Development and validation of a prognostic nomogram for colorectal cancer after radical resection based on individual patient data from three large-scale phase III trials

Purpose The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Methods Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. Results DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. Conclusion DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.

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Treatment breaks in first line treatment of advanced colorectal cancer: an individual patient data meta-analysis

Cancer Treatment Reviews ◽

10.1016/j.ctrv.2021.102226 ◽

2021 ◽

pp. 102226

Author(s):

Richard Adams ◽

Kaitlyn Goey ◽

Benoist Chibaudel ◽

Miriam Koopman ◽

Cornelis Punt ◽

...

Keyword(s):

Colorectal Cancer ◽

Advanced Colorectal Cancer ◽

Individual Patient Data ◽

Meta Analysis ◽

Patient Data ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286420975916 ◽

2021 ◽

Vol 14 ◽

pp. 175628642097591

Author(s):

Thomas F. Scott ◽

Ray Su ◽

Kuangnan Xiong ◽

Arman Altincatal ◽

Carmen Castrillo-Viguera ◽

...

Keyword(s):

Clinical Trials ◽

Propensity Score ◽

Clinical Outcomes ◽

Glatiramer Acetate ◽

Therapeutic Efficacy ◽

Individual Patient Data ◽

Patient Data ◽

Phase Iii ◽

Lower Probability ◽

Phase Iii Clinical Trials

Background: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. Methods: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1–3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. Results: Propensity-score-matched peginterferon beta-1a patients ( n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients ( n = 834). Conclusion: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

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Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

Journal of Clinical Oncology ◽

10.1200/jco.2004.11.037 ◽

2004 ◽

Vol 22 (7) ◽

pp. 1209-1214 ◽

Cited By ~ 761

Author(s):

Axel Grothey ◽

Daniel Sargent ◽

Richard M. Goldberg ◽

Hans-Joachim Schmoll

Keyword(s):

Colorectal Cancer ◽

Advanced Colorectal Cancer ◽

Cytotoxic Agents ◽

Phase Iii ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Phase Iii Trials

Purpose Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. Materials and Methods We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. Results The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083). Conclusion Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

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Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.5.1501 ◽

2001 ◽

Vol 19 (5) ◽

pp. 1501-1518 ◽

Cited By ~ 205

Author(s):

Udo Vanhoefer ◽

Andreas Harstrick ◽

Wolf Achterrath ◽

Shousong Cao ◽

Siegfried Seeber ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Topoisomerase I ◽

Clinical Status ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Phase Iii Trials ◽

Line Chemotherapy

PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I–interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.

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