Re-Evaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials

2021 ◽  
Author(s):  
Jun Yin ◽  
Mohamed E Salem ◽  
Jesse G Dixon ◽  
Zhaohui Jin ◽  
Romain Cohen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Surrogate Endpoint ◽  
Free Survival ◽  
A Value ◽  
Deficient Mismatch Repair ◽  
Disease Free

Abstract Background Disease-free survival with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence, in patients who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from nine randomized studies conducted between 1998 and 2009 were included; three trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18,396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (pT1-3 & pN1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high/deficient mismatch repair tumors. Trial level correlation between 3-year DFS and 5-year OS remained strong (R2 =0.82, 95% CI = 0.67 to 0.98; R2 =0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusion Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

scholarly journals Bevacizumab in Stage II-III Colon Cancer: 5-Year Update of the National Surgical Adjuvant Breast and Bowel Project C-08 Trial

2013 ◽  
Vol 31 (3) ◽  
pp. 359-364 ◽  
Author(s):  
Carmen J. Allegra ◽  
Greg Yothers ◽  
Michael J. O'Connell ◽  
Saima Sharif ◽  
Nicholas J. Petrelli ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Free Survival ◽  
National Surgical Adjuvant Breast ◽  
End Point ◽  
Bowel Project ◽  
Modified Folfox6 ◽  
Disease Free

PurposeThe National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary and secondary end points of disease-free and overall survival, respectively, with 5 years median follow-up time.Patients and MethodsPatients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point.ResultsOf 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35). Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year landmark (time-by-treatment interaction P value <.0001). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99).ConclusionBevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage 2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab. A transient effect on disease-free survival was observed during bevacizumab exposure in the study's experimental arm.

scholarly journals Association Between Disease-Free Survival and Overall Survival When Survival Is Prolonged After Recurrence in Patients Receiving Cytotoxic Adjuvant Therapy for Colon Cancer: Simulations Based on the 20,800 Patient ACCENT Data Set

2010 ◽  
Vol 28 (3) ◽  
pp. 460-465 ◽  
Author(s):  
Aimery de Gramont ◽  
Joleen Hubbard ◽  
Qian Shi ◽  
Michael J. O'Connell ◽  
Marc Buyse ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Disease Free Survival ◽  
Cancer Clinical Trials ◽  
Data Set ◽  
Free Survival ◽  
Disease Free ◽  
Extended Survival

Purpose We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. Methods The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. Results Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R2 = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R2 = 0.67 for both 2- and 3-year DFS) and 7-year OS (R2 = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. Conclusion Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.

Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials

2005 ◽  
Vol 23 (34) ◽  
pp. 8664-8670 ◽  
Author(s):  
Daniel J. Sargent ◽  
Harry S. Wieand ◽  
Daniel G. Haller ◽  
Richard Gray ◽  
Jacqueline K. Benedetti ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Individual Patient Data ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
End Point ◽  
Disease Free

Purpose A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Semimonthly Versus Monthly Regimen of Fluorouracil and Leucovorin Administered for 24 or 36 Weeks as Adjuvant Therapy in Stage II and III Colon Cancer: Results of a Randomized Trial

2003 ◽  
Vol 21 (15) ◽  
pp. 2896-2903 ◽  
Author(s):  
Thierry André ◽  
Philippe Colin ◽  
Christophe Louvet ◽  
Erik Gamelin ◽  
Olivier Bouche ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Free Survival ◽  
Treatment Groups ◽  
Significant Difference ◽  
Grade 3 ◽  
Disease Free

Purpose: This randomized, 2 × 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes’ B2) and III (Dukes’ C) colon cancer. Patients and Methods: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. Results: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P = .74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P = .63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P = .18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P < .001). Conclusion: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.

Radical hysterectomy in early cervical cancer in Europe: characteristics, outcomes and evaluation of ESGO quality indicators

2021 ◽  
pp. ijgc-2021-002587
Author(s):  
Felix Boria ◽  
Luis Chiva ◽  
Vanna Zanagnolo ◽  
Denis Querleu ◽  
Nerea Martin-Calvo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Overall Survival ◽  
Quality Indicators ◽  
Radical Hysterectomy ◽  
Disease Free Survival ◽  
Free Survival ◽  
Operative Complications ◽  
Early Cervical Cancer ◽  
Disease Free

