A Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer

2004 ◽  
Vol 22 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Richard M. Goldberg ◽  
Daniel J. Sargent ◽  
Roscoe F. Morton ◽  
Charles S. Fuchs ◽  
Ramesh K. Ramanathan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Survival Time ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Controlled Trial ◽  
Sensory Neuropathy ◽  
Time To Progression ◽  
Severe Nausea ◽  
End Points

Purpose Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. Patients and Methods Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. Results A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. Conclusion The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.

Randomized Controlled Trial of Reduced-Dose Bolus Fluorouracil Plus Leucovorin and Irinotecan or Infused Fluorouracil Plus Leucovorin and Oxaliplatin in Patients With Previously Untreated Metastatic Colorectal Cancer: A North American Intergroup Trial

2006 ◽  
Vol 24 (21) ◽  
pp. 3347-3353 ◽  
Author(s):  
Richard M. Goldberg ◽  
Daniel J. Sargent ◽  
Roscoe F. Morton ◽  
Charles S. Fuchs ◽  
Ramesh K. Ramanathan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Controlled Trial ◽  
Sensory Neuropathy ◽  
Second Line ◽  
Time To Progression ◽  
Second Line Therapy ◽  
The North ◽  
Line Therapy

Purpose Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade ≥ 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. Patients and Methods The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. Results Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. Conclusion FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

Tegafur combined with oxaliplatin and 5-FU versus FOLFOX4 for advanced colorectal cancer: a randomized controlled study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13566-13566
Author(s):  
L. Lingxiang ◽  
S. Yongqian ◽  
L. Ping ◽  
H. Puwen ◽  
Y. Yongmei
Keyword(s):  
Colorectal Cancer ◽  
Survival Time ◽  
Median Time ◽  
Side Effect ◽  
Median Survival Time ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Time To Progression ◽  
Group A ◽  
Group B

13566 Background: To determine the activity and side-effect of tegarfur injection combined with L-OHP and 5-FU, comparing with FOLFOX4 as the therapy for advanced colorectal cancer. Methods: 60 patients, proved pathologically, were divided into 2 groups at random. Group A received the intravenous administration of tegafur(800mg/m2 IV 3hrs qd d1–5),leucovorin(100mg/m2 IV 2hrs qd d1–5) and L-OHP(130mg/m2 IV 2hrs d1) every 21 days. FOLFOX4 was applied in the group B. The endpoint included response rate (RR), progression free survival (PFS), overall survival(OS) and quality of life(QOL). Results: The response rate was 39.3% in the group A, while median time to progression was 9.5 months with median survival time of 11.6 months. In the group B, the response rate was 48.1% and median time to progression was 9.4 months with median survival time of 12.1 months. No significant differences were found between treatment arms in curative effect, survival time and side effect(P>0.05). With respect to QOL, the group A achieved higher PS than B during treatment (P<0.001). Conclusions: The intravenous administration of tegafur, leucovorin and L-OHP is a well-tolerated, effective, and feasible schedule for advanced colorectal cancer that yields comparable efficacy and side effect compared with FOLFOX4. Meanwhile, the former achieves the better QOL. No significant financial relationships to disclose.

A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer.

1993 ◽  
Vol 11 (10) ◽  
pp. 1888-1893 ◽  
Author(s):  
L R Laufman ◽  
R M Bukowski ◽  
M A Collier ◽  
B A Sullivan ◽  
R A McKinnis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Failure ◽  
Metastatic Colorectal Cancer ◽  
Response Rate ◽  
Controlled Trial ◽  
Double Blind ◽  
Time To Treatment Failure ◽  
To Receive ◽  
Toxicity Pattern

PURPOSE A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.

1997 ◽  
Vol 15 (1) ◽  
pp. 251-260 ◽  
Author(s):  
P Rougier ◽  
R Bugat ◽  
J Y Douillard ◽  
S Culine ◽  
E Suc ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Objective Response ◽  
World Health ◽  
Who Grade ◽  
Pretreated Patients ◽  
Grade 3

PURPOSE To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

First-line single-agent cetuximab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3553-3553 ◽  
Author(s):  
A. Pessino ◽  
S. Artale ◽  
A. Guglielmi ◽  
S. Sciallero ◽  
G. Fornarini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Great Majority ◽  
Skin Toxicity ◽  
Common Adverse Event ◽  
Time To Progression ◽  
Grade 3

3553 Background: The most relevant recent advance in the treatment of metastatic colorectal cancer is the fact that cure is still possible under very selected conditions. However the goal of chemotherapy remains palliative in the great majority of patients, justifying less toxic innovative approaches in so- called “window of opportunity trials”. We have pursued this idea in a phase II study of cetuximab monotherapy in chemo-naive patients with advanced colorectal cancer beyond any possibility of curative resection. Methods: Patients with non-resectable metastatic colorectal cancer (at least two metastatic sites and/or otherwise inoperable metastatic disease) were treated with cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) until progressive disease (PD) or unacceptable toxicity. The primary end-point was objective response; secondary end-points were: stable disease, time to treatment failure and time to progression. According to Simon’s two-stage design, the number of responses/patients to stop the trial was 0/10 for stage 1 and 3/29 for stage 2. Results: Of the 44 patients screened, 42 (97%) had EGFR-expressing tumors. Thirty-nine patients (median age: 69) initiated the treatment. Two had grade 3 allergic reactions to cetuximab at the first administration leading to treatment discontinuation. The most common adverse event was skin toxicity, which occurred in 90% of the patients ( 31% grade 2, 10 % grade 3). We observed 1 complete response, 3 partial responses, 13 stable diseases (5 of which were minor responses), and 22 PD. The duration of the 4 responses were 12, 9, 9 and 6 months. Median time to progression was 2.0 months. Conclusions: The study is negative because the response rate is low. However, the duration of benefit in the few responding patients is such that it is imperative to find the molecular determinants of cetuximab activity in these cases. [Table: see text]

