Worse 3-year Disease-free Survival Research Articles

Correlation between spleen density and prognostic outcomes in patients with colorectal cancer after curative resection

ObjectiveThe objective of this study was to investigate the correlation between spleen density and the prognostic outcomes of patients who underwent curative resection for colorectal cancer (CRC).MethodsThe clinical data of patients who were diagnosed with CRC and underwent radical resection were retrospectively analyzed. Spleen density was determined using computed tomography. Analysis of spleen density in relation to overall survival (OS) and disease-free survival (DFS) utilizing the Kaplan–Meier method. Univariate and multivariate Cox regression models were used to screen for independent prognostic factors, and a nomogram was constructed to predict OS and DFS. Moreover, internally validated using a bootstrap resamplling method.ResultsTwo hundred twelve patients were included, of whom 23 (10.85%) were defined as having a diffuse reduction of spleen density (DROSD) based on diagnostic cutoff values (spleen density≦37.00HU). Kaplan–Meier analysis indicated that patients with DROSD had worse OS and DFS than those non-DROSD (P < 0.05). Multivariate Cox regression analysis revealed that DROSD, carbohydrate antigen 199 (CA199) > 37 U/mL, tumor node metastasis (TNM) stage III-IV, laparoscopy-assisted operation and American Society of Anesthesiology (ASA) score were independent risk factors for 3-year DFS. DROSD, CA199 > 37 U/mL, TNM stage III-IV, hypoalbuminemia, laparoscopy-assisted operation and ASA score were chosen as predictors of for 3-year OS. Nomograms showed satisfactory accuracy in predicting OS and DFS using calibration curves, decision curve analysis and bootstrap resamplling method.ConclusionPatients with DROSD who underwent curative resection have worse 3-year DFS and OS. The nomogram demonstrated good performance, particularly in predicting 3-year DFS with a net clinical benefit superior to well-established risk calculator.

Extranodal Extension at Pretreatment MRI and the Prognostic Value for Patients with Rectal Cancer.

Background Detection of extranodal extension (ENE) at pathology is a poor prognostic indicator for rectal cancer, but whether ENE can be identified at pretreatment MRI is, to the knowledge of the authors, unknown. Purpose To evaluate the performance of pretreatment MRI in detecting ENE using a matched pathologic reference standard and to assess its prognostic value in patients with rectal cancer. Materials and Methods This single-center study included a prospective development data set consisting of participants with rectal adenocarcinoma who underwent pretreatment MRI and radical surgery (December 2021 to January 2023). MRI characteristics were identified by their association with ENE-positive nodes (χ2 test and multivariable logistic regression) and the performance of these MRI features was assessed (area under the receiver operating characteristic curve [AUC]). Interobserver agreement was assessed by Cohen κ coefficient. The prognostic value of ENE detected with MRI for predicting 3-year disease-free survival was assessed by Cox regression analysis in a retrospective independent validation cohort of patients with locally advanced rectal cancer (December 2019 to July 2020). Results The development data set included 147 participants (mean age, 62 years ± 11 [SD]; 87 male participants). The retrospective cohort included 110 patients (mean age, 60 years ± 9; 79 male participants). Presence of vessel interruption and fusion (both P < .001), heterogeneous internal structure, and the broken-ring and tail signs (odds ratio range, 4.10-23.20; P value range, <.001 to .002) were predictors of ENE at MRI, and together achieved an AUC of 0.91 (95% CI: 0.88, 0.93) in detecting ENE. Interobserver agreement was moderate for the presence of vessel interruption and fusion (κ = 0.46 for both) and substantial for others (κ = 0.61-0.67). The presence of ENE at pretreatment MRI was independently associated with worse 3-year disease-free survival (hazard ratio, 3.00; P = .02). Conclusion ENE can be detected at pretreatment MRI, and its presence was associated with worse prognosis for patients with rectal cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Eberhardt in this issue.

High Exposure of Rabbit Anti-Thymocyte Globulin (ATG) Is Strongly Associated with Inferior DFS in Pediatric Patients with Malignancy Undergoing Alpha-Beta T-Cell Depleted Haploidentical HCT

