Disease-free Survival Hazard Ratio Research Articles

A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆

Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P= 0.042) and S-1 versus SOXRT, 0.724 (P= 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P= 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

Reactive oxygen species modulator 1 expression predicts lymph node metastasis and survival in early-stage non-small cell lung cancer.

Reactive oxygen species modulator 1 (romo1) causes cell hyperplasia and promotes cancer cell invasion. Based recent studies, the overexpression of romo1 is associated with lymphatic metastasis and poor prognosis in lung cancer. We aimed to evaluate associations between romo1 expression and lymph node metastasis in non-small cell lung cancer (NSCLC). Clinical data and pathological results were retrospectively reviewed for 98 subjects diagnosed with NSCLC and who underwent surgical biopsy between 1994 and 2009. A total 98 tumor specimens were analyzed. The romo1 H score was correlated with stage and was significantly higher in subjects with lymph node metastasis than in those without metastasis (173 vs 116; P < 0.05). The area (%) of grade 1 expression was significantly smaller (19.5 vs 37.0; P = 0.005) and the area of grade 3 expression was significantly larger (27.9 vs 6.00; P < 0.001) in subjects with lymph node metastasis than in those without metastasis. In stage I patients, disease free survival (DFS) (191 ± 18.8 vs. 75.6 ± 22.4 months, P = 0.004) was significantly longer in the low romo1 group than in the high romo1 group. A multivariate analysis showed a significant association between high romo1 expression and poor DFS (hazard ratio 5.59, 95 confidence interval, 1.54–20.3, P = 0.009). These findings support the prognostic value of romo1 in NSCLC, especially in stage I.

PCN24 Disease-Free Survival (DFS) As a Surrogate Endpoint for Overall Survival (OS) in HER2 Negative (HER2–) Primary Breast Cancer (BC)

OS is an endpoint for measuring lifetime clinical benefit of oncology therapies; however, studies in the adjuvant setting may not detect OS benefit owing to the time required to observe sufficient events. DFS is commonly measured in primary (neo)adjuvant BC trials when OS may be prolonged. We used linear regression analysis to assess DFS as a surrogate for OS in HER2– primary BC. MEDLINE, Embase, CENTRAL, CDSR, DARE, major oncology congresses and clinical trial databases were searched in August 2019 to identify studies reporting OS and DFS in a HER2– primary BC population. Studies were included if they were conducted in North America and/or Europe, if hazard ratios (HRs) were reported for both outcomes, and if patients had completed local treatment and (neo)adjuvant chemotherapy. Spearman’s rank correlation and linear regression analyses were performed to evaluate the correlation between HRs for OS and DFS. Among 2,596 records reviewed, eight studies (six RCTs, two comparative retrospective studies) were included. Studies comprised triple-negative BC populations (n=2), hormone receptor positive HER2– BC populations (n=2), and overall HER2– BC populations (n=4). The Spearman’s rank correlation coefficient between OS and DFS was 0.756 (p=0.030), which when weighted by study sample size was 0.803 (p=0.016). The regression coefficient on natural logarithm (ln) HROS versus ln HRDFS was 1.75 (95% confidence interval: 1.49–2.02; R2 = 0.972), suggesting a 10% relative risk reduction (RRR) for DFS was associated with an additional 7% RRR for OS. A nominally significant positive correlation was found between OS and DFS in HER2– primary BC, indicating that DFS can be used as a valid surrogate for OS, enabling earlier assessment of clinical benefit. Limitations include the number of studies. Validation of this correlation including future studies is required.

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer

In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited. ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).

Oncological Outcomes of Transanal Endoscopic Microsurgery Plus Adjuvant Chemoradiotherapy for Patients with High-Risk T1 and T2 Rectal Cancer.

