathologic study was conducted and serum levels of APPs (acute phase proteins) measured in all rabbits. Proteomics analysis was performed to screen the potential proteins related to NTLs progression after stent implantation. The serum levels of APPs and inflammatory cytokines were measured in 147 patients undergoing coronary angiography or PCI. Plaque burden in the NTLs was significantly increased 12 weeks after stent implantation in the stenting group versus sham group. Serum levels of APPs and their protein expression in NTLs were significantly increased and responsible for stenting-triggered inflammation. In patients receiving PCI, serum levels of SAA-1 (serum amyloid A protein 1), CRP (C-reactive protein), TNF (tumor necrosis factor)-α, and IL (interleukin)-6 were substantially elevated up to 1 month post-PCI. In a rabbit model of atherosclerosis, stent implantation triggered acute phase response and systemic inflammation, which was associated with increased plaque burden and pathological features of unstable plaque in NTLs. The potential mechanism involved vessel injury-triggered acute phase response manifested as increased serum levels of SAA-1, CRP, and LBP (lipopolysaccharide-binding protein) and their protein expression in NTLs. These findings provided a new insight into the relation between stent implantation and progression of NTLs, and further studies are warranted to clarify the detailed mechanism and clinical significance of these preliminary results. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900026393. Graphic Abstract: A graphic abstract is available for this article.

Abstract P2-20-01: Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): Findings from the NALA, NEfERT-T, and TBCRC 022 trials

Abstract Background: The development of metastatic disease in the CNS presents a considerable challenge in the management of patients with MBC as a result of the lack of evidence-based treatment options currently available. Up to 50% of patients with HER2+ MBC develop CNS metastases. A (non-significant) reduction in the cumulative incidence of CNS recurrences was seen in the randomized phase 3 ExteNET trial of neratinib as extended adjuvant treatment of patients with early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy (Martin et al. Lancet Oncol 2017). Here we review data from the following three trials of neratinib in the metastatic setting: the Phase 3 NALA trial (ClinicalTrials.gov: NCT01808573; Saura et al. ASCO 2019), the Phase 2 NEfERT-T trial (NCT00915018; Awada et al. JAMA Oncol 2016); and the TBCRC 022 trial (NCT01494662; Freedman et al. J Clin Oncol 2019), which suggest activity for neratinib in patients with MBC and CNS metastases. Methods: Patients in NALA (who had received at least 2 lines of HER2-directed therapy for MBC) were randomized 1:1 to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). In the NEfERT-T trial, previously untreated patients with recurrent and/or MBC were randomized 1:1 to N (240 mg qd po) or trastuzumab (T; 4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (P; 80 mg/m2 on days 1, 8, and 15 every 28 days). In TBCRC 022, patients with measurable, progressive HER2+ brain metastases received N (240 mg qd po) + C (750 mg/m2 qd po). The co-primary endpoints in NALA were centrally assessed progression-free survival (PFS) and overall survival (OS); time to intervention for symptomatic metastatic CNS disease was a secondary endpoint. PFS was the primary endpoint in NEfERT-T; frequency of and time to symptomatic and/or progressive CNS lesions was a secondary endpoint. The primary endpoint in TBCRC 022 was composite CNS objective response rate (ORR), requiring a reduction of ≥50% in the sum of target CNS lesion volumes without progression of non-target lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. Results: CNS outcomes in NALA, NEfERT-T, and TBCRC 022 are summarized in the Table. In NALA, significantly fewer N+C vs L+C-treated patients required intervention for symptomatic CNS metastases. In NEfERT-T, the frequency of symptomatic or progressive CNS recurrences was significantly reduced and the time to onset of CNS progression significantly delayed in the N+P group vs the T+P group. In TBCRC 022, almost half of L-naive patients had a partial response using composite criteria. Table. Overall/CNS outcomes in NALA, NEfERT-T, and TBCRC 022NALANEfERT-TTBCRC 022N+CL+CN+PT+PL-naive N+CL-treated N+CNo. of patients3073142422373712ORR, %332775781443Composite CNS ORR, %aN/AN/AN/AN/A4933CBR, %45*368885N/AN/APFSHR (p-value)0.76 (0.0059)1.02 (0.89)N/AMedian, months8.8b6.6b12.912.95.53.1OSHR (p-value)0.88 (0.2086)1.05 (0.77)N/AMedian, months24.0b22.2bNENE13.315.1Intervention for CNS disease, overall cumulative incidence, %22.8*29.2N/AN/AN/AN/AProgressive CNS disease, cumulative incidence, %c11.213.910.1**20.2N/AN/A*p&amp;lt;0.05 for N+C vs L+C. **p=0.002 for N+P vs T+P. aDefined as a reduction of ≥50% in the sum of target CNS lesion volumes without progression of non-target lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. bRestricted mean values. cOverall cumulative index in NALA; 2-year cumulative index in NEfERT-T. CBR = clinical benefit rate; N/A = not applicable. NE = not estimable.Conclusions: Neratinib has demonstrated activity against CNS brain metastasis in the setting of advanced and metastatic breast cancer and may also limit the development of new CNS metastases in the adjuvant setting. A pooled analysis of data from NALA and NEfERT-T, which will enable subgroup analyses to be performed, is underway and will be presented at the meeting. Citation Format: Ahmad H Awada, Adam M Brufsky, Cristina Saura, Rachel A Freedman, Nancy U Lin, Judith Bebchuk, Feng Xu, Sara Hurvitz. Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): Findings from the NALA, NEfERT-T, and TBCRC 022 trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-01.