The PTCTC ONC1401 trial reported a 75% 2-year disease-free survival (DFS) for pediatric patients with acute leukemia or MDS undergoing AB-TCR/CD19 depleted (AB-TCD) haploidentical HCT. Patients ≥10 years had significantly worse DFS. Conditioning for AB-TCD HCT typically includes rATG (Thymoglobulin®) 3 mg/kg/day on days -12 to -10. Models of rATG pharmacokinetics (PK) show slower clearance in older children. We hypothesized worse DFS seen in older patients may be due to excessive in vivo T-cell depletion by residual rATG post HCT. Patients undergoing first AB-TCD haploidentical HCT with rATG as the sole serotherapy agent for treatment of malignancy from Dec 2015 to Jan 2023 were included. Patients were treated on PTCTC ONC1401 or institutional prospective trials of AB-TCD. Minimal residual disease (MRD) was determined by the best-available method (multi-parameter flow or next-generation sequencing) for each patient. Predicted pre- and post-HCT AUC of rATG (in AU*day/mL) were retrospectively determined using the software platform InsightRx© (InsightRx, Inc., San Francisco, CA) and a validated PK model for rATG clearance. Quadratic regression was used to identify optimal target windows of rATG exposure for cumulative incidence and Kaplan-Meier estimations. Multivariate analysis (MVA) Cox regression models were built using all covariates with a univariate p-value &amp;lt;0.2. The dataset included 134 patients ( Table 1); median (range) follow-up of survivors was 3.4 years (0.5-7.6). The median age at HCT was 12.3 years (0.4-27.4), and median donor age was 32 years (5-61). The median infused cell doses for CD34 and AB-T-cells were 15.2 (2.5-45.8) x10^6/kg and 7.0 (0.1-27.6) x10^4/kg. The 100-day incidence of rejection was 11.3% (5.8-16.8) with a 3-year EFS of 59% (50.2-67.8). The 3-year incidence of non-relapse mortality (NRM) and relapse were 13.8% (6.9-20.7) and 21.4% (13.8-29). The 100-day incidence of grades 2-4 and 3-4 aGVHD were 24.4% (16.2-32.6) and 8.5% (3.4-13.6), while 3-year incidence of cGVHD was 16.7% (9.1-24.3). The 3-year DFS and OS were 67.6% (59.2-76) and 73.8% (64-83.6). Increased 3-year NRM was seen in patients ≥10 years: 19.9% (10.6-31.4) vs. 5.6% (0.1-13.4) ( p=0.03); in those with sibling vs. parent donors: 27.3% (12.4-42.2) vs. 8.5% (1.6-15.4) (p=0.008); and CMV mismatched donors: 25.5% (9.1-41.3) vs. 10.4% (3.3-17.5) ( p=0.03). There was no difference in relapse between MRD-techniques, so these were combined for subsequent analyses. Lower 3-year relapse was seen in patients who were MRD-negative: 12.6% (5.5-19.7) vs. 45.7% (26.7-64.7) ( p&amp;lt;0.001); and who received targeted small-molecule therapy post-HCT: 0% (0-19.8) vs. 24.1% (15.5-32.7) ( p=0.04). The median predicted pre-HCT AUC of rATG was 63.7 AU*day/mL (16.4-109). A pre-HCT exposure of ≥40 AU*day/mL was associated with decreased rejection: 8.1% (3-13.2) vs. 27.3% (8.8-45.9; p=0.008). A pre-HCT exposure of &amp;lt;80 AU*day/mL was associated with lower 3-year TRM: 8% (1.7-14.3) vs. 33.4% (14.8-52; p&amp;lt;0.001). The 3-year EFS for patients with a pre-HCT AUC of 40-79.9 AU*day/mL was 69.7% (58.7-80.7) vs. 45.4% (31.9-58.9) for those not in goal range ( p=0.004). The median post-HCT AUC of rATG was 9.5 AU*day/mL (1-42.5). There was no different in grade 2-4 (p=0.61) or grade 3-4 (p=0.25) aGVHD or cGVHD (p=0.9) between those with low (&amp;lt;13 AU*day/mL) vs. high (≥13 AU*day/mL) exposure. A low post-HCT AUC was associated with both lower 3-year NRM: 7.2% (0.9-13.5) vs. 28.1% (11.6-44.6) ( p=0.002), and lower 3-year relapse incidence: 15.5% (7-23.7) vs. 34.3% (18.6-50) ( p=0.01). In MRD-negative patients, low vs. high post-HCT rATG AUC was associated with a 3-year DFS of 81.2% (71-91.4) vs. 60.2% (42-78.4) ( p=0.03); in MRD-positive patients, low vs. high post-HCT rATG AUC was associated with a 3-year DFS of 69.3% (47.9-90.7) vs. 17.9% (0.1-39.5) ( p&amp;lt;0.001). MVA showed that high post-HCT rATG exposure, MRD-positivity, and CMV-mismatched donors were associated with worse 3-year DFS ( Table 2). We identified optimal windows for rATG exposure - pre-HCT of 40-79.9 AU*day/mL, post-HCT &amp;lt;13 AU*day/mL - associated with lower rates of rejection, NRM, relapse, and improved DFS. Validation with prospective drug levels and an independent cohort would strengthen these conclusions. Our data indicates that model-based dosing of rATG to target pre- and post-HCT exposure may be superior to weight-based dosing in patients undergoing AB-TCD HCT.