Phase II clinical study of combination therapy with irinotecan and S-1(IRIS) for inoperable recurrent advanced colorectal cancer: Hokkaido Gastrointestinal Cancer Study Group study HGCSG-0302)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3589-3589
Author(s):  
Y. Komatsu ◽  
S. Yuki ◽  
H. Akita ◽  
M. Kudo ◽  
M. Tateyama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Study ◽  
Combination Therapy ◽  
Survival Time ◽  
Phase Ii ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Dose Intensity ◽  
Outpatient Basis ◽  
Phase Ii Clinical Study

3589 Background: We planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. We reported the interium reports of this study in colorectal cancer patients at GI cancer Symposium 2006. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: Forty patients were enrolled in the present study. There were 23 men and 17 women. The median age was 62 years (range: 34 to 74 years). Two patient showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Three patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrheal drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. To date, 231 cycles (median 8, range 1–19) have been administered. Median relative dose intensity was 97% for S-1 and 87% for irinotecan. 36 pts are evaluable for efficacy: RR was 47.2% (95% CI, 30.9–63.5%) and Disease Control Rate (PR + SD) was seen in 94.4% of pts. PFS of this regimen is 320 days. MST is not reached. Conclusions: IRIS therapy achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. It seems that IRIS is a good treatment equal to FOLFIRI. In addition, this regimen could qualify as a candidate for future combination therapy with a molecular-targeting drug. The latest data will be reported at the meeting. No significant financial relationships to disclose.

A phase II study of apatinib combined with S-1 in previously treated refractory metastatic colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15016-e15016
Author(s):  
Ning Li ◽  
Wenying Deng ◽  
Guifang Zhang ◽  
Yanwei Guo ◽  
Yijie Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Survival Time ◽  
Response Rate ◽  
Phase Ii Study ◽  
Line Treatment ◽  
Third Line ◽  
Grade 3 ◽  
Third Line Treatment

e15016 Background: Although regorafenib and fruquintinib have been recommended as the third-line treatment for patients with refractory metastatic colorectal cancer (mCRC), the median survival time of mCRC is still only for 4-8 months and the low response rate and unpleasant side effects limit their use in Chinese patients. Apatinib, an oral VEGFR-2 inhibitor, has been approved as a third line treatment in metastatic gastric cancer. In addition, apatinib has demonstrated good safety, tolerability, and efficacy in the treatment of advanced solid tumors. The aim of this study was to assess the efficacy and safety of apatinib combined with S-1 in the treatment of refractory mCRC. Methods: In this prospective, open-label, single-arm, multicenter, phase II study, patients after failure of second-line chemotherapy were enrolled and took apatinib (250mg, daily) combined with S-1 (standard dose). The primary endpoint was progression free survival (PFS) and the second endpoint was response rate and overall survival time. Results: From December 2017, 22 patients (14 male) with a median age of 56y (range: 34-71 y) were enrolled and eligible for evaluation of the PFS, response rate and safety. The median PFS was 105d (95% CI: 79.01-130.98). two patients (9%) achieved partial response, 15 (68.18%) achieved stable disease, and 5 (22.72%) were progressive disease. The objective response rate and the disease control rate were 9% and 77.27%, respectively. Median overall survival was not reached. The common adverse effects were abnormal liver function (7/22; 31.81%), leukopenia (5/22; 22.72%) and thrombocytopenia (4/22; 18.18%). The incidence for grade 3-4 side effect was very low. One patient experienced grade 3 proteinuria and there were no toxic deaths. Conclusions: This preliminary result indicated that apatinib combined with S-1 may extend the PFS in mCRC, with well-tolerated toxicities, making it a promising therapeutic target for mCRC treatment. Clinical trial information: NCT03397199 .

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.

Randomized Multicenter Phase II Trial of Oxaliplatin Plus Irinotecan Versus Raltitrexed as First-Line Treatment in Advanced Colorectal Cancer

2002 ◽  
Vol 20 (1) ◽  
pp. 165-172 ◽  
Author(s):  
Werner Scheithauer ◽  
Gabriela V. Kornek ◽  
Markus Raderer ◽  
Herbert Ulrich-Pur ◽  
Wolfgang Fiebiger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Therapeutic Potential ◽  
Sensory Neuropathy ◽  
Line Treatment ◽  
Second Line ◽  
First Line

PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m2 plus irinotecan 175 mg/m2 or raltitrexed 3 mg/m2 given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P = .0025) and longer progression-free survival (median, 7.1 v 5.0 months; P = .0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P = .3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m2, tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

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