Discrepancies of assessments in a RECIST 1.1 phase II clinical trial \u2013 association between adjudication rate and variability in images and tumors selection

BackgroundIn imaging-based clinical trials, it is common practice to perform double reads for each image, discrepant interpretations can result from these two different evaluations. In this study we analyzed discrepancies that occurred between local investigators (LI) and blinded independent central review (BICR) by comparing reader-selected imaging scans and lesions. Our goal was to identify the causes of discrepant declarations of progressive disease (PD) between LI and BICR in a clinical trial.MethodsWe retrospectively analyzed imaging data from a RECIST 1.1-based, multi-sites, phase II clinical trial of 179 patients with adult small cell lung cancer, treated with Cabazitaxel compared to Topotecan. Any discrepancies in the determination of PD between LI and BICR readers were reviewed by a third-party adjudicator. For each imaging time point and reader, we recorded the selected target lesions, non-target lesions, and new lesions. Odds ratios were calculated to measure the association between discrepant declarations of PD and the differences in reviewed imaging scans (e.g. same imaging modality but with different reconstruction parameters) and selected lesions. Reasons for discrepancies were analyzed.ResultsThe average number of target lesions found by LI and BICR was respectively 2.9 and 3.4 per patient (p < 0.05), 18.4% of these target lesions were actually non-measurable. LI and BICR performed their evaluations based on different baseline imaging scans for 59% of the patients, they selected at least one different target lesion in 85% of patients. A total of 36.7% of patients required adjudication. Reasons of adjudication included differences in 1) reporting new lesions (53.7%), 2) the measured change of the tumor burden (18.5%), and 3) the progression of non-target lesions (11.2%). The rate of discrepancy was not associated with the selection of non-measurable target lesions or with the readers’ assessment of different images. Paradoxically, more discrepancies occurred when LI and BICR selected exactly the same target lesions at baseline compared to when readers selected not exactly the same lesions.ConclusionsFor a large proportion of evaluations, LI and BICR did not select the same imaging scans and target lesions but with a limited impact on the rate of discrepancy. The majority of discrepancies were explained by the difference in detecting new lesions.Trial RegistrationARD12166 (https://clinicaltrials.gov/ct2/show/NCT01500720).

The upregulated scavenger receptor CD36 is associated with the progression of nontarget lesions after stent implantation in atherosclerotic rabbits.

BackgroundThe incidence of recurrent cardiovascular events from the progression of nontarget lesions (NTLs) is high for percutaneous coronary intervention-treated patients. However, the underlying mechanisms have not been thoroughly elucidated.MethodsIn this study, ten atherosclerotic rabbits with multiple plaques in the upper and lower segments of abdominal aorta (group A) were randomly divided into two subgroups: group A1 underwent intravascular ultrasound examination and stent implantation in the lower segments of the abdominal aorta (n=5), whereas group A2 was without stenting (n=5). Group B was a control group without balloon injury. The serum levels of high-sensitivity CRP, interleukin-6 (IL-6), oxidized low-density lipoprotein, and CD36 were assessed via ELISA at five time points between the 10th and 18th weeks. The upper abdominal aorta was examined via the immunohistochemical stain and Western blotting of matrix metallopeptidase 9 (MMP-9), CD36, IL-6, and tumor necrosis factor α.ResultsAs a result, we found that stent implantation aggravated serum levels of CD36, oxidative stress, and inflammatory cytokines. Meanwhile, the upper abdominal arterial plaque burden significantly increased after stenting by intravascular ultrasound. Immunohistochemistry and Western blotting showed that the local NTLs’ matrix metallopeptidase 9, CD36, IL-6, and tumor necrosis factor α expressions in group A1 were significantly higher than those in groups A2 and B (P<0.05–0.01). More importantly, a strong correlation was identified between CD36 expression and NTLs’ plaque burden before the rabbits were killed.ConclusionTaken together, stent implantation accelerated inflammation, induced oxidative stress, and increased the NTLs’ progression, which were associated with the upregulated CD36 expression.

