© The Author (2008). Published by Oxford University Press. All rights reserved
Impact of Baseline Sum of Longest Diameter in Target Lesions by RECIST on Survival of Patients with Metastatic Colorectal Cancer
1 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka
2 Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
For reprints and all correspondence: Narikazu Boku, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan. E-mail: n.boku{at}scchr.jp
Received April 11, 2008; accepted July 27, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: In patients with metastatic colorectal cancer (mCRC), several prognostic factors such as performance status (PS), number of metastatic sites, carcinoembryonic antigen (CEA), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) have been reported. The objective of this study was to clarify the prognostic impact of Baseline Sum of Longest Diameter (BSLD) of target lesions by Response Evaluation Criteria in Solid Tumor (RECIST) in patients with mCRC.
Methods: The subjects of this study were consecutive 103 patients with mCRC who had been received the first line systemic chemotherapy between September 2002 and March 2005.
Results: The chemotherapy regimens included leucovorin-modulated 5-fluorouracil (5-FU) (n = 27) and 5-FU plus irinotecan (n = 76). The median overall survival time was 547 days. The median BSLD was 14.3 cm (range, 1.1–54.7). In univariate analysis, identified prognostic variables on survival were PS (0, 1 versus 2), number of metastatic sites (1 versus >1), peritoneal dissemination (+ versus –), pleural effusion (PE) and/or ascites, white blood cell (
versus <10 000/mm3), ALP ( versus <300 IU), LDH ( versus <300 IU), CEA ( versus <5 ng/ml), chemotherapy regimen, presence of liver metastasis, and BSLD. In multivariate analysis with covariates of the above significant factors, BSLD ( versus <10 cm) (HR 0.431, 95% CI 0.237–0.785, P = 0.0059), PS (HR 0.248, 95% CI 0.107–0.577, P = 0.0012), PE and/or ascites (HR 0.402, 95% CI 0.228–0.708, P = 0.0016) were independent prognostic factors.
Conclusion: BSLD of target lesions by RECIST representing tumor volume might be an independent prognostic factor of patients with mCRC after systemic chemotherapy.
Key Words: RECIST • colorectal cancer • prognostic factor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Colorectal cancer (CRC) is one of the most common causes of cancer death in Western countries and Japan (1–3). More than 50% of the patients have unresectable locally advanced or metastatic disease. Chemotherapy of CRC has improved substantially over the last 10 years. Combination chemotherapy with modulated 5-fluorouracil (5-FU) plus irinotecan and oxaliplatin along the treatment course of the first and the second line can achieve response rates over 50% and median overall survival times reach in excess of 20 months (4–11). Moreover, bevacizumab has demonstrated an additional survival advantage (11,12).
Several studies have shown that performance status (PS) (14–20), lactate dehydrogenase (LDH), white blood cell (WBC) (20), carcinoembryonic antigen (CEA) (24) and alkaline phosphatase (ALP) are prognostic factors after chemotherapy (13–15,21,22). Recently, Köhne et al. (15) reported prognostic factors on the multivariate analysis, using databases of 3825 metastatic CRC (mCRC) patients enrolled in prospective trials. Four independent baseline prognostic parameters, PS, WBC, ALP and number of metastatic sites were identified. Combination of these factors could categorize patients with mCRC into three groups according to survival time: high risk, 6.1–6.4 months; intermediate risk, 10.7–10.9 months and low risk, 14.7–15.0 months (15). However, the subject had been treated with only 5-FU with leucovorin (LV) because other active agents, such as irinotecan, oxaliplatin and molecular targeting agents, had not been available at that time. Hurwitz et al. (23) reported that this model may be applicable to irinotecan-based regimen.
However, the above independent variables never reflect tumor volume (TV), although patients with large TV tended to have short survival times. RECIST (response evaluation criteria in solid tumor) was established for the purpose to uniform reporting of outcomes of clinical trials (25). Overall response rate has usually been adopted for primary endpoint of a phase II study, in which documentation of the baseline sum of longest diameter (BSLD) of target lesions is mandatory. BSLD can be considered to represent TV. The aims of this analysis are to clarify the prognostic significance of baseline sum longest diameter of target lesions by RECIST for mCRC patients after chemotherapy.
