1 CHU Ambroise Pare, AP-HP, Boulogne-Billancourt; 2 Centre Rene Gauducheau, Saint-Herblain, France; 3 University Hospital Gasthuisberg, Leuven, Belgium; 4 Royal Marsden Hospital, London, UK; 5 Aventis, Paris, France
*Correspondence to: Dr E. Mitry, Service d'hépato-gastroentérologie et oncologie digestive, CHU Ambroise Paré, AP-HP, 9 avenue Charles de Gaulle, 92100 Boulogne, France. Tel: +33-1-49-09-58-79; Fax: +33-1-49-09-45-08; Email: emmanuel.mitry{at}apr.ap-hop-paris.fr
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Abstract |
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Patients and methods: Univariate and multivariate analyses based on the individual data of 602 patients included in two phase III trials were performed to determine predictive factors of survival in advanced colorectal cancer.
Results: Three factors were independently associated with a better progression-free survival: weight loss <5% [hazard ratio (HR) 1.25; 95% confidence interval (CI) 1.001.58], World Health Organization performance status (WHO PS) 01 (HR 1.29; 95% CI 1.081.54) and irinotecan (CPT-11)-containing regimens (HR 1.48; 95% CI 1.032.13). Five factors were independently associated with a better overall survival: weight loss <5% (HR 1.67; 95% CI 1.292.14), WHO PS 01 (HR 1.88; 95% CI 1.272.75), one or two metastatic sites (HR 1.24; 95% CI 1.011.53), alkaline phosphatase values not over twice the normal range (HR 1.71; 95% CI 1.302.24) and CPT-11-containing regimens (HR 1.31; 95% CI 1.071.61).
Conclusions: The present analysis confirms that CPT-11-based chemotherapy regimens are independently associated with a better survival in patients with advanced colorectal cancer. Age was not identified as a prognostic factor in this analysis.
Key words: chemotherapy, colorectal neoplasms, irinotecan, prognostic factors
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Introduction |
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Studies evaluating prognostic factors of survival in ACC patients treated with a bolus 5-FU-based regimen [11] or with the irinotecan (CPT-11)-based IFL (CPT-115-FUleucovorin) regimen [12
] have recently been published, but there were no available data on prognostic factors of survival in patients treated with the LV5FU2 or AIO regimen, with or without CPT-11. We have therefore performed a pooled analysis of data from the two published randomized trials using infusional based 5-FU regimens with or without CPT-11 [7
, 10
].
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Patients and methods |
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Trial V302 [10]
Trial V302 included 267 patients (256 treated) whose cancer had progressed after 5-FU-based treatment and who where randomized to either CPT-11 monotherapy or infusional 5-FU (AIO, LV5FU2 or Lockich regimens). Patient entry criteria included: age 1875 years; histologically proven progressive metastatic adenocarcinoma of the colon or rectum; World Health Organization performance status (WHO PS) of 2; and adequate hematological, renal and hepatic functions. One hundred and twenty-seven patients were randomly allocated to CPT-11 350 mg/m2 as a 90-min intravenous infusion once every 3 weeks (300 mg/m2 in patients aged >70 years or with WHO PS 2). One hundred and twenty-nine patients were randomly assigned to 5-FU by continuous infusion and received the LV5FU2, AIO or Lockich regimen. The LV5FU2 regimen consisted of FA 200 mg/m2 intravenously over 2 h followed by 5-FU 400 mg/m2 intravenous bolus followed by 5-FU 600 mg/m2 continuous intravenous infusion over 22 h/day on the first 2 days of every 2-week period. The AIO regimen consisted of 5-FU 2.63 g/m2/day intravenously over 24 h with or without FA 20500 mg/m2/day intravenously weekly for 6 weeks, with 2-week rests between cycles. Thirty-nine patients treated with the Lockich regimen were not included in the present analysis, since this regimen was not used in the V303 trial.
Trial V303 [7]
Trial V303 included a total of 387 patients (385 treated) with ACC who were randomized to first-line treatment with infusional 5-FU (AIO or LV5FU2) with or without CPT-11. Patients had to meet the following criteria: age 1875 years; histologically proven adenocarcinoma of the colon or rectum; WHO PS of 2; adequate hematological, renal and hepatic functions; and no previous chemotherapy other than adjuvant chemotherapy finished >6 months before randomization. For the no CPT-11 group (186 patients), the AIO and LV5FU2 regimens were the same as for the V302 trial. For the CPT-11 group (199 patients), the regimens were: once weekly CPT-11 80 mg/m2 with fluorouracil 2300 mg/m2 in a 24 h infusion, plus FA 500 mg/m2 (AIO-CPT-11 regimen); or every 2 weeks, CPT-11 180 mg/m2 on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 h infusion, plus FA 200 mg/m2 on days 1 and 2 (LV5FU2-CPT-11 regimen).
Statistical analysis
PFS was calculated from the date of randomization to the date of progression (or date of death in patient without progression). OS was calculated from the date of randomization to the date of death. The survival function was estimated using the KaplanMeier method [13].