Background: Radical surgery is recommended for high-risk pathological stage T1 (pT1) or pT2 rectal cancer after transanal endoscopic microsurgery (TEM). However, in clinical practice, many patients may unfit or decline radical surgery. In recent years, adjuvant chemoradiotherapy (CRT) after TEM was considered as an alternative to radical surgery for these patients. This study aimed to assess oncological outcomes of adjuvant CRT after TEM for high-risk early rectal cancer. Materials and Methods: We collected retrospectively data of 97 patients who underwent TEM with pT1 and pT2 between January 2008 and December 2018. Of these, 35 patients were excluded. Of the remaining 62 patients, 42 were managed by TEM alone and 20 by TEM plus adjuvant CRT. Demographics, recurrence, and survival were analyzed between the two groups. Results: At a median follow-up of 52.5 months, the 3-year local recurrence-free survival and disease-free survival (DFS) in TEM alone group were significantly lower than those in TEM+CRT group (66.6% versus 93.3%, P = .035; 63.7% versus 93.3%, P = .022). Although the 3-year overall survival in TEM+CRT group was higher than TEM alone group (100% versus 83.3%), the difference was not statistically significant (P = .13). The local recurrence rate in TEM alone was 31%, compared with 5% in TEM+CRT group (P = .025). Multivariate analysis showed that adjuvant CRT was an independent prognostic factor for DFS (hazard ratio: 0.094; 95% confidence interval: 0.001-0.764; P = .027). Conclusions: Our study suggests that adjuvant CRT after TEM may be an alternative for pT1 high-risk and T2 rectal cancer who are not suitable or unwilling to undergo salvage radical surgery.

Prognostic Role of MicroRNA 222 in Patients with Glioma: A Meta-analysis.

Background Several studies have focused on the prognostic role of microRNA 222 in glioma. But different conclusions were drawn by these studies. We aimed to systematically evaluate the role of microRNA 222 in glioma by conducting a meta-analysis. Methods A systematic literature search until January 2020 was conducted in Web of Science, EMBASE, Cochrane Library, PubMed, and China National Knowledge Infrastructure. The general characteristics and relevant data of nine articles were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the prognostic role of microRNA 222 in glioma. The primary outcomes were overall survival (OS) and disease-free survival (DFS). Results Nine articles (11 data sets) with 1564 patients were included. We systematically evaluated the role of microRNA 222 for OS and DFS in glioma patients (HR for OS = 1.72; 95% CI, 1.31-2.26; p = 0.001; HR for DFS = 1.02; 95% CI, 0.86-1.22; p = 0.032). Subgroup analyses were performed according to the sources of patients, the types of the samples, the stages of the tumors, the methods for detecting the microRNA 222, and the sample size. No significant publication bias was found. Conclusion In conclusion, our study provided evidence that a high expression of microRNA 222 was related to worse overall survival in glioma patients. However, given the limited study number, more high-quality studies are warranted in the future.

Impact of Positive Pleural Lavage Cytology for Each Stage of Non-Small Cell Lung Cancer Patients

Positive preresection pleural lavage cytology (PLC+) is a poor prognostic factor in non-small cell lung cancer (NSCLC). This study evaluated the prognostic value of PLC+ for the different pathologic stages (p-stages) of NSCLC. A retrospective analysis was conducted of all 1293 staged patients who underwent curative resection in the Shizuoka Cancer Center Hospital, Shizuoka, Japan, for NSCLC to evaluate the impact of PLC+ on survival, specifically in patients with p-stage I NSCLC. The survival rate between patients with and without PLC+ was compared using the Kaplan-Meier method with the log-rank test for comparison. PLC+ was identified in 50 of the 1293 patients (3.9%) and was correlated with lymph node metastasis (P < .001), a pathologic tumor size larger than 3 cm (P= .033), the presence of pleural invasion (P < .001), and adenocarcinoma (P= .038). In patients with PLC+, the 5-year disease-free survival (DFS) was 31.1%, compared with 75.7% for patients with a negative PLC (PLC-) (P < .001). On multivariate analysis, the PLC+ status was an independent prognostic factor of DFS (hazard ratio 1.70; P= .013). Among the 818 patients with p-stage I NSCLC, PLC+ was identified in 22, with a 5-year DFS of 40.4%. The prognosis in patients with p-stage I NSCLC with PLC+ was equal to that in patients with p-stage IIIA NSCLC with PLC- (5-year DFS, 40.4% and 39.0%). PLC is an independent prognostic factor in early-stage NSCLC. Therefore, it may be appropriate to up-stage an NSCLC diagnosis in the presence of PLC+, especially for patients with p stage I.