Abstract 28: Prognostic value of baseline and early changes of circulating cell-free (cf)DNA in the neoadjuvant setting of early stage colon cancer (CC)

Abstract Introduction Circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III CC treated with surgery +/- adjuvant chemotherapy. No study, however, has ever analysed the prognostic value of this biomarker in CC patients (pts) treated with neoadjuvant chemotherapy. We sought to evaluate the prognostic value of baseline and early, on-treatment changes of cfDNA and ctDNA in stage II-III CC pts who were treated with one cycle of neoadjuvant FOLFOX chemotherapy followed by surgery +/- adjuvant FOLFOX chemotherapy in the PePiTA trial. Methods PePITA was a multicentre, single-arm, prospective phase II trial aiming to test in vivo tumour chemosensitivity as assessd by metabolic response using 18F-FDG PET/CT scan of early stage CC and to evaluate its association with survival outcome (NCT00994864). Plasma samples were prospectively collected at baseline and 2 weeks (ie, after one cycle of neoadjuvant FOLFOX chemotherapy). cfDNA was isolated with the QIAmp circulating nucleic acid kit (Qiagen), and quantified with the Qubit fluorometer (Life-Technologies). cfDNA samples were bisulfite converted using the EZ DNA Methylation-Gold™ Kit (Zymo Research), with NPY and WIF1 being selected as universal methylation markers for ctDNA and analysed with digital droplet (dd)PCR technology. Data from ddPCR were processed with the QuantaSoft V1.6 software (BioRad). The primary outcome measure was 3-year disease-free survival (DFS). Receiver operating characteristics curve analyses, Kaplan-Meier method, cox proportional hazards models and log-rank tests were used. Statistical analyses were carried out with the SPSS for MacOS version 25.0 (SPSS Inc). Results 80 pts were included (ypStage I-II 56%, ypStage III 44%). After a median follow-up of 52.5 months, 3-year DFS was 80% (95%CI 71.2-90.8) and 5-year OS 84% (95%CI 75.2-94.9). Pts with high (≥1.2 ng/µl) baseline cfDNA level had worse 3-year DFS (48% vs 80%; HR 2.72, 95%CI 1.02-7.25; p=0.036) and 5-year OS (71% vs 90%; HR 5.36, 95%CI 1.14-25.28; p=0.017) than those with low baseline cfDNA level. In a multivariable analysis (including sex, ypStage and CEA), baseline cfDNA was the only factor showing a trend towards statistical significance (HR DFS 2.6, 95%CI 0.96-7.01; p=0.059; HR OS 4.65, 95%CI 0.97-22.32; p=0.055). Early changes of cfDNA (Δ ≥11%) after one cycle of neoadjuvant FOLFOX chemotherapy failed to predict survival (HR DFS 1.08, 95%CI 0.42-2.81; p=0.873; HR OS 0.68, 95%CI 0.19-2.39; p=0.543). ctDNA analyses are ongoing and will be presented at the meeting. Conclusions For the first time, we have shown that baseline cfDNA may predict survival outcome in early stage CC pts treated with neoadjuvant chemotherapy. Pending confirmation in larger series, testing for cfDNA at baseline could help select high-risk pts who may benefit from neoadjuvant, FOXTROT-like, treatment strategies. Citation Format: Giacomo Bregni, Elena Trevisi, Chiara Senti, Andrea Pretta, Caroline Vandeputte, Pashalina Kehagias, Elena Acedo Reina, Amélie Deleporte, Paraskevas Gkolfakis, Jean-Luc Van Laethem, Philippe Vergauwe, Marc Van den Eynde, Guido Deboever, Jos Janssens, Gauthier Demolin, Stephane Holbrechts, Marylene Clausse, Thierry De Grez, Marc Peeters, Lionel D'Hondt, Karen Geboes, Tatiana Besse-Hammer, Alexis Buggenhout, Françoise Rothé, Patrick Flamen, Alain Hendlisz, Francesco Sclafani. Prognostic value of baseline and early changes of circulating cell-free (cf)DNA in the neoadjuvant setting of early stage colon cancer (CC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 28.

Prognostic value of tumor deposits in rectal cancer: A monocentric series of 505 patients.