The first part of the analysis consisted of the univariate comparison of survival functions for factors that could potentially affect the survival time using the log rank test. Univariate analysis describes the survival with respect to the factor under investigation, but necessarily ignores the impact of any others. We therefore performed a multivariate survival analysis to compare prognostic factors of survival after adjustment for the impact of other factors [14]. Different potential predictive variables were evaluated in univariate analyses: age (<65 versus 6575 years), sex, weight loss (<5% versus
5%), WHO PS (01 versus 2), tumor site (colon versus rectum), number of metastatic sites (12 versus
3), liver metastases (yes versus no), lung metastases (yes versus no), peritoneal carcinomatosis (yes versus no), serum carcinoembryonic antigen (CEA) value (
50 versus >50 ng/ml), alkaline phosphatase value [
2xN upper normal limit() versus >2N], lactate dehydrogenase (LDH) value (N versus > N), leukocyte count (<10 000 versus
10 000/mm3), treatment line (1 versus 2) and CPT-11-containing regimen (yes versus no). A Cox proportional hazard regression, stratified on treatment line, was performed to estimate prognostic factors associated with survival in the multivariate analysis. The LDH value was only available for 503 patients and was excluded from the multivariate analysis. All other variables associated with survival in the univariate analysis at the 0.1 level were entered into the Cox model.
The calculations were performed using Stata statistical software (Stata Corporation, College Station, TX, USA).
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Results |
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Results of the multivariate analysis are presented Table 4. Five factors were independently associated with a better OS in multivariate analysis: weight loss <5% (HR 1.67; 95% CI 1.292.14; P<0.001), WHO PS 01 (HR 1.88; 95% CI 1.272.75; P=0.002), two or less metastatic sites (HR 1.24; 95% CI 1.011.53; P=0.04), alkaline phosphatase
2xN (HR 1.71; 95% CI 1.302.24; P<0.001) and CPT-11-containing regimen (HR 1.31; 95% CI 1.071.61; P=0.009). Age was not associated with OS.
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Discussion |
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Khöne et al. [11] recently published a multivariate analysis of 3825 patients with 5-FU-based treatment for metastatic colorectal cancer. PS, number of metastatic sites, white blood cell count and alkaline phosphatase were the main clinical parameters associated with survival, and were correlated with three risk groups for patients: low, medium and high, with corresponding median survivals of 15, 10.7 and 6.1 months. The major prognostic significance of PS has previously been reported in several studies [9
, 12
, 15
17
] and indeed, a good performance status (WHO 01) is associated with a better PFS or OS in our analysis. As also reported previously [9
], weight loss >5% was independently associated with a worse PFS and OS. The number of metastatic sites, CEA, alkaline phosphatase and LDH were significantly associated with PFS and OS in the univariate analysis. In the multivariate analysis, no tumor-related factors were associated with PFS, whereas the number of metastatic sites and alkaline phosphatase were significantly associated with OS, as previously reported [9
, 11
, 12
, 18
]. Despite a strong association with survival in the univariate analysis, LDH was not introduced in the multivariate analysis, since its value was not available for almost 20% of the patients and this may have distorted the regression results. A CPT-11-based regimen also independently predict for a better PFS and OS compared with 5-FU-based regimen, which was previously demonstrated in randomized trials [7
, 8
, 10
, 19
]. A CPT-11-based regimen seems to be the most important factor associated with PFS (HR 1.48 compared with 1.29 for PS and 1.25 for weight loss), but PS and weight loss remain the main prognostic factors for OS (HR 1.88 and 1.71, respectively, compared with 1.31 for CPT-11).
Age was not associated with survival, and patients between 65 and 75 years old had the same prognosis as younger patients. It was noted that multivariate analyses results were similar when 70 years was chosen as the cut-point for young and elderly patients. Age has rarely been reported as a prognostic factor of colorectal cancer survival in randomized trials [20], whereas epidemiological data clearly show that patients above the age of 75 years have a worse prognosis than younger patients [21
, 22
], mainly because they are less frequently actively treated. By design, most clinical trials in colorectal cancer have limited recruitment to generally fit patients <75 years old, and very few data on efficacy and tolerance of the current standard regimen are available for this population. This is problematic, since the incidence of colorectal cancer in the elderly is steadily increasing, with >40% of the cases occurring in patients aged 75 years and above [23
]. A subgroup analysis performed among patients treated with the LV5FU2CPT-11 regimen in the V303 trial demonstrated that there was no difference in tumoral response rate or PFS and OS rates for patients aged between 65 and 75 or younger patients [24
], but more data in patients older than 75 years is needed to confirm treatment recommendations. To resolve this issue, randomized clinical trials focusing on elderly patients are awaited, and indeed, the Fédération Francophone de Cancérologie Digestive is conducting a study comparing treatment by LV5FU2 or simplified LV5FU2 with the same regimen with CPT-11 (LV5FU2-CPT-11 and FOLFIRI regimens) in the first-line treatment of ACC in patients aged 75 years and above. Trials such as this one will enable us to confirm whether the prognostic factors identified in this analysis for patients under 75 years old hold true for those over 75.
Received for publication January 8, 2004. Revision received February 25, 2004. Accepted for publication February 27, 2004.
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