Cellular immunotherapy plus chemotherapy ameliorates survival in gastric cancer patients: a meta-analysis.

The efficacy of cellular immunotherapy plus chemotherapy in treatment of gastric cancer (GC) remains inconsistent even controversial. Hence, we performed a meta-analysis to better comprehend the clinical value of cellular immunotherapy plus chemotherapy for GC patients. We searched PubMed, Embase and EBSCO databases to identify the studies evaluating the association of cellular immunotherapy plus chemotherapy and overall survival (OS) and/or disease-free survival (DFS) in patients with GC, and then combined relevant data into hazard ratios (HRs) for OS, DFS and clinicopathological features such as TNM stage, etc. with STATA 12.0. Eleven studies with 1244 patients were included in this meta-analysis. We found that cellular immunotherapy plus chemotherapy remarkably improved overall survival (OS) and diseases-free survival (DFS) as compared to the chemotherapy for GC patients. In subgroup analyses, pooled data showed that the combined therapy was significantly associated with better 3-year and 5-year survival rate, but not with 1-year survival rate of patients; the application of cellular immunotherapy based on either CIK or DC-CIK cells could enhance survival as well as NK, γδT and CIK cells-based immunotherapy. More importantly, the addition of cellular immunotherapy considerably improved OS and DFS only in patients with stage III rather than stage II. In addition, we also discovered that the combined therapy did not cause intolerable side effects to patients. Cellular immunotherapy plus chemotherapy ameliorates survival in GC, especially in patients with stage III, implicating that it is a valuable therapeutic strategy for these patients.

Influence of surgical approach and quality of resection on the probability of cure for early-stage HCC occurring in cirrhosis.

Background & AimsThe quality of surgical care of patients with HCC is associated with improved long-term prognosis and may also be influenced by the type of surgical approach. The present study aimed at evaluating the role of the laparoscopic approach on quality of surgical care and long-term prognosis in optimal HCC surgical candidates.MethodsAll consecutive patients undergoing open (OLR) or laparoscopic liver resection (LLR) for early-stage HCC in cirrhosis (METAVIR F4) at 5 French expert hepato-pancreatico-biliary centres between 2010 and 2018 were enrolled. Quality of surgical care was defined by textbook outcome (TO), a combination of 6 criteria representing ideal hospitalisation. Factors associated with TO were determined on multivariate analysis. Comparison between LLR and OLR was performed after propensity score matching (PSM). The primary endpoint was disease-free survival (DFS). Statistical cure was modelled using a non-mixture model.ResultsOverall, 425 patients were included. Median follow-up was 42.0 months. LLR was performed in 267 (62.8%) patients. TO was achieved in 140 (32.9%) patients. LLR was independently associated with TO (odds ratio [OR] 2.81; 95% CI 1.29–6.12; p = 0.009). After PSM, LLR patients cumulated higher number of TO criteria than OLR patients (5 vs. 4; p = 0.012). The 1-, 3-, and 5-year DFS of LLR patients with and without TO were 82.3%, 64.4%, and 62.5%, and 76.9%, 51.4%, and 30.2%, respectively (p = 0.003). On multivariable Cox regression, TO was independently associated with improved DFS (hazard ratio 0.34; p = 0.001). The cure fraction of the whole population was 24.4%. Patients achieving TO had increased cure fraction than patients not achieving TO (32.6% vs. 18.1%).ConclusionsQuality of surgical care improves the prognosis of patients with early-stage HCC and is promoted by the laparoscopic approach.Lay summaryThe overall quality of surgical care, as measured by TO, plays a pivotal role in the prognosis and, in particular, on the probability of statistical cure of patients with resectable early-stage HCC occurring in cirrhosis. By influencing TO, laparoscopy has an indirect impact on the probability of cure and long-term management of these patients. This study strongly supports the promising curative role of mini-invasive treatments for early-stage HCC, such as low-difficulty LLR.

Differences in the immunosurveillance pattern associated with DNA mismatch repair status between right-sided and left-sided colorectal cancer.

