Physical activity program in patients with metastatic colorectal cancer who receive palliative first-line chemotherapy: A randomized controlled phase III trial—(ACTIVE-2 SAKK 41/14).

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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Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2006.08.1935 ◽

2007 ◽

Vol 25 (29) ◽

pp. 4562-4568 ◽

Cited By ~ 169

Author(s):

Patricia A. Tang ◽

Søren M. Bentzen ◽

Eric X. Chen ◽

Lillian L. Siu

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Randomized Controlled Trials ◽

Metastatic Colorectal Cancer ◽

Controlled Trials ◽

First Line ◽

End Points ◽

Randomized Controlled ◽

Hazard Ratios ◽

Line Chemotherapy

Purpose Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS. Methods Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points. Results Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (rs) between differences (Δ) in surrogate end points (ΔPFS, ΔTTP, and ΔRR) and ΔOS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The rs for ΔPFS was not significantly different from the rs ΔTTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 ± 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% ± 1% risk reduction for OS. Conclusion In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.

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Outcome and dose intensity (DI) in the elderly subgroup of the AGITG MAX phase III trial of capecitabine (C), bevacizumab (B), and mitomycin C (M) in first-line metastatic colorectal cancer (CRC).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.3621 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 3621-3621

Author(s):

T. J. Price ◽

D. Zannino ◽

K. Wilson ◽

J. Simes ◽

G. A. Van Hazel ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Mitomycin C ◽

Dose Intensity ◽

The Elderly ◽

Max Phase ◽

Phase Iii ◽

First Line ◽

Phase Iii Trial

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Retrospective cohort study on the safety and efficacy of bevacizumab for metastatic colorectal cancer patients: The HGCSG0801 study—Analysis of bevacizumab beyond progression (BBP).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.684 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 684-684

Author(s):

Hiraku Fukushima ◽

Satoshi Yuki ◽

Yoshimitsu Kobayashi ◽

Kazuteru Hatanaka ◽

Takaya Kusumi ◽

...

Keyword(s):

Colorectal Cancer ◽

Cohort Study ◽

Adverse Events ◽

Metastatic Colorectal Cancer ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Phase Iii ◽

Second Line ◽

First Line ◽

Line Chemotherapy

684 Background: Bevacizumab (BV) is widely used in first-line chemotherapy for metastatic colorectal cancer in Japan, but the use of beyond bevacizumab first progression (BBP) has been controversial yet. Methods: Of patients treated with first-line BV in our retrospective cohort study (HGCSG0801), patients treated with BBP (n=22) and those without BBP ( n=19) in second-line setting were analyzed. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to assess adverse events. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine PFS and OS. Log-rank test was used to compare each group in terms of PFS and OS. All statistical tests were performed using SPSS. Results: PS (0/1/2) before second line chemotherapy was 18/3/1 in BBP and 10/8/1 in NBBP, respectively. In the safety analysis, five patients in BBP showed a worsening/newer hypertension, which wasn’t a clinical problem. In the efficacy analysis, the response rate was 22.8% in BBP and 0% in NBBP. The median PFS was better in BBP (6.7 months in BBP and 2.7 months in NBBP), but there was no significant difference in median OS from first BV administration between two groups (27.3 months in BBP and 22.2 months in NBBP). Conclusions: We analyzed BBP in daily practice in Japan. Adverse events were well tolerated, but survival advantage of BBP was not suggested. About the efficacy of BBP, we are waiting the results of ongoing Phase III trials.

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Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients with metastatic colorectal cancer (mCRC): Efficacy and safety results of the international GERCOR DREAM phase III trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.lba3500 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. LBA3500-LBA3500

Author(s):

Christophe Tournigand ◽

Benoit Samson ◽

Werner Scheithauer ◽

Gérard Lledo ◽

Frédéric Viret ◽

...

Keyword(s):

Colorectal Cancer ◽

Maintenance Therapy ◽

Phase Iii ◽

Efficacy And Safety ◽

First Line ◽

Daily News ◽

Phase Iii Trial ◽

Online Supplement ◽

Final Text ◽

Line Chemotherapy

LBA3500^ The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

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Sequential first-line treatment for metastatic colorectal cancer with capecitabine, irinotecan, and bevacizumab: Capecitabine plus bevacizumab (Cape-Bev) versus capecitabine, irinotecan plus bevacizumab (CAPIRI-Bev): The AIO KRK 0110/ML22011 randomized, phase III trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps3639 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS3639-TPS3639

Author(s):

Clemens Albrecht Giessen ◽

Dominik Paul Modest ◽

Sebastian Stintzing ◽

Ludwig Fischer von Weikersthal ◽

Ursula Vehling-Kaiser ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Single Agent ◽

Cytotoxic Agents ◽

Phase Iii ◽

Time To Failure ◽

Line Treatment ◽

First Line ◽

Phase Iii Trial ◽

First Line Treatment

TPS3639 Background: Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question in bevacizumab-based first-line treatment including escalation- and de-escalation strategies. Methods: The AIO KRK 0110/ML22011 trial (ClinicalTrials.gov NCT01249638) is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of Cape-Bev versus CAPIRI-Bev in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, ECOG PS 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14), irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumor tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are ORR, OS, PFS, safety and quality of life. Conclusion: The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with CAPIRI-Bev and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary. By January 2012, 79 of planned 516 patients have been enrolled.

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