1 Department of Medicine, 2 Department of Histopathology, 3 Department of Computing and Information, Royal Marsden Hospital, London and Sutton, Surrey, UK
* Correspondence to: Prof. D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-661-3156; Fax: +44-208-643-9414; Email: david.cunningham{at}icr.ac.uk
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Abstract |
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Patients and methods:: All patients with advanced mucinous CRC enrolled in three prospective randomized trials evaluating infused 5-fluorouracil as first-line treatment were compared with patients with non-mucinous subtypes enrolled in the same trials in a casecontrol study. Prognostic factors associated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses.
Results:: The study included 135 patients (45 cases and 90 controls). The response rates for cases and controls were 22% [95% confidence interval (CI), 11% to 38%] and 47% (95% CI, 36.1% to 58.2%), respectively (P=0.0058). Median OS for the mucinous CRC patients was 11.8 months (95% CI, 8.8714.8) compared with 17.9 months (95% CI, 13.3822.39) in the control group (univariate analysis, P=0.056); after correcting for significant prognostic factors by multivariate Cox regression analysis, P=0.0372 and hazard ratio (HR)=1.497 (1.022.19).
Conclusion:: Patients with advanced mucinous CRC have a poorer response to fluorouracil-based first-line chemotherapy and reduced survival compared with patients with non-mucinous CRC.
Key words: colorectal cancer, 5-fluorouracil, mucinous
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Introduction |
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It has been suggested that mucinous adenocarcinoma behaves differently from more common histological subtypes of colorectal cancer; however, its clinical implications remain unclear. According to published series, mucinous carcinoma affects younger patients, is more frequent in the proximal part of the colon and tends to present at a more advanced stage [5, 6
]. Indeed, recent molecular biology studies have shown characteristic features of mucinous carcinoma (i.e. lower expression of p53, more frequent DNA replication errors expressed as microsatellite instability, specific codon 12 K-ras mutations) and, when ploidy has been determined, a higher index of diploidy was found than for non-mucinous carcinoma [7
11
]. A poor prognosis has been reported by most studies, but some failed to show a correlation with prognosis or found a prognostic significance only for certain subgroups [2
, 3
, 12
]. However, these series studied prognosis from diagnosis, generally in patients managed with surgery alone rather than with chemotherapy.
Fluoropyrimidine-based chemotherapy remains the standard treatment for advanced CRC. While response rates and overall survival duration have improved with modern combinations, there is a paucity of data comparing outcomes in patients with mucinous and non-mucinous histology [13, 14
]. Reports of prognostic, clinical and epidemiological differences, together with the preliminary reports about differences in genetic features, suggest that mucinous CRC is a distinct biological entity behaving differently from the more common non-mucinous CRC. This raises the possibility that the efficacy of fluorouracil-based chemotherapy may differ in patients with mucinous and non-mucinous CRCs.
To examine this possibility we specifically investigated the efficacy of fluorouracil-based first-line chemotherapy in patients with advanced colorectal cancer.
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Patients and methods |
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Data of cases and controls were obtained using original trial records prospectively recorded and the following parameters were examined: histology (defining cases and controls), age, gender, site of primary tumour, previous adjuvant treatment, site of advanced disease, number of metastatic sites, Eastern Cooperative Oncology Group performance status (PS), baseline carcinoembryonic antigen (CEA) level, date of randomization (matched), arm of the trial (matched), number of cycles, response to treatment, reasons for premature treatment cessation, date of progressive disease and number of patients who underwent second-line treatment. Date of death or last follow-up and cause of death were updated for this analysis. Response to chemotherapy was evaluated according to the WHO criteria [18] Radiological reassessment was performed at 12 weeks and treatment continued in patients with stable disease to a total of 24 weeks when reassessment was repeated.
Primary tumours were classified as right-sided tumours (arising in the caecum, ascending colon or hepatic flexure), tumours arising in the transverse colon, left-sided tumours (arising in the descending or in the sigmoid colon) and tumours arising in the rectum or rectosigmoid junction. Follow-up was maintained until death.
Statistical analysis
The study design was a retrospective casecontrol study and the case-to-control ratio was 1:2. The two groups were compared using 2 x 2 tables for binary factors (cases versus controls, locally advanced (LAD) versus metastatic, PS 01 versus PS 2, age <60 years versus age
60 years, responders to first-line therapy versus non-responders and single-agent 5-FU versus fluorouracil-based combination) using the
2 test, with Fisher's exact test used where appropriate. The KaplanMeier method was used to estimate survival (death from any cause) and progression-free survival (PFS) curves (time to progression or death) and the log-rank test was used to compare the curves. Survival and time to events were measured from the date of randomization for all patients.
Hazard ratios (HRs) for both univariate and multivariate analysis were calculated using the Cox proportional hazards model. The significance level for all analyses was 0.05.