Tumor location and immunity play important roles in the progression of colorectal cancer (CRC). This study aimed to investigate the differences in the immunosurveillance pattern between right‐ and left‐sided CRC and analyze their association with clinicopathologic features, including mismatch repair (MMR) status. We included surgically resected stage II/III CRC cases and evaluated the immunohistochemical findings of HLA class I, HLA class II, programmed cell death‐ligand 1 (PD‐L1), PD‐1, CTLA‐4, CD3, CD4, CD8, TIA‐1, T‐bet, GATA3, RORγT, Foxp3, and CD163. A total of 117 patients were included in the analyses; of these, 30 and 87 had right‐ and left‐sided cancer, respectively. Tumor immunity varied according to the tumor location in the overall cohort. Analysis of the tumors excluding those with DNA mismatch repair (MMR) deficiency also revealed that tumor immunity differed according to the tumor location. In right‐sided colon cancer (CC), high expression of Foxp3 (P = .0055) and TIA‐1 (P = .0396) were associated with significantly better disease‐free survival (DFS). High CD8 (P = .0808) and CD3 (P = .0863) expression tended to have better DFS. Furthermore, in left‐sided CRC, only high PD‐L1 expression in the stroma (P = .0426) was associated with better DFS. In multivariate analysis, high Foxp3 expression in right‐sided CC was an independent prognostic factor for DFS (hazard ratio, 7.6445; 95% confidence interval, 1.2091‐150.35; P = .0284). In conclusion, the immunosurveillance pattern differs between right‐ and left‐sided CRC, even after adjusting for MMR deficiency.

P-349 Clinical significance of lymph node radio to predict prognosis in colon cancer

Metastases to regional lymph nodes (LN) has been considered to be a strong outcome predictor following surgical resection and a key determinant factor for adjuvant chemotherapy in colon cancer. According to the tumor-node-metastasis system reflected by the American Joint Committee on Cancer (AJCC), which has been the most popular cancer staging system, patients with positive LN involvement without distant metastasis are classified as stage III and they are subclassified into pN1 and pN2 based on the number of involved LN. However, in the current staging system, low LN harvest may lead to inadequate nodal staging which might result in overestimation of patient prognosis. In this perspective, recent studies recommended the lymph node ratio (LNR; the number of positive LN divided ty the number of harvested LN) as a prognostic indicator, rather than current nodal staging by AJCC. In the present study, we investigated the clinical significance of LNR to predict survival outcomes in colon cancer. Patients who underwent radical resection for colon cancer and presented with positive LN involvement from January 2014 to December 2016 were included in the present study. Among the included patients, who were candidates for adjuvant chemotherapy, patients who had not undergone chemotherapy were excluded. Patient medical records were reviewed retrospectively and the number of harvested LN, positive LN and other pathological factors for prognosis including pT stage by AJCC, lymphovascular invasion, perineural invasion and histologic grade were recorded. As survival outcomes, disease-free survival (DFS) and overall survival (OS) were investigated. A total of 84 patients with positive LN involvement who underwent adjuvant chemotherapy were enrolled in the present study. Their median duration of follow-up was 43.5 months (interquartile range, 29.8-56.8 month). The median number of harvested LN was 22 (interquartile range, 16-27) and positive LN was 2 (interquartile range, 1-5). Median LNR was 14.3% (interquartile range, 5.3-25.0%). Hazard ratio (HR) for DFS of LNR by multivariate Cox regression analysis including putative confounding factors for prognosis was 1.009 (95% confidence interval [CI], 0.991-1.027), which was not statistically significant. (p=0.338). For OS, the HR of LNR was 1.005 (CI, 0.667-1.005) and it was not significant either. In the present study, LNR was not a significant predictor for prognosis in colon cancer. Further evaluation with a larger cohort with detailed co-variate investigation would be required to verify the clinical significance of LNR.

Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA.