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PATIENTS AND METHODS |
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Subjects
A total of 125 patients with mCRC treated with LV-modulated 5-FU or irinotecan in combination with 5-FU as the first-line treatment initiated from September 2002 to March 2005 at our institution were included. The selection criteria for the inclusion on this retrospective analysis were (i) histologically or cytologically proven adenocarcinoma of the colon or rectum, (ii) unresectable or recurrent cases after previous surgery, (iii) having at least one unidimensionally measurable lesion (>10 by 5 mm slice CT), (iv) age of
20, (v) Eastern Cooperative Oncology Group PS (ECOG PS) of 
2, (vi) WBC of 3000 cells/µl, (vii) hemoglobin of 8 g/dl, (viii) platelet of 100 000/µl, (ix) bilirubin of 1.1 mg/dl, (x) serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 100 U/l; (xi) serum creatinine level of <1.1 mg/dl (for men) or 0.8 mg/dl (for women), (xii) available survival data and (xiii) no prior chemotherapy except prior adjuvant chemotherapy after resection of the primary tumor completed more than 6 months before recurrence. Patients with symptomatic central nervous system metastasis and any active extracolonic cancer were excluded. Patients who were treated with oxaliplatin-containing regimen in the first-line setting were not included because oxaliplatin had not been approved for mCRC in Japan until April 2005.
Treatment
The treatment schedules consisted of the following six types of regimens: (i) 5-FU+l-LV [Roswell Park Memorial Institute (RPMI) regimen]: l-LV of 500 mg/m2 in a 2-h intravenous (IV) infusion with 5-FU of 600 mg/m2 as an IV bolus 1 h after the l-LV had begun, given once every week for 4 weeks, and repeated every 6 weeks, (ii) tefafure-uracil (UFT)/LV: UFT of 300 mg/m2 and LV of 75 mg/body were orally administered daily for 4 weeks followed by 1-week rest and repeated every 5 weeks, (iii) bolus 5-FU plus irinotecan, fluorouracil and levofolinate (IFL): irinotecan of 100 mg/m2 as a 90-min IV infusion, l-LV of 10 mg/m2 as an IV bolus, and then 5-FU of 500 mg/m2 as an IV bolus infusion, given once every week for 4 weeks, and repeated every 6 weeks, (iv) infusional 5-FU plus irinotecan FOLic acid, Fluorouracil and IRInotecan (FOLFIRI): l-LV of 200 mg/m2 as a 2-h IV infusion, irinotecan of 180 mg/m2 as a 90-min IV infusion followed by IV bolus 5-FU of 400 mg/m2, and a 46-h infusion of 5-FU of 2400 mg/m2 given every other week. All patients routinely received 3 mg of granisetron plus 8 mg of dexamethasone in a 30-min IV infusion before administration of irinotecan. Treatment continued until disease progression, unacceptable toxicity, or patient refusal. Whenever severe adverse events occurred, the doses were adjusted to appropriate levels of tolerance based on the physician's assessment. Any Grade 3 or 4 adverse event resulted in 
20% dose reduction of bolus 5-FU for subsequent cycles for RPMI and UFT/LV, 20% dose reduction of irinotecan and bolus 5-FU for IFL, 20% dose reduction of irinotecan and infusional 5-FU and 50% dose reduction of bolus 5-FU for FOLFIRI. Persistent Grade 2 or worse adverse events delayed therapy until recovery. The use of colony-stimulating factors was allowed if medically justified. Intensive treatment with loperamide, if needed, was used for diarrhea. Other supportive treatments were given if required.
Evaluation of Patients
We retrospectively reviewed medical records of patients including characteristics [age, sex, ECOG PS, inoperative/recurrence, primary tumor location, history of primary resection, the existence of peritoneal dissemination, the presence of pleural effusion (PE) and/or ascites, number of metastatic sites, the existence of liver metastasis, metastatic site, chemotherapy regimen, WBC, ALP, LDH and serum CEA]. All target lesions (10 mm or larger in longest diameter, up to a maximum of five lesions per organ and 10 lesions in total) and non-target lesions at baseline were identified and measured by CT scans using 5 mm slice within 28 days before the initial treatment of chemotherapy. The overall survival was calculated from the date of starting initial chemotherapy to death or last contact.