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Results |
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Forty-four per cent of patients with mucinous CRC and 37% of the control group had two or more metastatic sites (P=0.383). The peritoneum was the most common metastatic site in patients with mucinous CRC (44%), but nodal and liver metastases were noted in 31% and 40% of patients, respectively. Non-mucinous tumours were associated with a lower proportion of patients with nodal metastases (13%, P=0.014) and peritoneal metastases (21%, P=0.005). The most common site of metastases for patients with non-mucinous histology was the liver (63%).
Chemotherapy
Patients were matched for the date of randomization and arm of the trial to correct for differences in treatment. One-third of patients were treated with infused 5-FU alone (31%). 5-FU combined with either mitomycin C or interferon- was administered to 69% of patients. The mean number of administered courses of first-line chemotherapy was 19 cycles in the study group and 21 in the control group. Treatment was stopped prematurely in 36% of mucinous CRC patients compared with 24% in the control group (P=0.48). Reasons for stopping treatment were progressive disease in 27% of patients with mucinous CRC and 16% of patients in the control group, patient request in 2% of mucinous CRC patients compared with 1% of controls, and toxicity in 7% of mucinous CRC patients compared with 6% of controls (P=0.26).
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Response and survival |
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Discussion |
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This casecontrol study shows that mucinous CRC is less responsive to 5-FU-based chemotherapy than non-mucinous adenocarcinomas. On univariate and multivariate analyses histology, together with PS and number of metastatic sites, was found to be significantly predictive of response to treatment. Furthermore, we showed significantly worse overall survival for patients with advanced mucinous CRC on multivariate analysis (P=0.0372).
Although this analysis is subject to the limitations of a casecontrol study, we utilized data from prospective randomized trials, each of which studied similar patient populations with infused 5-FU-based chemotherapy. In order to minimize bias further, randomly selected controls were matched for treatment arm and date of initial randomization. This rigorous study design reinforces our findings.
Mucinous tumours were associated with a higher proportion of patients with nodal metastases (31%, P=0.04) and peritoneal metastases (44%, P=0.005), while the most common site of metastases for patients with non-mucinous histology was the liver (63%). However, these imbalances do not explain the effect on survival. A higher proportion of peritoneal metastases in patients with mucinous CRC was also reported in previous studies [6, 12
, 19
]. Conversely, in the present study, the other main characteristics of patients, such age, performance status, primary tumour side, baseline CEA level and number of metastatic sites, were comparable in cases and controls.
The significant difference in the 5-FU sensitivity of mucinous CRC compared with non-mucinous carcinoma, as shown here, raises the possibility that therapeutic benefit may be largely reduced in this histological subtype. Microsatellite instability (MSI) appears to occur more frequently in mucinous than in non-mucinous CRC [9]. In vitro, colon cancer cell lines displaying high-frequency MSI are less responsive to 5-FU than microsatellite stable cell lines [20
]. In addition, a recent study showed that adjuvant chemotherapy with 5-FU benefited patients with tumours exhibiting chromosomal instability, but not those with microsatellite instability [21
]. However, the predictive value of MSI for treatment response in mucinous CRC remains to be determined. Investigating mucinous CRC as a separate entity is challenging, mainly because the rarity of the disease limits the power to detect statistically significant differences in survival between subgroups. The experience at RMH suggests that the proportion of patients with advanced mucinous CRC treated on clinical trials is <10%.
Recent molecular studies support the hypothesis that mucinous CRC represents a biologically distinct entity. The analysis of the peculiarities of mucinous tumours has led to the hypothesis that there is a mucinous pathway of carcinogenesis leading to the emergence of the mucinous phenotype [22]. These tumours are characterized by frequent and strong expression of the MUC2 gene and a higher frequency of K-ras mutations than non-mucinous carcinomas [23
25
]. In contrast, the frequency of DCC gene loss and mutations in the p53 gene is lower in mucinous than in non-mucinous colonic carcinomas [7
, 26
, 27
]. Similar findings were associated with the development of mucinous carcinomas of the breast, ovary and pancreas [28
30
]. These observations suggest that perhaps we should base our treatments on the molecular characteristics of tumours rather than their organ of origin [31
].
A current challenge is to define the biological characteristics of colon tumour cells resistant to chemotherapy. For example, in a recent published study it has been shown that the differential expression of mucins in human colon cancer cells is related to their specific resistance to anticancer drugs [32]. In particular, the clone resistant to 5-FU mainly produced MUC2, the mucin associated with the mucinous carcinoma subtype of colon carcinoma. Interestingly, the clone resistant to 5-FU was very sensitive to methotrexate. Therefore it is tempting to speculate that mucins may play a role in the resistance of tumour cells to chemotherapy, although the precise nature of this role is not clear.
In conclusion, our data suggest that mucinous CRC is characterized by relative resistance to 5-FU chemotherapy and reduced overall survival. The mechanism of this resistance is unknown and requires further investigation. Microarray gene expression profiling may enhance the prediction of tumour response to chemotherapy and provide further insights into the characterization of mucinous CRC.
Received for publication December 24, 2004. Revision received March 10, 2005. Accepted for publication March 11, 2005.
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