It has been suggested that tumor deposits (TDs) may have a worse prognosis in rectal cancer compared with colonic cancer. The aim of this study was to assess TDs prognosis in rectal cancer. Patients who underwent total mesorectum excision for rectal adenocarcinoma (2011-2016) were included. A case-matched analysis was performed to assess the accurate impact of TDs for each pN category after exclusion of synchronous metastasis. A total of 505 patients were included. TDs were observed in 99 (19.6%) patients, (pN1c = 37 [7.3%]). TDs were associated with pT3-T4 stage (P = .037), synchronous metastasis (P = .003), lymph node (LN) invasion (P = .041), vascular invasion (P = .001), and perineural invasion (P < .001). TD was associated with a worse 3-year disease-free survival (DFS) among pN0 (51.2% vs 79.8%; P < .001); pN1 patients (35.2% vs 70.1%; P = .004) but not among pN2 patients (37.5% vs 44.7%; P = .499). After matching, pN1c patients had a worse 3-year DFS compared with pN0 patients (58.6% vs 82.4%; P = .035) and a tendency toward a worse DFS among N1 patients (40.1% vs 64.2%; P = .153). DFS was worse when one TD was compared with one invaded LN (40.8% vs 81.3%; P < .001). In rectal cancer, TDs have a metastatic risk comparable to a pN2 stage which may lead to changes in adjuvant treatment.

FIGO Classification 2018: Validation Study in Patients With Locally Advanced Cervix Cancer Treated With Chemoradiation

In 2018, the International Federation of Gynecology and Obstetrics (FIGO) proposed a new staging for cervical cancer. The present study was designed to reclassify patients with locally advanced cervix cancer and perform a comparative evaluation with FIGO2009. Patients with locally advanced cervical cancer (stage IB2-IVA) who had baseline cross-sectional imaging and received (chemo-) radiation and brachytherapy were included. Survival outcomes were analyzed according to FIGO 2009. Patients were then reclassified according to FIGO 2018, and TNM classification outcomes were analyzed. FIGO stage and known prognostic factors were included in univariate analysis, and multivariate analysis was performed to investigate the prognostic value of clinical stage. Six hundred thirty-two patients were included. Overall, 185 (29.3%) patients had pelvic adenopathy, and 51 (8.2%) had positive paraortic nodes. At a median follow-up of 33 months, 116 (18.3%) patients had recurrence. Three-year disease-free survival (DFS) according to FIGO 2009 for stage IB, IIA, IIB, IIIA, IIIB, and IVA was 86%, 91%, 76%, 57%, 65%, and 61%, respectively. The 3-year DFS after restaging according to FIGO 2018 for stage IB, IIA, IIB, IIIA, IIIB, IIIC1, IIIC2, and IVA was 100%, 93%, 84%, 53%, 77%, 74%, 61%, and 61%, respectively. Patients with clinically significant lymphadenopathy had inferior outcomes compared with node-negative patients (62.9% vs 77.8%; P = .002). Patients with ≥3 paraortic nodes had poorer DFS than patients with <3 paraortic lymphadenopathy (13.6% vs 56.3%; P = .001). Furthermore, patients with primary tumor volume >30 cm3 had worse 3-year DFS than those with primary tumor volume ≤30 cm3 (67.4% vs 78.5%; P = .002). FIGO 2018 modification is associated with heterogenous outcomes in node-positive patients that are affected by primary tumor and nodal volume. We propose a modification to the existing TNM staging system to allow more robust classification of outcomes.

Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery.

Tumor response to preoperative chemoradiotherapy and postoperative survival differs among patients with locally advanced rectal cancer. The objective was to find correlations of mutated oncogenes and clinical outcomes in locally advanced rectal cancer. A total of 70 patients with preoperative preoperative chemoradiotherapy followed by radical surgery at a single cancer center between 2006 and 2012 were enrolled. Pretreatment tumor biopsy samples were assayed for 238 mutation hotspots harboring 19 oncogenes by time-of-flight mass spectrometry and OncoCarta Array. Oncogene mutations were found in 48.6% of patients (34/70). KRAS was the most frequent driver mutation, found in 35.7% of patients (25/70), followed by PIK3CA (14.3%), NRAS (5.7%), FLT3 (2.9%), and BRAF (1.4%). Multiple gene mutations were observed in eight patients (11.4%). Tumors with KRAS mutations responded poorly to preoperative chemoradiotherapy (p = 0.044). Patients with oncogene mutations had worse 3-year disease-free survival than those without mutations (67.2% vs 94.2%, p = 0.010). Patients with KRAS or RAS mutations had lower 3-year disease-free survival (68% vs 88.3%, p = 0.016; 65.5% vs 92.3%, p = 0.004, respectively) and 3-year overall survival (88% vs 95.4%, p = 0.020; 89.7% vs 94.9%, p = 0.036, respectively) than those without KRAS or RAS mutations. Oncogene mutation status affected tumor response to treatment and long-term survival in locally advanced rectal cancer.