Systemic Therapy for Metastatic Colorectal Cancer: Current Options, Current Evidence

2005 ◽  
Vol 23 (20) ◽  
pp. 4553-4560 ◽  
Author(s):  
Hanna Kelly ◽  
Richard M. Goldberg
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Response Rate ◽  
Single Agent ◽  
Chemotherapeutic Agents ◽  
Current Data ◽  
Phase Iii ◽  
Current Evidence ◽  
First Line ◽  
Improve Response Rate

Combination chemotherapy regimens including irinotecan and oxaliplatin markedly improve response rate and prolong median survival over fluorouracil with leucovorin (FU/LV), and have supplanted FU/LV as the standard systemic approach for metastatic colorectal cancer. The recent availability of five active chemotherapeutic agents has doubled the median overall survival for metastatic colorectal cancer from 10 to 20 months, and though the optimal strategy for incorporation of all drugs is still unclear, current data support the use of chemotherapy doublets in first-line rather than sequential single-agent therapy. Multidrug regimens increase both response rate and the proportion of patients able to undergo potentially curative resection. In addition, as many as 20% to 30% of patients never receive second-line chemotherapy. When used as single agents, bolus and infusional FU/LV and capecitabine are similarly effective but have differing toxicity. Chemotherapy combinations that incorporate infusion of FU are less toxic and more effective than those using bolus FU dosing. Capecitabine is under study as an alternative dosing method for use in combination regimens; however, the optimal dose has not been defined and final safety and efficacy outcomes are being addressed in ongoing phase II and III investigations. Three combinations have shown excellent first-line efficacy in phase III trials—IFL with bevacizumab, FOLFOX, and FOLFIRI—but neither of these combinations is clearly superior. Sound clinical judgment must continue to guide treatment decisions while we await data regarding the optimal combination and sequence of fluorouracil, irinotecan, oxaliplatin, bevacizumab, and cetuximab.

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.

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.

Comparison of Oral Capecitabine Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Treatment in 605 Patients With Metastatic Colorectal Cancer: Results of a Randomized Phase III Study

2001 ◽  
Vol 19 (8) ◽  
pp. 2282-2292 ◽  
Author(s):  
Paulo M. Hoff ◽  
Rafat Ansari ◽  
Gerald Batist ◽  
John Cox ◽  
Walter Kocha ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Response Rate ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Oral Capecitabine ◽  
Grade 3 ◽  
First Line Treatment

PURPOSE: To compare the response rate, efficacy parameters, and toxicity profile of oral capecitabine with bolus intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 605 patients to treatment with oral capecitabine for 14 days every 3 weeks or 5-FU/LV by rapid IV injection daily for 5 days in 4-week cycles. RESULTS: The overall objective tumor response rate among all randomized patients was significantly higher in the capecitabine group (24.8%) than in the 5-FU/LV group (15.5%; P = .005). In the capecitabine and 5-FU/LV groups, median times to disease progression were 4.3 and 4.7 months (log-rank P = .72), median times to treatment failure were 4.1 and 3.1 months (P = .19), and median overall survival times were 12.5 and 13.3 months (P = .974), respectively. Capecitabine, compared with bolus 5-FU/LV treatment, produced a significantly lower incidence (P < .0002) of diarrhea, stomatitis, nausea, and alopecia. Patients treated with capecitabine also displayed lower incidences of grade 3/4 stomatitis and grade 3/4 neutropenia (P < .0001) leading to significantly less neutropenic fever/sepsis. Grade 3 hand-foot syndrome (P < .00001) and grade 3/4 hyperbilirubinemia were the only toxicities more frequently associated with capecitabine than with 5-FU/LV treatment. CONCLUSION: Oral capecitabine was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability.

