Tumour response rate alone does not reliably predict survival in people undergoing treatment for advanced colorectal cancer

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.

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Assessment of multiple markers for association with response rate (RR) and failure-free survival (FFS) in patients with advanced colorectal cancer (CRC) treated with chemotherapy in the MRC CR08 (FOCUS) randomized trial

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.9506 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 9506-9506

Author(s):

J. W. Adlard ◽

S. D. Richman ◽

P. Royston ◽

J. M. Allan ◽

A. Meade ◽

...

Keyword(s):

Colorectal Cancer ◽

Randomized Trial ◽

Advanced Colorectal Cancer ◽

Response Rate ◽

Free Survival ◽

Multiple Markers

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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)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3589 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2003.09.016 ◽

2003 ◽

Vol 21 (7) ◽

pp. 1307-1312 ◽

Cited By ~ 129

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.

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Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Advanced Colorectal Cancer Meta-Analysis Project.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.5.960 ◽

1994 ◽

Vol 12 (5) ◽

pp. 960-969 ◽

Cited By ~ 169

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Clinical Trials ◽

Regression Model ◽

Randomized Clinical Trials ◽

Tumor Response ◽

Advanced Colorectal Cancer ◽

Response Rate ◽

Meta Analysis ◽

Biochemical Modulation

PURPOSE Even though fluorouracil (5FU) remains the standard treatment of advanced colorectal cancer, almost 90% of patients treated with 5FU alone do not achieve an objective response to chemotherapy. Biochemical modulation of 5FU by methotrexate (MTX) is an attempt to increase the sensitivity of tumor cells to 5FU. However, despite the inclusion of several hundreds of patients in randomized clinical trials, no definitive evidence is available on the clinical benefit of 5FU/MTX over 5FU alone. A meta-analysis was performed to assess this benefit objectively and quantitatively for tumor response rate and overall survival. DESIGN The meta-analysis was based on individual data of 1,178 patients included in eight randomized clinical trials comparing 5FU alone with 5FU/MTX. Patient data were provided by all principal investigators. The analyses were performed by an independent secretariat, and then discussed with all collaborators. RESULTS Tumor response rate was 10% for patients allocated to 5FU alone (complete response [CR] rate, 2%; partial response [PR] rate, 8%) compared with 19% for patients allocated to 5FU/MTX (CR rate, 3%; PR rate, 16%). This difference was highly significant, with an overall response odds ratio (OR) of 0.51 (95% confidence interval [CI], 0.37 to 0.70) (P < .0001). Median overall survival times were 9.1 months and 10.7 months in the 5FU-alone and 5FU/MTX groups, respectively. This difference was also statistically significant, with an overall survival OR of 0.87 (95% CI, 0.77 to 0.98) (P = .024). Logistic regression model and Cox regression model showed that performance status and randomized treatment were the only two significant predictors of tumor response and survival. CONCLUSION It is concluded that the modulation of 5FU by MTX doubles the response rate to 5FU, and yields a small improvement in survival.

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Bi-weekly administration of capecitabine + oxaliplatin (Xelox-2) in first-line treatment of advanced colorectal cancer (ACRC): A phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15066 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15066-e15066

Author(s):

P. Fedele ◽

G. Di Maggio ◽

S. Leo ◽

L. Nanni ◽

F. Giuliani ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase Ii ◽

Overall Response Rate ◽

Advanced Colorectal Cancer ◽

Response Rate ◽

Phase Ii Study ◽

First Line ◽

Main Site ◽

First Line Therapy ◽

Ecog Ps

e15066 Introduction: FOLFOX regimen represents a standard first-line therapy for ACRC pts. Oral capecitabine (XEL) has been shown to be a convenient and well tolerated alternative to intravenous 5-fluorouracil (5-FU) in the treatment of ACRC. Experimental data demonstrated the synergism of XEL with Oxaliplatin (OHP), but the questions about the most appropriate dosage and schedule of capecitabine have not yet been completely resolved. Taking into account these data the GOIM started a phase II study to evaluate the activity and the toxicity of biweekly administration of XEL plus OHP (XELOX-2) in ACRC pts. Methods: Previously untreated pts with histological diagnosis of metastatic colorectal cancer, measurable disease, ECOG PS<2, and age 18–75 yrs entered into this trial. The schedule of treatment was as follows: OHP at 100 mg/mq i.v. on days 1 and XEL at 2,000 mg/mq p.o. in two daily administrations from the 1 to the 7 day, every 2 weeks. RECIST and NCI criteria were employed to determine the activity and the toxicity of this regimen. Results: Fifty-one pts have been enrolled and up to now forty-seven are evaluable for activity and toxicity. The main characteristics of the entered pts were: sex (M/F) 38/13, median age 66,5 yrs (range 54–75 yrs), 28 (55%) single and 23 (45%) multiple site of disease. The main site of disease were liver in 38 pts (75%), lymph-nodes in 17 (33%), lung in 9 (18%). Two CR (4%) and 22 PR (47%), 13 SD (28%) and 10 PD (21%) were observed, with an overall response rate of 51% and a disease control rate (CR+PR+SD) of 79%. Median TTP was 5+ months (range 2–19). A total of 413 cycles were administered. In the evaluable pts the main toxicity rate (G1- 2 vs G3–4) were as follows: thrombocytopenia 51/6, anemia 42/0, neutropenia 15/0, nausea/vomiting 30/2, diarrhea 19/2, neurotoxicity 57/0 and asthenia 30/2. Only one pts presented G4 toxicity (diarrhea). Conclusions: These preliminary data show that the combination of XEL and OHP with a biweekly administration is active and well tolerated in ACRC pts. No significant financial relationships to disclose.

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Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer

Current Oncology ◽

10.3747/co.24.3516 ◽

2017 ◽

Vol 24 (4) ◽

pp. 261 ◽

Cited By ~ 4

Author(s):

M.D. Vincent ◽

D. Breader ◽

M.C. Cripps ◽

D.J. Jonker ◽

P. Klimo ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Advanced Colorectal Cancer ◽

Response Rate ◽

Performance Status ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Survival Duration ◽

Ecog Performance Status ◽

Pelvic Radiation

BackgroundCombination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial.MethodsA multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1–14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity.Results Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0–50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand–foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh).Conclusions Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

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

Journal of Clinical Oncology ◽

10.1200/jco.2004.09.046 ◽

2004 ◽

Vol 22 (1) ◽

pp. 23-30 ◽

Cited By ~ 1611

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.

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