Annals of Oncology Advance Access published online on May 7, 2008
Annals of Oncology, doi:10.1093/annonc/mdn176
Significant improvement in survival of patients presenting with metastatic colon cancer in the south of The Netherlands from 1990 to 2004
1 Department of Internal Medicine, Catharina Hospital, Eindhoven
2 Eindhoven Cancer Registry, Comprehensive Cancer Centre South Eindhoven, The Netherlands
* Correspondence to: Dr G. J. Creemers MD, PhD, Department of Internal Medicine, Catharina Hospital, Michelangelolaan 2, 5632 EJ, Eindhoven, The Netherlands. Tel: +31-40-2397210; Fax: +31-40-2396026; E-mail: geert-jan.creemers{at}cze.nl
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Background: In randomised controlled trials, the median overall survival (OS) for patients with metastatic colon cancer has improved. However, the results of randomised controlled trials should be interpreted with caution and cannot simply be extrapolated to the general practice. We retrospectively analysed population-based survival data of patients who presented with metastatic colon cancer at diagnosis.
Patients and methods: All patients diagnosed with primary metastatic colon cancer from 1990 to 2004 in the registration area of the Eindhoven Cancer Registry were included. Date of diagnosis was divided into four periods (1990–1994, 1995–1999, 2000–2002, and 2003–2004) according to the availability of chemotherapy for metastatic colon cancer. We assessed OS according to chemotherapy use and period.
Results: Of the 1769 patients, 30.6% received chemotherapy. Chemotherapy use over time increased from 24% in 1990–1994 to 55% in 2000–2004 for patients aged <70 years and from 2% to 22% in patients aged 70 years and older. Median survival for patients diagnosed in 1990–1994 was 26 [95% confidence interval (CI) 22–32] weeks, while patients diagnosed in 2003–2004 had a median survival of 39 (95% CI 31–48) weeks. Patients who did not receive chemotherapy had a survival of 22 (95% CI 20–25) weeks, while the survival for patients who did receive chemotherapy was 57 (95% CI 51–65) weeks. OS decreased with increasing age (P < 0.0001). In the multivariate survival analysis, chemotherapy use, increasing age, having multiple comorbid conditions, and having more than one tumour site significantly affect survival, with the strongest effect of chemotherapy use.
Conclusion: Palliative chemotherapy significantly improved OS in unselected patients with metastatic colon cancer.
chemotherapy, colon cancer, population-based cancer registries, survival
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introduction |
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Colon cancer is a common and often lethal disease. In The Netherlands, 9898 new cases of colorectal cancer were diagnosed and 4429 patients (45%) died from the disease [1]. Since the mid-80s, improvement in survival has been achieved, in particular by detection of the disease at an earlier stage and advances in chemotherapy, surgery, and radiotherapy. However, the prognosis for patients with metastatic disease remains dismal.
Approximately 20% of patients with colon cancer present with metastatic disease at the time of diagnosis and treatment remain palliative, excluding a small subset of patients with resectable liver and/or lung metastases who are potentially curable [2–5].
The median overall survival (OS) for patients with metastatic colon cancer who receive supportive care alone is approximately 5–6 months [4]. For decades, 5-fluorouracil (5-FU)-based chemotherapy was the only effective treatment against colorectal cancer. Randomised controlled trials in the mid-90s showed a better quality of life and a small improvement in OS for patients who received chemotherapy treatment than for those receiving supportive care alone [6, 7].
Since 2000, with the introduction of the new agents irinotecan and oxaliplatin added to 5-FU-based regimens, the median OS increased to 14–16 months [8–10]. More recently, in randomised controlled trials, the OS further prolonged with 4–5 months by combining chemotherapy with targeted therapy (bevacizumab, cetuximab) somewhere in the treatment of this fatal disease [11–17].
The results of randomised controlled trials should be interpreted with caution and cannot simply be extrapolated to the general practice. Patients entering these studies fulfil the strict selection criteria of these studies. They are often younger, have a better performance status, less comorbidity, and they often have a limited tumourload. Such selection limits the applicability of these results to the general practice.
In addition, another important contributing and confounding factor to prolonged survival might be the early treatment of metastatic disease. Possibly, survival of metastatic colorectal cancer is prolonged more by early diagnosis than a true effect of chemotherapy.
To investigate the effect of chemotherapy in unselected patients, we retrospectively analysed the population-based survival data of patients who presented with metastatic colon cancer at diagnosis in the period from 1990 until 2004 in the south of The Netherlands.