Phase IV study of first-line bevacizumab plus irinotecan and infusional 5-FU/LV in patients with metastatic colorectal cancer: AVIRI

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4068-4068 ◽  
Author(s):  
A. F. Sobrero ◽  
S. Young ◽  
M. Balcewicz ◽  
S. Chiarra ◽  
R. Perez Carrion ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Safety Profile ◽  
Overall Response Rate ◽  
Response Rate ◽  
Primary Objective ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Overall Response

4068 Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF. In a phase III trial (AVF2107g), BEV significantly improved overall (OS) and progression-free survival (PFS) when combined with first-line irinotecan plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (IFL) in patients with metastatic colorectal cancer (mCRC). A multicentre, open-label trial is being conducted to evaluate the efficacy and safety of first-line BEV in combination with irinotecan and infusional 5-FU (FOLFIRI), a widely used first-line chemotherapy (CT) regimen. Methods: Patients had to have: mCRC; no surgery within 28 days; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function; no CNS metastases. CT consisted of a minimum of six cycles of irinotecan plus infusional 5-FU/LV according to the classical FOLFIRI regimen; variations like the simplified FOLFIRI and the weekly regimen were also allowed. BEV 5mg/kg was given on day 1 with CT and then every 2 weeks until disease progression. Tumour assessments were performed every 3 months during the first 12 months and every 4 months thereafter. Safety was assessed at the time of CT administration and every 4 weeks thereafter. The primary objective was PFS; secondary objectives included safety, overall response rate, time to response, duration of response and OS. Results: A total of 209 patients were enrolled at 31 centres worldwide, between April and November 2005. An interim analysis showed that the safety profile of BEV plus FOLFIRI appeared to be similar to that reported for Avastin plus IFL. The 44% overall response rate and 90% disease control rate are at least equivalent to that reported in comparable trials. Additionally, the 6 months PFS estimate of 82% was superior to that reported in AVF2107. Mature PFS data will be presented. Conclusions: AVIRI is the largest clinical trial, to date, to report data for BEV in combination with FOLFIRI in first-line patients with mCRC. The safety profile appears consistent with that observed in other BEV trials in mCRC, while the preliminary efficacy data suggest that this regimen is as active as the bolus regimen. No significant financial relationships to disclose.

Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3521-3521 ◽  
Author(s):  
Mark P. Saunders ◽  
Istvan Lang ◽  
Eugenio Marcuello ◽  
Vito Lorusso ◽  
Janja Ocvirk ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Elderly Patients ◽  
Metastatic Colorectal Cancer ◽  
Statistical Significance ◽  
Single Agent ◽  
Age Groups ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Phase Iii Trial

3521 Background: Elderly patients (pts) are underrepresented in clinical trials. The open-label phase III trial AVEX evaluated the benefit of adding bevacizumab (BEV) to capecitabine (cape) in elderly pts with previously untreated metastatic colorectal cancer (mCRC). This analysis explores clinical outcomes by age subgroup. Methods: In AVEX, 280 pts ≥70 y with mCRC for whom single-agent chemotherapy was deemed appropriate, were randomized to first-line cape (1000 mg/m2bid days 1–14) alone (n=140) or with BEV (7.5 mg/kg) q3w (n=140). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate, and safety. The study was powered to show a difference in PFS but not OS. A post hoc analysis was conducted to assess PFS, OS, and safety in pts 70–74 y, 75–79 y, and ≥80 y. Results: Median age was 76 y (range, 70–87). In the overall population, BEV + cape significantly prolonged PFS compared with cape (median 9.1 vs 5.1 mo; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<.001). Differences in OS did not reach statistical significance in the overall population (HR, 0.79; 95% CI, 0.57–1.09; p=.182). Treatment was well tolerated. Results according to age are shown (Table). Conclusions: The addition of BEV to cape was associated with significant improvements in PFS in the overall elderly mCRC population and within age subgroups. The safety profile of BEV + cape was consistent across age groups. Clinical trial information: NCT00484939. [Table: see text]

scholarly journals Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group

2017 ◽  
Vol 28 (6) ◽  
pp. 1288-1293 ◽  
Author(s):  
J.J.M. Kwakman ◽  
L.H.J. Simkens ◽  
J.M. van Rooijen ◽  
A.J. van de Wouw ◽  
A.J. ten Tije ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Phase Iii Trial ◽  
Cancer Group ◽  
First Line Treatment
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