Percutaneous Coronary Intervention Rates and Associated Independent Predictors for Progression of Nontarget Lesions in Patients With Diabetes Mellitus After Drug-Eluting Stent Implantation.

Little is known about clinically driven percutaneous coronary intervention (PCI) rates and predictors for progression of nontarget lesions in diabetic patients who have undergone drug-eluting stent (DES) implantation. We retrospectively analyzed the clinical and angiographic data of 2187 diabetic patients undergoing DES implantation. The cumulative rate of nontarget lesion PCI was 6.3% at 1 year, 14.3% at 2 years, and 19.8% at 3 years. The independent predictors of need for clinically driven PCI in patients with diabetes mellitus after DES implantation included obesity (odds ratio [OR] 2.303, 95% confidence interval [CI] 1.657-3.199, P < .001), low levels of high-density lipoprotein cholesterol (OR 1.412, 95% CI 1.114-1.789, P = .004), statin use (OR 0.669, 95% CI 0.454-0.986, P = .042), insulin use (OR 1.310, 95% CI 1.030-1.665, P = .027), and Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score (OR 1.061, 95% CI 1.045-1.077, P < .001) at baseline PCI. These findings may facilitate prediction of the risk of repeat revascularization and improve repeat revascularization rates in diabetic patients after DES implantation.

AT-17 * RE-ANALYSIS OF PFS/RESPONSE USING ORIGINAL MACDONALD CRITERIA AND RESPONSE EVALUATION CRITERIA IN SOLID TUMORS IN THE PHASE III AVAGLIO STUDY OF BEVACIZUMAB PLUS RADIOTHERAPY AND TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA

BACKGROUND: AVAglio: bevacizumab (BEV) plus radiotherapy (RT) plus temozolomide (TMZ) extended investigator-assessed PFS versus placebo + RT/TMZ (HR = 0.64, p 5mm increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, non-measurable/non-enhancing lesions, new lesion[s]). RESULTS: BEV + RT/TMZ versus placebo + RT/TMZ, respectively. Median PFS: Macdonald-A, 10.0 vs 6.0 months (HR = 0.67); Macdonald1990, 10.1 vs 6.0 months (HR = 0.67); RECIST, 11.0 vs 6.7 months (HR = 0.64). In patients with Macdonald-A PD, 316/338 (93.5%) and 336/357 (94.1%) had Macdonald1990 PD, 22/338 (6.5%) and 21/357 (5.9%) did not have Macdonald1990 PD, and no patient had Macdonald1990 PD determined at an earlier time. In patients with Macdonald-A PD, 229/338 (67.8%) and 240/357 (67.2%) had RECIST PD, 101/338 (29.9%) and 93/357 (26.1%) did not have RECIST PD, and 8/338 (2.4%) and 24/357 (6.7%) had RECIST PD determined at an earlier time than Macdonald-A. CONCLUSION: This analysis is limited in its conclusions as it was retrospective and there were no scans collected after PD was determined by the investigator. These results confirm the gain in sensitivity of the progression assessment by the introduction of bi-dimensional measurements and neurologic evaluation.

Early tumor shrinkage (ETS) and deepness of response (DoR) to predict progression-free, postprogression, and overall survival: Results from the phase III TRIBE trial.

521 Background: The TRIBE trial demonstrated that first-line FOLFOXIRI plus bevacizumab (bev) improves PFS, response rate (RECIST), and OS in comparison to FOLFIRI plus bev (ASCO Annual Meeting 2013). Recent experiences evidenced that both ETS and DoR may implement the assessment of response and correlate with survival in metastatic colorectal cancer (mCRC). Methods: ETS was defined as the relative change in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline. A 20% decrease was adopted as cut-off value to discriminate early responders and non-responders. DoR was defined as the relative change in the sum of longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. The median value was used as cut-off. Results: Out of 508 randomized patients, 443 and 484 patients were evaluable for ETS and DoR, respectively. Early responders achieved longer PFS (median PFS: 12.7 vs 10.0 mos, HR: 0.66 [0.52-0.79], p&lt;0.0001), post-progression survival (median PPS: 17.1 vs 10.7 mos, HR: 0.64 [0.47-0.81], p=0.0005) and OS (median OS: 35.8 vs 22.4 mos, HR: 0.54 [0.39-0.67], p&lt;0.0001). Patients achieving a DoR higher than the median reported longer PFS (median PFS: 13.1 vs 9.3 mos, HR: 0.61 [0.49-0.73], p&lt;0.0001), PPS (median PPS: 18.4 vs 10.5 mos, HR: 0.58 [0.44-0.73], p&lt;0.0001) and OS (median OS: 36.8 vs 21.3 mos, HR: 0.47 [0.35-0.58], p&lt;0.0001). A significant correlation of DoR as a continuous variable with PFS (HR: 0.983 [0.979-0.986], p&lt;0.0001), PPS (HR: 0.987 [0.984-0.991], p&lt;0.0001) and OS (HR: 0.979 [0.975-0.983], p&lt;0.0001) was observed. No differences across arms were reported. Conclusions: ETS and DoR predict PFS, PPS and OS. These findings support the hypothesis that the adoption of active upfront regimens, able to induce a rapid and deep tumor shrinkage, may positively affect the subsequent disease history, thus translating into an advantage in survival. Clinical trial information: NCT00719797.

Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).

513 Background: The anti-tumor and anti-edema effects of BEV provide a rationale for testing in BCBM. Carboplatin (C) is associated with CNS responses across multiple tumor types. We evaluated BEV + C in pts with BCBM. Methods: Pts with progressive, measurable BCBM (&gt;/= 1 cm in longest dimension) were eligible. Cycle 1: BEV 15 mg/kg on Day 1, followed on Day 8 by carboplatin AUC=5 (plus trastuzumab if HER2+). In subsequent cycles, pts received BEV + C on Day 1 (plus trastuzumab if HER2+) of a 3 week (wk) cycle. Standard brain MRI was obtained at baseline (BL) and every 2 cycles. Non-CNS scans (CT or MRI) were performed after 2 cycles, 4 cycles, then every 4 cycles. Correlative brain imaging was obtained at BL, 12-96 hours after the first dose of BEV, and after 2 cycles. Circulating tumor cells and blood for VEGF polymorphisms were also collected. The primary endpoint was composite CNS objective response rate (CNS ORR). CNS partial response required all of the following: &gt;/= 50% reduction in volumetric sum of target CNS lesions compared to BL, no progression of non-target lesions, no new lesions, stable/decreasing steroid dose, no progressive neurologic signs or symptoms, and no progression of non-CNS disease by RECIST 1.0. The study used a 2-stage design to distinguish between ORR 5% vs 20% (responses in &gt;/= 1/12 pts to enter 2ndstage; responses in &gt;/= 4/37 pts needed to be promising). Results: 38 pts were enrolled between 11/3/09-8/24/12 (30 HER2+; 8 HER2-negative). Most (76%) pts had received &gt;/=2 lines of metastatic chemotherapy. 97% of pts with HER2+ disease received prior trastuzumab; 73% had prior lapatinib. All but 5 pts progressed after WBRT and/or SRS. As of 1/15/13, 3 pts remain on protocol therapy; 22 patients have died. The composite CNS ORR was 63% (95% CI 46%-78%). CNS ORR by RECIST was 45%. CNS responses were observed in both HER2+ and HER2-negative pts. Of 34 pts with &gt;/= 24 wks potential follow-up time, median number of cycles was 8 (range 1-19). One grade 2 CNS hemorrhage event was reported; there were no cases of grade 3/4 CNS hemorrhage. Conclusions: BEV + carboplatin is associated with a high rate of durable CNS response in pts with BCBM. Updated results, including progression-free and overall survival will be presented. Clinical trial information: NCT01004172.

Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy

The aim of this was to determine whether the change of size observed at the first response evaluation after initiation of first-line combination chemotherapy correlates with overall survival (OS) in patients with metastatic breast cancer (MBC). The change in size of tumors derived from measurements according to Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation on computed tomography (CT) was obtained from a multicenter, randomized phase III trial ("TEX trial," n = 287) comparing treatment with a combination of epirubicin and paclitaxel alone or with capecitabine (TEX). Cox regression and Kaplan-Meier analyses were performed to evaluate the correlations between the first change in tumor size, response according to RECIST and OS. Data from CT evaluations of 233 patients were available. Appearance of new lesions or progression of non-target lesions (new/non-target) indicated short OS by univariable regression analysis (HR 3.76, 95 % CI 1.90-7.42, p < 0.001). A decrease by >30 % at this early time point was prognostic favorable (HR 0.69, 95 % CI 0.49-0.98, p = 0.04) and not significantly less than the best overall response according to RECIST. After adjustment for previous adjuvant treatment and the treatment given within the frame of the randomized trial, OS was still significantly shorter in patients with new/non-target lesions after a median 8 weeks of treatment (HR 4.41, 95 % CI 2.74-7.11, p < 0.001). Disease progression at the first evaluation correlates with OS in patients with MBC treated with first-line combination chemotherapy. The main reason for early disease progression was the appearance of new lesions or progression of non-target lesions. These patients had poor OS even though more lines of treatment were available. Thus, these factors should be focused on in the response evaluations besides tumor size changes.