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Population-based data from the Eindhoven Cancer Registry (ECR) was used, which is maintained by the Comprehensive Cancer Centre South. The ECR records data on all patients newly diagnosed with cancer in the southern part of The Netherlands, an area with 2.3 million inhabitants. Data of patients diagnosed from 1990 to 2004 were included. The ECR is served by 10 community hospitals, six pathology departments, and two radiotherapy institutes. Data on patient characteristics like gender, date of birth, and postal code and tumour characteristics like date of diagnosis, tumour type, histology, subsite, stage, and treatment are routinely extracted from the medical records by trained registrars, according to the national guidelines [18]. Subsite was classified according to the International Classification of Diseases for Oncology (ICD-O-3) [19]. Clinical stage of the disease was defined according to tumour–lymph node–metastasis clinical classification [20]. Chemotherapy (yes versus no), also in combination with surgery, was defined as prescription of any chemotherapy at initial diagnosis. Date of diagnosis was divided into four periods according to the availability of chemotherapy for metastatic colon cancer patients: 1990–1994 (period in which almost no chemotherapy was given to metastatic colon cancer patients), 1994–1999 (main treatment was 5-FU/leucovorin), 2000–2002 (more agents were available, but not generally used yet), and 2003–2004 (combination therapy more generally used due to the CAIRO study). The quality of the data is content due to thorough training of the registrars and computerised consistency checks at regional and national level. Completeness is estimated to be at least 95% [21].
All patients diagnosed with primary metastatic colon cancer (C18.0–C18.9) from 1990 to 2004 aged >40 years in the registration area of Eindhoven were included (n = 1769). Patients diagnosed in the west of the ECR region from 1990 to 1994 for which the follow-up data are not complete and patients with cancer diagnosed at autopsy were excluded.
Follow-up of vital status of all patients was complete up to 1 January 2006. In addition to passive follow-up via the hospitals, this information was actively obtained from the municipal personal records database Central Bureau for Genealogy.
Crude survival rates were computed. Survival time was defined as the time from diagnosis to death or 1 January 2006 for the patients who were still alive. A log-rank test was carried out to evaluate significant differences between survival curves. A multivariable proportional hazards regression analysis was used to discriminate independent risk factors for death. The SAS/STAT® statistical software (SAS system 9.1, SAS Institute, Cary, NC) was used for the analyses.
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In the period from 1990 to 2004, 1769 patients were diagnosed with metastatic colon cancer in the ECR region. In only 5% of the patients, a (liver) metastasectomy was carried out and this percentage remained stable over the entire study period. Additionally, the majority of the study population consists of patients with one tumour site (74%). From the total study population, 1127 (69.4%) patients did not receive chemotherapy compared with 542 (30.6%) who did. Patients who received chemotherapy were logically diagnosed in the more recent periods and they were significantly younger (median age 62 years in chemotherapy group versus median age 71 years in no-chemotherapy group). Chemotherapy use over time increased from 24% in 1990–1994 to 58% in 2000–2004 in patients aged <70 years. For patients aged 70 years and older, an increase in chemotherapy use from 2% to 23% was seen. Patients with one or several comorbid conditions received less chemotherapy compared with patients without comorbidity. Furthermore, patients with a low socioeconomic status received less chemotherapy than patients with a high socioeconomic status. However, this inequality tends to disappear in the most recent period (Table 1). There was a significant improvement in OS for patients with metastatic colon cancer over time (P = 0.01). This was seen in the first 2 years after diagnosis (Figure 1). Patients diagnosed in the first period (1990–1994) had a median survival of 26 [95% confidence interval (CI) 22–32] weeks, while patients diagnosed in the latest period (2003–2004) had a median survival of 39 (95% CI 31–48) weeks. Survival was better in patients who received chemotherapy compared with patients who did not receive chemotherapy (P < 0.0001). Patients who did not receive chemotherapy had a survival of 22 (95% CI 20–25) weeks, while the survival for patients who did receive chemotherapy was 57 (95% CI 51–65) weeks. After 2 years of diagnosis, survival of metastatic colon cancer patients is almost similar, independent of chemotherapy use or period of diagnosis. A prolonged survival of patients using chemotherapy was seen compared with patients who received no chemotherapy in all periods. Median survival increased from 54 (95% CI 37–81) in 1990–1994 to 72 (95% CI 58–76) weeks in 2003–2004 for patients who received chemotherapy. Survival of patients who did not receive any chemotherapy treatment remained stable at
22 weeks for all periods. In addition, OS decreased with increasing age, comorbidity, and number of tumour sites (Table 2). Median survival increased more in patients aged <70 years compared with patients aged >70 years. Median survival of patients with one tumour site was 37 (95% CI 33–41) weeks, while median survival for patients with two tumour sites or more was 25 (95% CI 21–29) weeks. Comorbidity also affected survival negatively with the median survival decreasing from 41 (95% CI 35–45) weeks for patients without comorbidity to 28 (95% CI 22–32) weeks in patients with two or more comorbid conditions. Furthermore, socioeconomic status did not influence median survival of metastatic colon cancer patients (Table 2). In the unadjusted multivariate survival analysis, a significant effect of period was found. However, this effect disappeared after adjusting for chemotherapy (Table 3). After adjustment for confounders, chemotherapy use, increasing age, having multiple comorbid conditions, and having more than one tumour site significantly affect survival, with the strongest effect of chemotherapy use.
