Toward Progression-Free Survival As a Primary End Point in Advanced Colorectal Cancer

2007 ◽  
Vol 25 (33) ◽  
pp. 5153-5154 ◽  
Author(s):  
Greg Yothers
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Free Survival ◽  
End Point

Progression-Free Survival Is a Surrogate for Survival in Advanced Colorectal Cancer

2007 ◽  
Vol 25 (33) ◽  
pp. 5218-5224 ◽  
Author(s):  
Marc Buyse ◽  
Tomasz Burzykowski ◽  
Kevin Carroll ◽  
Stefan Michiels ◽  
Daniel J. Sargent ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Correlation Coefficient ◽  
Treatment Effects ◽  
Advanced Colorectal Cancer ◽  
Rank Correlation ◽  
Correlation Coefficients ◽  
Progression Free Survival ◽  
End Points ◽  
Free Survival ◽  
End Point

Purpose The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. Patients and Methods Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. Results In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. Conclusion PFS is an acceptable surrogate for OS in advanced colorectal cancer.

scholarly journals Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Wei Yu ◽  
Qiaomeng Tao ◽  
Yufeng Zhang ◽  
Fengming Yi ◽  
Long Feng
Keyword(s):  
Colorectal Cancer ◽  
Adverse Reactions ◽  
Advanced Colorectal Cancer ◽  
Cox Regression ◽  
Combined Therapy ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Free Survival ◽  
The Third ◽  
Third Line

Background. The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. Methods. We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan–Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). Results. The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0–272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment ( p = 0.005 ). Lung metastasis was a negative factor in combined therapy ( p = 0.032 ). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy ( p = 0.034 ). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 ( p = 0.034 ). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. Conclusions. Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy.

Randomized Multicenter Phase II Trial of Two Different Schedules of Capecitabine Plus Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

2003 ◽  
Vol 21 (7) ◽  
pp. 1307-1312 ◽  
Author(s):  
Werner Scheithauer ◽  
Gabriela V. Kornek ◽  
Markus Raderer ◽  
Birgit Schüll ◽  
Katharina Schmid ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Time ◽  
Phase Ii ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Progression Free Survival ◽  
Synergistic Activity ◽  
Free Survival ◽  
Multicenter Phase ◽  
To Receive

Purpose: Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study. Patients and Methods: Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m2 day 1 plus capecitabine 2,000 mg/m2/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m2 days 1 and 14 combined with capecitabine 3,500 mg/m2 days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease. Results: Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P = .0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%). Conclusion: Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.

scholarly journals The Role of Serum CEA and CA19-9 in Efficacy Evaluations and Progression-Free Survival Predictions for Patients Treated with Cetuximab Combined with FOLFOX4 or FOLFIRI as a First-Line Treatment for Advanced Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jun Jia ◽  
Pengfei Zhang ◽  
Miaomiao Gou ◽  
Fan Yang ◽  
Niansong Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Baseline Level ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Effective Rate ◽  
First Line ◽  
Free Survival ◽  
Early Predictors ◽  
First Line Treatment

Background. Previously, it was demonstrated that serum levels of tumor markers, CEA and CA19-9, correlated with chemotherapy. Consequently, it has been hypothesized that dynamic monitoring of changes in these markers may predict the shrinkage or growth of colorectal cancers. To test this hypothesis, we analyzed CEA and CA19-9 serum levels in patients with advanced colorectal cancer who received cetuximab in combination with chemotherapy. These levels were evaluated at various time points to identify their potential to serve as early efficacy predictors during treatment and early predictors of disease progression. Patients and Methods. Measurements of tumor markers, CEA and CA 19-9, in patients with metastatic colorectal cancer (n=73) who received cetuximab plus folinic acid, fluorouracil, and oxaliplatin or irinotecan (FOLFOX4/FOLFIRI) as a first-line treatment at our center were retrospectively analyzed. These levels were also compared with objective responses according to the World Health Organization criteria. Initially, 65 patients had elevated CEA levels (>5 ng/ml), and 59 patients had elevated levels of CA19-9 (>37 U/ml). A total of 172 cycles and 165 cycles of computed tomography/magnetic resonance imaging observations were available for review from these two patient groups. Results. After completing three cycles of treatment, the best diagnosis of cetuximab resistance was achieved when CEA increased by 35% (efficacy, 83.33%; sensitivity, 75.41%) and when CA19-9 increased by 28% (efficacy, 80.00%; sensitivity, 84.31%). Next, the efficacy of cetuximab at the time of diagnosis (at the first imaging examination/after three cycles of treatment) was evaluated after the first cycle of chemotherapy. When CEA decreased by 60% from its baseline level, the best effective rate and sensitivity were observed (63.64% and 80.95%, respectively). Similarly, when CA19-9 was 45% lower than its baseline level, the best effective rate and sensitivity were observed (84.21% and 93.18%, respectively). To evaluate progression-free survival (PFS), levels of both CEA and CA19-9 were evaluated after the third cycle of chemotherapy. Increases of 35% and 28%, respectively, resulted in a shorter PFS period compared with the other patients (3.15 months vs. 9.10 months, respectively; P<0.0001). Conversely, when the evaluation was performed after the first cycle of chemotherapy, patients exhibiting a 60% decrease in CEA and a 45% decrease in CA19-9 had a longer PFS period (11.13 months vs. 8.10 months, respectively; P=0.0395). Conclusions. CEA and CA19-9 are useful indicators of therapeutic curative effect from cetuximab combined with first-line chemotherapy. These markers also helped assess cetuximab resistance and served as early predictors of initial treatment effectiveness. Furthermore, a simultaneous increase or decrease in the levels of both indicators was consistent with the observed differences in PFS.