LBA5 Background: Osimertinib is a 3rd-generation, CNS-active, EGFR-TKI with superior efficacy to comparator EGFR-TKI (gefitinib/erlotinib) in treatment-naïve EGFRm advanced NSCLC. Approx. 30% of pts with NSCLC present with early stage (I–IIIA) disease; surgery is the primary treatment. Adjuvant chemotherapy is standard of care in pts with resected stage II–III NSCLC and select stage IB pts; however, recurrence rates are high and other therapies are needed. ADAURA (NCT02511106) is a Ph III, double-blind, randomized study assessing the efficacy and safety of osimertinib vs placebo (PBO) in pts with stage IB–IIIA EGFRm NSCLC after complete tumor resection and adjuvant chemotherapy, when indicated. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early due to efficacy; we report an unplanned interim analysis. Methods: Eligible pts: ≥18 years (Japan/Taiwan: ≥20), WHO PS 0/1, primary non-squamous stage IB/II/IIIA NSCLC, confirmed EGFRm (ex19del/L858R), complete resection of primary NSCLC with full recovery from surgery; postoperative chemotherapy was allowed. Pts were randomized 1:1 to osimertinib 80 mg once daily orally or PBO to receive treatment for up to 3 years and stratified by stage (IB/II/IIIA), mutation type (ex19del/L858R), and race (Asian/non-Asian). Primary endpoint: disease-free survival (DFS) by investigator in stage II–IIIA pts. Secondary endpoints: overall survival (OS) and safety. Data cutoff (DCO): 17 Jan 2020. Results: Globally, 682 pts were randomized to treatment: osimertinib n=339, PBO n=343. Baseline characteristics were balanced across arms (osimertinib/PBO): stage IB 31/31%, stage II/IIIA 69/69%, female 68/72%, ex19del 55/56%, L858R 45/44%. In stage II–IIIA pts, DFS hazard ratio (HR) was 0.17 (95% CI 0.12, 0.23); p&lt;0.0001 (156/470 events); 2-year DFS rate was 90% with osimertinib vs 44% with PBO. In the overall population, DFS HR was 0.21 (0.16, 0.28); p&lt;0.0001 (196/682 events); 2-year DFS rate was 89% with osimertinib vs 53% with PBO. OS was immature (4% maturity) with 29/682 deaths (osimertinib n=9, PBO n=20) at DCO. The safety profile was consistent with the known safety profile of osimertinib. Conclusions: Adjuvant osimertinib is the 1st targeted agent in a global trial to show a statistically significant and clinically meaningful improvement in DFS in pts with stage IB/II/IIIA EGFRm NSCLC after complete tumor resection and adjuvant chemotherapy, when indicated. Adjuvant osimertinib provides an effective new treatment strategy for these pts. Clinical trial information: NCT02511106 .

Cervical Cancer in Young Women: Do They Have a Worse Prognosis? A Retrospective Cohort Analysis in a Population of Mexico.

Cervical cancer (CC) is a global problem; it is among the five leading causes of cancer death in women. Several studies have examined the association between age and disease prognosis; however, controversy still exists. The objective of the present study is to determine if age at diagnosis has an impact on overall survival (OS) and disease-free survival (DFS). Retrospective cohort of 2,982 patients with CC treated at the National Cancer Institute of Mexico from 2005 to 2015. We collected demographic, clinical, and treatment data, as well as current status, of 2 groups: women under and over 40 years of age. We calculated OS and DFS rates with Kaplan-Meier estimates. Cox proportional hazards modeling was used to determine risks. The median follow-up time was 26.5 months (percentile [P]25 -P75 , 11-60.23). When comparing DFS, OS, stage, and histologic subtype between young patients <40 and adult patients >40, we did not observe any difference. We found that in both groups, locally advanced and advanced stage, neuroendocrine subtype, hydronephrosis, and positive inguinal lymph nodes increased the risks of death and recurrence. Having been pregnant was identified as protective factor in DFS (hazard ratio, 0.54; 95% confidence interval, 0.04-0.71). We corroborated that age at diagnosis is not a prognostic factor for decreased or increased OS or DFS, and in both groups, the stage, histologic subtype, hydronephrosis, and node involvement were identified as factors adverse to OS and DFS, and pregnancy history was a protective factor in DFS. The present study directly affects everyday clinical practice because it allows us to focus on the most relevant prognostic factors in patients with cervical cancer. When planning treatment and follow-up, clinicians should focus on stage at diagnosis, histologic subtype, hydronephrosis, and distant metastasis instead of patients' age. They should also be aware of any previous pregnancies and poor response, or nonresponse, to treatment, which results in disease progression and persistence. Paying attention to these factors affecting overall survival and disease-free survival will help treat patients better and increase their chances of survival and improve their quality of life.

Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomized controlled trials.

4533 Background: Disease-free survival (DFS) is an appealing surrogate endpoint for overall survival (OS) in trials on neoadjuvant or adjuvant cancer therapy, because it is available faster and with less follow-up effort. The aim of this study was to assess if DFS can be a valid surrogate endpoint for OS when comparing neoadjuvant treatment followed by surgery to surgery alone for gastroesophageal adenocarcinoma. Methods: Individual patient data (IPD) from eight randomized controlled trials (n = 1,126 patients) which compared neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma were used for the analysis. Correlation between OS-time and DFS-time was calculated. Kaplan-Meier survival curves and corresponding hazard ratios (HRs) for treatment effects were separately determined for each trial. Subsequently, HRs were pooled in a meta-analysis using a random-effects model. An error-in-variables linear regression model was used to compare observed and predicted values. The minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS was estimated by calculating the surrogate threshold effect. Results: OS-time correlated strongly with DFS-time. HRs for OS and DFS were highly similar for all single trials. The meta-analysis yielded almost identical overall HRs for treatment effects on OS and DFS. The determination coefficient for the association between HRs for OS and DFS was 0.912 (95% confidence interval 0.75-1.0), indicating a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect was calculated at 0.79, indicating that a future trial yielding a hazard ratio for the treatment effect on DFS &lt; 0.79 could be expected with a 95% probability to yield a hazard ratio for the treatment effect on OS &lt; 1. Conclusions: DFS and OS strongly correlate both after neoadjuvant therapy followed by surgery and after surgery alone for gastroesophageal adenocarcinoma. Likewise, the treatment effects on the two endpoints are very similar. Consequently, DFS can be regarded an appropriate surrogate endpoint for OS in trials on neoadjuvant therapy for gastroesophageal adenocarcinoma.

Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration.

4004 Background: In overall population, IDEA pooled analysis did not demonstrate non-inferiority (NI) regarding 3y DFS in pts with stage III CC receiving 3m vs. 6m of adj FOLFOX/CAPOX. However, in pts treated with CAPOX (especially in low-risk pts), 3m of therapy was as effective as 6m. Results of OS and 5y DFS are reported. Methods: OS was defined as time from enrollment to death due to all causes. OS NI margin was conservatively set to be Hazard Ratio (HR) = 1.11, which is equivalent to: the maximum acceptable loss of OS efficacy, by shortening treatment to 3m, was half of the OS efficacy gained in MOSAIC trial (i.e., 2.26% absolute reduction in 5y OS rate). Pre-planned sub-group analyses included by regimen and risk group for both OS and 5y DFS. NI was to be declared if the one-sided false discovery rate adjusted (FDRa) NI p-value &lt; 0.025. Results: With an overall median survival follow-up of 72 m (range per study, 62 to 84 m), 2584 deaths and 3777 DFS events among 12,835 pts from six trials were observed. Across 6 studies, 39.5% of pts received CAPOX (rate by study, 0% to 75.1%). Overall, the 5y OS rate was 82.4% (3m) and 82.8% (6m), with estimated OS HR of 1.02 (95% confidence interval [CI], 0.95-1.11; FDRa NI p, 0.058) and absolute 5-y OS rate difference of -0.4% (95% CI, -2.1 to 1.3%). Overall, the 5y DFS rate was 69.1% (3m) and 70.8% (6m), with estimated DFS HR of 1.08 (95%CI, 1.01-1.15, FDRa NI p, 0.22). HRs (95% CI) within subgroups see table. Conclusions: 5y OS rate reported in IDEA trials was higher than historical rates, regardless of duration of therapy. While overall survival in IDEA did not meet prior statistical assumptions for NI in overall population, the 0.4% difference in 5y OS should be placed in clinical context. OS and 5y DFS results continue to support the use of 3m adjuvant CAPOX for the vast majority of stage III colon cancer pts. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies and cost associated with shorter treatment duration. Clinical trial information: NCT01150045; 2009-010384-16; NCT00749450; ISRCTN59757862; 2007-003957-10; UMIN000008543; 2007-000354 . [Table: see text]