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discussion |
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In this population-based study, we investigated the effect of chemotherapy on survival in patients who presented with metastatic colon cancer at diagnosis. The proportion of colon cancer patients diagnosed with stage IV in the ECR area remained stable at 19% between 1990 and 2004 [1]. Thus, a possible positive effect of early diagnosis of metastatic disease with intensive follow-up (e.g. carcinoembryonic antigen measurement, computed tomography scans) on survival was probably limited. Furthermore, in our study, OS in patients who did not receive chemotherapy in the subsequent periods remained stable at 22 weeks and is equal to the 5–6 months survival in supportive care arms in different randomised controlled trials [22].
Our study showed that of all metastatic colon cancer patients, only 31% patients received chemotherapy in the period 1990–2004 and that chemotherapy significantly improved OS, 22 weeks in the no-chemotherapy group versus 57 weeks in the chemotherapy group.
Chemotherapy use increased over time from 14% in 1990–1994 to 44% in 2003–2004, resulting in an increased survival from 26 to 39 weeks. For the patients receiving chemotherapy, the survival in the period 1990–1994 was 54 weeks, compared with 52 weeks in 1995–1999, 51 weeks in 2000–-2002, and 72 weeks in the period 2003–2004. It is not surprising that the median OS with chemotherapy in the period 1990–1994 and 1995–1999 are similar, as in these periods 5-FU-modulated regimens were the only effective regimens producing median OS of 12 months [23]. With the availability of new effective agents, such as irinotecan and oxaliplatin, a new exciting era in the treatment of colorectal cancer started and resulted in many new combination chemotherapy regimens. With the introduction of capecitabine, an oral fluoropyrimidine that mimics continuous infusion of 5-FU, the convenience for patients improved. Three key trials were conducted in metastatic colorectal cancer and published in 2000 [8]. On the basis of these trials, using all the three effective drugs preferentially in combination, chemotherapy regimens became the standard of care. Initially, we analysed the periods 2000–2002 and 2003–2004 together. However, the increase in survival was less than expected and therefore the periods were analysed separately. In our study, the period 2000–2004 showed an improvement of OS of 8 weeks compared with 1995–1999. This in contrast to the reported results that showed 4–5 months improvement of OS since these drugs augmented the therapeutic armamentarium. It was hypothesised that the use of polychemotherapy was delayed to 2003 as in that year the Dutch Colorectal Cancer Group initiated the CAIRO trial [24, 25] studying sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer and might be the time that regional oncologists became familiar with the use of these drugs. In the period 2003–2004, 21 patients (13% of patients who received chemotherapy) participated in the CAIRO trial and 137 patients were treated outside this trial with (poly)chemotherapy. The OS of all the patients in the period 2003–2004 treated with chemotherapy increased to 72 (95% CI 58–76) weeks. It is remarkable that these survival data outside a trial are similar to the results in the CAIRO study and other randomised trials [24, 25]. In addition, these results support the importance that for metastatic colorectal cancer patients, all active drugs should be considered during the course of the disease to prolong survival. For patients who received chemotherapy, OS in the period 2000–2002 was similar to that in the period 1995–1999, achieved by monotherapy 5-FU, suggesting that in that period polychemotherapy for treatment of metastatic colon cancer was not standard practice. This doctor's delay in accepting and using new active drugs for the treatment of colorectal cancer is now seen again with the bevacizumab and cetuximab. This phenomenon is not uncommon since there is an enormous difference in the use of these new drugs between several European countries [26].
The percentage of patients receiving chemotherapy increased enormously in both patients <70 years and in patients 70 years and older. These findings subscribe to the ventilated opinion, but not prospectively studied, that all patients profit from chemotherapy, if they are fit enough to tolerate chemotherapy, irrespective of age. In view of the results of the CAIRO study, especially for the aged, sequential chemotherapy is preferential as toxicity is reduced in this often fragile group of patients. Chemotherapy treatment differed slightly between low and high socioeconomic status patients, which is in line with previous results [27].
In conclusion, survival of metastatic colon cancer significantly improved in unselected patients. Since 1994, this improvement can be ascribed to the increased use of chemotherapy, especially polychemotherapy. Since our results are comparable to results from randomised controlled trials, the recent introduction of targeted therapy might result in a median survival of >20 months for metastatic colon cancer patients in the general oncology practice.
Received for publication November 4, 2007.
Revision received March 26, 2008. Revision received March 27, 2008.
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