Correlation of immunological effects of anti-VEGF therapy with progression-free survival of advanced colorectal cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14559-e14559
Author(s):  
M. Manzoni ◽  
B. Rovati ◽  
S. Delfanti ◽  
K. Bencardino ◽  
S. Chatzileontiadou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Efficacy ◽  
Advanced Colorectal Cancer ◽  
Immune Surveillance ◽  
Flow Cytometric Analysis ◽  
Progression Free Survival ◽  
Absolute Number ◽  
Biological Data ◽  
Free Survival ◽  
Colorectal Cancer Patients

e14559 Background: The clinical efficacy of Bevacizumab (BEV) in advanced colorectal cancer (mCRC) could be related not only to its well-established effect on tumor neoangiogenesis but also to a counteraction of VEGF-mediated dendritic cell (DC) abnormalities. The addition of BEV to chemotherapy (CT) may improve the number and function of blood DCs in cancer pts. We have focused on the correlation between this effect and the clinical efficacy of a BEV-based, 1st-line treatment for mCRC. Methods: Starting from January 2007 we performed a flow cytometric analysis of PB lymphocytes and DC subsets in 53 mCRC pts who had not received prior CT for metastatic disease or for whom 6 months had elapsed since adjuvant CT (M/F: 31/22, median age: 59yrs; range 32–75; ECOG PS <2), before and every 3 courses of a BEV+CT (5-FU± CPT11± Oxaliplatin) program. Biological data of the 42 evaluable pts that received all the planned treatment were correlated to both tumor response (OR) and progression free survival (PFS). Results: During treatment, DCs and their subsets showed a progressive, significant increase in absolute number, with respect to baseline, both in responder (CR,PR,SD) (67%) and in non responder pts. This effect on the DC profile was evidenced in responder pts up to 4 weeks since the last treatment course. After therapy completion, pts with PFS > 15 months (58%) showed DC and DC1 absolute number significantly higher with respect to pts with shorter PFS (p< .02). Conclusions: The recovery of blood DCs induced by 1st- line, BEV-based therapy in mCRC pts indicates a potential additional anticancer mechanism of this drug. The improvement of DC number does not influence OR but correlates with longer PFS. This suggests that BEV can influence tumor regrowth by contributing to overcome the impairement of the host immune surveillance induced by VEGF. No significant financial relationships to disclose.

Gemcitabine and capecitabine as third-line treatment in patients with metastatic colorectal cancer after failure of irinotecan and oxaliplatin.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 620-620 ◽  
Author(s):  
M. Qiu ◽  
F. Bi ◽  
J. Liu ◽  
Q. Li ◽  
C. Yi
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Performance Status ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Disease Stabilization ◽  
Third Line ◽  
Third Line Treatment

620 Background: There is no standard chemotherapeutic regimen for patients with advanced colorectal cancer (CRC) progressing after combination regimens including irinotecan and oxaliplatin and having good performance status. 5-FU and gemcitabine are synergistic in preclinical studies of colon cancer cells. And gemcitabine also increases intracellular release of 5-FU from capecitabine. The aim of this study is to evaluate the efficacy and tolerance of the gemcitabine/capecitabine combination as third-line treatment for patients with advanced colorectal cancer. Methods: Between May 2007 and September 2009, the data on 12 patients with metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens reviewed retrospectively. The median patient age was 54.0 years (range 37-77). The ECOG performance status was 0, 1 or 2. All patients has 2 or more previous chemotherapy. Patients received GemCap regimen (oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 on days 1 and 8 every 3 weeks). Eleven patients were evaluable for the response and all patients were evaluable for toxicity. Results: No partial response was achieved and disease stabilization in 4 (36.4.3%) cases. Median progression-free survival and median overall survival were 9.1 weeks (range 3.0-18.0) and 22.3 weeks (range 10.5- 53.0). Four patients with disease stabilization had longer median progression-free survival than those with disease progression (13 weeks vs. 6.2 weeks). No toxic deaths occurred. Grade 3 toxicities were thrombocytopenia (in 2 patients), neutropenia (in 2 patients) and mucositis (in 1 patient), hand-foot syndrome (in 1 patient) and GI toxicity (in 2 patients). Conclusions: The combination of gemcitabine and capecitabine was found to be a safe palliative regimen for heavily pretreated patients with metastatic CRC. Despite no patients had radiologic response, patients with disease stabilization achieved better progression-free survival. This regimen seems to be potentially effective regimen in the treatment of CRC. No significant financial relationships to disclose.

scholarly journals Individual Patient Data Analysis of Progression-Free Survival Versus Overall Survival As a First-Line End Point for Metastatic Colorectal Cancer in Modern Randomized Trials: Findings From the Analysis and Research in Cancers of the Digestive System Database

2015 ◽  
Vol 33 (1) ◽  
pp. 22-28 ◽  
Author(s):  
Qian Shi ◽  
Aimery de Gramont ◽  
Axel Grothey ◽  
John Zalcberg ◽  
Benoist Chibaudel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Individual Patient Data ◽  
Progression Free Survival ◽  
Patient Data ◽  
Biologic Agents ◽  
First Line ◽  
Free Survival ◽  
End Point

Purpose Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Results Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. Conclusion In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

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