Disease-free survival as a surrogate endpoint for overall survival in adjuvant trials of pancreatic cancer: a meta-analysis of 20 randomized controlled trials

BackgroundWe aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer.MethodsWe systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings.ResultsAfter screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS.ConclusionsTherefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

4P Independent validation of the PAM50-based chemoendocrine score (CES) as pathologic complete response (pCR) and disease-free survival (DFS) predictor in hormone receptor (HR)+/HER2+ breast cancer (BC)

HR+/HER2+ BC is heterogeneous and there is a need to identify predictive biomarkers. We previously reported the ability of the PAM50-based CES to predict chemoendocrine sensitivity in HR+/HER2-negative BC beyond intrinsic subtype and risk of relapse (ROR) (Prat.CCR.2017). Here we evaluate the association of CES with pCR and DFS following different anti-HER2 combinations in HR+/HER2+ BC. Intrinsic subtype and clinicopathologic data were obtained from 8 independent studies for a total of 485 HR+/HER2+ early BC. Patients (pts) were treated with anti-HER2 therapy either with endocrine therapy (PAMELA and PER-ELISA) or with chemotherapy (CHERLOB, OptiHER, LPT109096, ICO, HCB, PER-ELISA and CALGB 40601 [Alliance]). CES was evaluated as a continuous variable and categorically (CES-E [endocrine-sensitive], CES-U [uncertain] and CES-C [chemosensitive]) using previously reported cutoffs. We first performed statistical analyses in each dataset individually, and then all 8 combined. Multivariable analyses were used to test the association of the CES score with pCR and DFS. In the combined cohort, CES-E, CES-U and CES-C were identified in 16%, 22% and 62% of the pts, respectively. CES (continuous variable) was associated with higher pCR rates independent of clinical characteristics, treatment type, intrinsic subtype and study (adjusted Odd Ratio [OR]=0.42; p = 0.02). In the PER-ELISA trial, CES was also found associated with response (decrease in ki67) following 2 weeks of letrozole alone (OR=29.1, p 0.01). 295 pts (CHERLOB, ICO, HCB and CALGB40601) were analyzed for DFS with a median follow-up of 66 months (IQR 37-82). The adjusted DFS hazard ratio of the CES (continuous variable) was 0.13 (p < 0.01) independent of pCR, clinical characteristics, ROR and intrinsic subtype. In pts without pCR, disease recurrence occurred in 4% of CES-E, 19% of CES-U and 34% of CES-C pts (p < 0.01). In HR+/HER+ BC, CES shows clinical validity for predicting chemoendocrine sensitivity in combination with anti-HER2 targeted therapies and is a good prognostic factor beyond intrinsic subtype and clinicopathologic characteristics.

Postoperative Radiation Therapy in Patients with Extracranial Chondrosarcoma: A Joint Study of the French Sarcoma Group and Rare Cancer Network