IntroductionComprehensive updated information on cervical cancer surgical treatment in Europe is scarce.ObjectiveTo evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database.MethodsThe SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified.ResultsThe mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m2 (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) <2 cm was observed in 667 (57.7%) patients. The most frequent histology type was squamous carcinoma (794 (68.7%) patients), and positive lymph nodes were found in 143 (12.4%) patients. A total of 633 (54.8%) patients were operated by open abdominal surgery. Intra-operative complications occurred in 108 (9.3%) patients, and post-operative complications during the first month occurred in 249 (21.5%) patients, with bladder dysfunction as the most frequent event (119 (10.3%) patients). Clavien-Dindo grade III or higher complication occurred in 56 (4.8%) patients. A total of 510 (44.1%) patients received adjuvant therapy. After a median follow-up of 58 months (range 0–84), the 5-year disease-free survival was 88.3%, and the overall survival was 94.9%. In our population, 10 of the 11 surgical-related quality indicators currently recommended by ESGO were fully fulfilled 5 years before its implementation.ConclusionsIn this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.

scholarly journals Ecoendoscopia en la estadificación del cáncer de esófago y de estómago

2021 ◽  
Vol 113 (1) ◽  
pp. 32-42
Author(s):  
Martín Galvarini Recabarren ◽  
◽  
Francisco Schlottmann ◽  
C. Agustín Angeramo ◽  
Javier Kerman Cabo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Neoadjuvant Therapy ◽  
Preoperative Staging ◽  
Disease Free Survival ◽  
Perioperative Chemotherapy ◽  
Free Survival ◽  
Causes Of Mortality ◽  
Node Metastases ◽  
Disease Free

Background: Gastric adenocarcinoma (GAC) and esophageal adenocarcinoma (EAC) are one of the leading causes of mortality from gastrointestinal cancer worldwide. Endoscopic ultrasound (EUS) has proved to be a valuable tool for preoperative staging of GAC and EAC in selected cases. Objective: The aim of this study was to evaluate the usefulness of EUS for staging of EAC and GAC and selecting patients who are candidates for neoadjuvant therapy, as compared with the previous stage before the implementation of EUS, in a surgical center in Argentina. Material and methods: Consecutive patients with EAC and GAC between 2013-2019 were included. Patients with criteria of unresectable cancer or who underwent emergency surgery were excluded. The sample was divided into four groups G1 and G2 (EAC with and without EUS, respectively) and G3 and G4 (GAC with and without EUS, respectively). The clinical and anatomopathological variables and survival were evaluated in all the groups. Results: A total of 89 patients were included, 40 with EAC (30 in G1 and 10 in G2, and 49 with GAC, 20 in G3 and 29 in G4. Of the patients undergoing EUS staging in G1, 23 (75%) received neoadjuvant therapy vs. 2 patients in G2 (20%) (P ≤ 0.005). Eight patients (40%) in G3 and 2 (7%) in G4 received perioperative chemotherapy (P ≤ 0.005). Lymph node metastases were observed in 9 (30%) of surgical specimens of EAC in G1 and in 60% in G2 (P ≤ 0.005), and in 45% in G3 and G4. After a mean follow-up of 36 months (6-72), we observed a non-significant trend toward higher overall survival and disease-free survival in patients undergoing EUS staging. Conclusion: EUS for preoperative staging pf EAC and GAC is a useful tool. Although the use of EUS use may be a challenging task in many centers in Argentina, future efforts are needed to include this test in selected cases for staging patients with these types of cancers

scholarly journals Combination of CDX2 expression and T stage improves prognostic prediction of colorectal cancer

2019 ◽  
Vol 47 (5) ◽  
pp. 1829-1842 ◽  
Author(s):  
Weimin Xu ◽  
Yilian Zhu ◽  
Wei Shen ◽  
Wenjun Ding ◽  
Tingyu Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Hazard Ratio ◽  
Free Survival ◽  
T Stage ◽  
Cdx2 Expression ◽  
Prognostic Prediction ◽  
Disease Free

Objective Prognostic prediction of colorectal cancer (CRC) remains challenging because of its heterogeneity. Aberrant expression of caudal-type homeobox transcription factor 2 (CDX2) is strongly correlated with the prognosis of CRC. Methods Tissue samples of patients with CRC who underwent surgery in Xinhua Hospital (Shanghai, China) from January 2010 to January 2013 were collected. CDX2 expression was semiquantitatively evaluated via immunohistochemistry. Results In total, 138 patients were enrolled in this study from a prospectively maintained institutional cancer database. The median follow-up duration was 57.5 months (interquartile range, 17.0–71.0 months). In the Cox proportional hazards model, low CDX2 expression combined with stage T4 CRC was significantly the worst prognostic factor for disease-free survival (hazard ratio = 7.020, 95% confidence interval = 3.922–12.564) and overall survival (hazard ratio = 5.176, 95% CI = 3.237–10.091). In the Kaplan–Meier survival analysis, patients with low CDX2 expression and stage T4 CRC showed significantly worse disease-free survival and overall survival than those with low CDX2 expression alone. Conclusion CDX2 expression combined with the T stage was more accurate for predicting the prognosis of CRC. Determining the prognosis of CRC using more than one variable is valuable in developing appropriate treatment and follow-up strategies.

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