Statistical Methods
The Kaplan–Meier method was used to evaluate median overall survival. The univariate and multivariate analyses of prognostic factors using a Cox proportional hazard model were carried out with categorized variables to calculate risks and their 95% confidence interval (95% CI). The factors with substantial impacts (P< 0.10) in the univariate analysis were introduced to a Cox proportional hazard model in the multivariate analysis with backward selection. The following 18 categories were examined: age; gender, ECOG PS; 0 or 1 versus 2, recurrence or unresectable, primary tumor resection; – versus +, tumor location; rectum versus colon, peritoneal dissemination; + versus –, PE and/or ascites; + versus –, number of metastatic sites; 1 versus >1, treatment regimen: LV-modulated 5-FU regimen versus irinotecan containing regimen, WBC; 10 000 versus <10 000/mm3, ALP; 300 versus <300 IU, LDH; 300 versus <300 IU, CEA; 5 versus <5 ng/ml, liver metastasis; +versus –, BSLD (cm), BSLD; 5 versus <5 cm, BSLD; 10 versus <10 cm, BSLD; median versus <median. The calculations were performed using the SAS Version 8.02 (SAS Inc, USA).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patient Background
The subjects selected for the retrospective study were 103 patients. Twenty-two patients (18%) were excluded according to the selection criteria. Patients were excluded by the following reason: four for histologically proven neuroendocrine tumors, seven for unavailable survival data, three for multiple cancers, six for no measurable lesion, one for no CT scan before chemotherapy and one for oxaliplatin regimen.
Patient characteristics are given in Table 1. Their median age was 62 years. Sixty-six percent of the patients had an ECOG PS of 0 at base line. Seventy-six percent of the patients had at least two organs involved, liver being the most common site of metastasis. Forty-seven percent of the patients received IFL regimen, and 27% did FOLFIRI regimen.
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Univariate Analysis
Median overall survival was 547 days, with a median follow-up time among survivors of 694 days (Fig. 1). BSLD ranged from 1.1 to 54.7 cm and the median is 14.3 cm. Variables significantly associated with overall survival in the univariate analysis were ECOG PS, number of metastatic sites, peritoneal dissemination, PE and/or ascites, treatment regimen, WBC, LDH, liver metastasis, BSLD (
5, 10 and 14.3 cm) (Table 2). The BSLD (10 cm) showed a hazard ratio (HR), the most significant variable compared with BSLD (5 cm, 14.3 cm) in the univariate. Figure 2 shows the overall survival curves divided by BSLD (10 cm), which were clearly separated.
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Multivariate Analysis
The results of the multivariate analysis are given in Table 3. Variables significantly associated with overall survival in the multivariate analysis were PS, PE and/or ascites and BSLD (10 cm) (Table 3). PE and/or ascites could become the most significant variable in the present study.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Although we have experienced that the patients with huge TV would have poor prognosis and have used RECIST in many clinical trials, it is not clear whether BSLD of target lesion could be one of prognostic factors on overall survival in patients with unresectable or mCRC. We retrospectively investigated the correlation of overall survival with clinical characteristics of patients who underwent the front-line chemotherapy at our institution. In the present study, patients treated with oxaliplatin-containing regimen in the first-line setting were excluded because the application of Köhne's index to oxaliplatin-based regimen was not validated and oxaliplatin had not been approved for mCRC in Japan until April 2005. On the other hand, irinotecan-containing regimen was included because the Köhne's index can be applicable to irinotecan-based regimen and to 5-FU monotherapy (23).
In this study, PE and/or ascites was the most significant variable and was not in the previous reports. Although patients having PE and/or ascites are usually excluded from clinical trials, they were not excluded from the selection criteria in the present study, because they are routinely treated in clinical practice setting. The reason that PE and/or ascites could be the most significant variable might be derived from the difference of the patient population. And this study suggests that it may be reasonable that usual clinical trials exclude patients with PE and/or ascites.
The univariate and subsequent multivariate analyses demonstrated that ECOG PS, PE and/or ascites and BSLD (10 cm) before the initial chemotherapy could be the independent prognostic factors on overall survival. The ECOG PS had previously been reported as one of the prognostic factors in mCRC patients in several studies (14–20). The results of the present study were compatible with those of the past studies.
It is suggested that the BSLD (10 cm) might be an independent prognostic factor.
As our findings were based on a retrospective analysis in the single institution, validation of the usefulness of BSLD of target lesions is necessary and ongoing, using the other prospective cohorts.
In conclusion, the retrospective study might suggest that the BSLD of target lesions could become an independent prognostic factor for mCRC.
Conflict of interest statement
None declared.
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References |
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