Postoperative radiation therapy (poRT) of intracranial/skull base chondrosarcomas (CHSs) is standard treatment. However, consensus is lacking for poRT in extracranial CHS (eCHS) owing to their easier resectability and intrinsic radioresistance. We assessed the practice and efficacy of poRT in eCHS. This multicentric retrospective study of the French Sarcoma Group/Rare Cancer Network included patients with eCHS who were operated on between 1985 and 2015. Inverse propensity score weighting (IPTW) was used to minimize poRT allocation biases. Of 182 patients, 60.4% had bone and 39.6% had soft-tissue eCHS. eCHS were of conventional (31.9%), myxoid (28.6%; 41 extraskeletal, 11 skeletal), mesenchymal (9.9%), or other subtypes. En-bloc surgery with complete resection was performed in 52.6% and poRT in 36.8% of patients (median dose, 54 Gy). Irradiated patients had unfavorable initial characteristics, with higher grade and incomplete resection. Median follow-up time was 61 months. Five-year incidence of local relapse was 10% with poRT versus 21.6% without (P = .050). Using the IPTW method, poRT reduced the local relapse risk (hazard ratio, 0.27; 95% confidence interval, 0.14-0.52; P < .001). Five-year disease-free survival (DFS) was 71.8% with poRT and 64.2% without (P = .680). Using the IPTW method, poRT improved DFS (hazard ratio, 0.51; 95% confidence interval, 0.30-0.85; P = .010). The benefit of poRT on local relapse and DFS was confirmed after exclusion of the extraskeletal subtype. There was no difference in overall survival. Prognostic factors of poorer DFS in multivariate analysis were deeper location, higher grade, incomplete resection, and no poRT. poRT should be offered in patients with eCHS and high-grade or incomplete resection, regardless of the histologic subtype.

Overexpression of Sal-like protein 4 in head and neck cancer: epigenetic effects and clinical correlations.

Sal-like protein 4 (SALL4), an embryonic stem cell factor, has been reported to play an essential role in embryogenesis and oncogenesis. As yet, however, the expression and role of this transcription factor in head and neck squamous cell carcinoma (HNSCC) has not been established. We assessed SALL4 mRNA expression in a well-characterised dataset of 230 HNSCC samples (test cohort 110 cases and validation cohort 120 cases). We also transfected HNSCC cells (FaDu and UM-SCC-6) with SALL4 siRNA and assessed its effects on proliferation and expression of specific epigenetic factors in order to uncover the role of SALL4 in HNSCC. Overexpression of SALL4 was detected in tumour samples of both cohorts. HNSCC cells treated with SALL4 siRNA showed a reduction in growth and a decrease in DNA methyltransferase 3 alpha (DNMT3A) expression. In the patient cohorts, SALL4 overexpression was found to significantly correlate with disease recurrence (p < 0.001) and SALL4 methylation status (p = 0.002). We also found that DNMT3A was significantly upregulated upon SALL4 upregulation (p < 0.001). High expression levels of SALL4 correlated with decreases in disease-free survival (DFS) rates (log-rank test, p < 0.001). Multivariate analysis revealed that SALL4 expression served as an independent prognostic factor for DFS (hazard ratio: 2.566, 95% confidence interval: 1.598-4.121; p < 0.001). Our findings indicate that SALL4 upregulation correlates with HNSCC tumour aggressiveness and an adverse patient outcome. Our findings also indicate that DNMT3A may synergistically contribute to the regulatory effects of SALL4. Our findings provide insight into SALL4-mediated HNSCC development via epigenetic modulation.

Recurrence rates and long-term survival factors in young women with breast cancer.

Objectives:To evaluate the factors related to breast cancer (BC) recurrence as well as survival in women ≤40 years old.Methods:This is a retrospective medical record review of women aged ≤40 years diagnosed with BC stages I to III between January 2009 and June 2017 at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. Demographic data collected included patients’ initial presentation (including age and date of diagnosis), imaging studies, tumor characteristics, type of surgery, systemic therapy (if any) received, and site of first recurrence. Data was analyzed to assess recurrence rate, disease-free survival (DFS), and overall survival (OS), and determine associated factors. Descriptive statistics were used to calculate the mean, median, standard deviation, and quartiles. Chi-square test was performed to test the association between 2 variables. Kaplan-Meier analyses were performed to assess survival distribution.Results:A total of 117 patients were included for analysis. Median follow-up was 16 months (range 0 to 99). Five-year DFS 57% and OS was 89%. Adjuvant chemotherapy was associated with a better DFS (hazard ratio of 0.204; 95% confidence interval, 0.050 to 0.832; p=0.027). Higher tumor, node, metastasis stage was significantly associated with worse DFS (p=0.034). Fewer postoperative follow-up visits significantly predicted recurrence (p=0.003).Conclusion:We found a high risk of BC recurrence among patients at our institution. Higher cancer stage, nonuse adjuvant chemotherapy, and low follow-up rate were significant predictive factors for recurrence.