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Prognostic clinical factors in metastatic colorectal cancer.


Clinical trials, although in theory using similar patient selection criteria, often display surprising heterogeneity in response and survival rates. One likely cause of this phenomenon is differences in patient characteristics or prognostic factors. The joint influence of patient and tumour characteristics on outcome in patients with metastatic colorectal cancer is not well understood. Clinical, tumour-related and laboratory factors can influence survival of patients with metastatic colorectal cancer (mCRC) more than any chemotherapy treatment. In a database of 3825 patients with mCRC treated with 5-fluorouracil, median survival predicted for individual patients from clinical factors ranged from 4 to 16 months [1]. In a study in which patients with mCRC were given first-line oxaliplatin-based chemotherapy, those with normal alkaline phosphatase (ALP) and platelet levels had a median survival of 23 months, whereas median survival was only 10 months if levels of both factors were elevated [2]. Median survival in mCRC patients receiving first-line combination treatment with bevacizumab was 26 months in a low-risk group, 20 months in an intermediate-risk group and 14 months in a high-risk group, when patients were grouped by performance status (PS), number of tumour sites, ALP levels and white blood cell count [3]. Recently, we found great inconsistency in the reporting of patient characteristics in published clinical trials of medical treatment for mCRC [4]. In our survey, only age, gender and PS were regularly reported. Many of the important prognostic factors, particularly laboratory values, were rarely reported. We therefore proposed a list of patient characteristics that should be reported in future trials. Patients enrolled in clinical trials may bear little resemblance to the larger population of patients to which the results should be relevant [5,6]. It is a general phenomenon that participants in clinical trials tend to have better survival outcomes than non-participants [7].

It is therefore important to know the clinical, laboratory and tumour-related factors that affect the prognosis of patients with mCRC. All study reports must provide adequate data concerning patient characteristics. The baseline patient characteristics in a study report should be carefully looked at to ensure that the study population is representative of the whole patient population with this type of cancer seen in clinical practice.

Clinical prognostic factors

Demographic factors

Older patients are under-represented in clinical trials. Whereas the median age of a patient with mCRC is about 75 years, the median age of patients in mCRC studies is 62 years [4]. In a large retrospective comparison, there was no difference between younger and older (>70 years) patients enrolled in trials with respect to response rate or survival [8]. Some studies have, however, shown a better prognosis for patients <70 years of age [9]. In most studies sex does not affect survival, but a few studies have found longer progression-free survival or overall survival in male patients [10,11]. Race should be reported in studies as the development and use of germline polymorphisms will probably increase in clinical oncology practice. Selection bias can occur for previously unknown or unstudied variables. For example, patients who travel for elective care in specialised medical centres have better outcome than local patients with the same conditions who are treated at the same centres, and a longer travel distance from the treating centre has been associated with better survival [12].

Performance status

PS is an attempt to quantify a cancer patient's general wellbeing. The Eastern Cooperative Oncology Group (ECOG) score, also known as the World health Organization (WHO) score, is on a scale from 0 to 4 (PS 0, perfect health; PS 1, symptomatic disease but completely ambulant; PS 2, symptomatic disease and in bed <50% during the day; PS 3, symptomatic disease and in bed >50% during the day; PS 4, completely disabled and confined to bed or chair). It has been suggested that only the ECOG classification should be used, as it is difficult to compare this score with the Karnofsky PS score. When comparing PS status, subdividing groups into PS 0/1 versus 2 is more informative than PS 0 versus 1/2. PS is one of the most useful variables in oncology trials, and probably one of the most important prognostic factors of all. Poor PS (usually PS 2) has in almost all studies shown a negative effect on survival in mCRC patients receiving chemotherapy [1,3,9,11,13-28]. In a pooled analysis of 6286 patients in first-line mCRC trials, median survival was 17.3 months in patients with PS 0/1 and only 8.5 months in patients with PS 2 [28]. Few patients with PS 2 (approximately 6-8% of the study population) are included in mCRC clinical trials [4,28]. Almost all studies exclude patients with PS >2, as survival is usually short in these patients. Patients with PS 2 starting first-line chemotherapy, later receive second-line chemotherapy less frequently than patients with PS <2 [13]. Median survival of mCRC patients with poor PS after progression on first-line chemotherapy is only 1.7 months [13]. Apart from centre stratification, PS is the most commonly used stratification factor in mCRC Phase III trials [4].

Other clinical factors

Weight loss of more than 5-10% during the previous 3 months is a negative prognostic factor [16,19,29]. Use of analgesics has also been associated with a poor prognosis [11]. Prior adjuvant chemotherapy can be an important prognostic factor [22].

Tumour-related prognostic factors

Primary tumour and metastasis

Sites of primary and synchronous metastatic disease may be important characteristics; however, they are not often tested in multivariate analyses for prognostic factors. In two studies, a primary colon tumour was shown to be a negative prognostic factor compared to a primary rectal cancer [1,20]. Patients without surgery of the primary tumour seem to have a shorter survival; in one study median survival was only 6 months compared to 17 months following removal of the primary tumour [2,26]. Number of metastatic sites is a characteristic that has repeatedly been shown to have an important effect on prognosis. Patients with one tumour site have a much better prognosis than patients with >1 tumour site

[1,3,14,16,18,19,21,23,24,26,27]. Metastasis to the liver has been shown to be a negative prognostic factor in some studies [1,17,19]. Patients with less liver involvement have a longer survival time [10]. Patients with metastasis to the peritoneum are generally considered to have a worse prognosis [1]. A minimum in reporting sites and location of metastases is to report primary tumour site, 1 site versus >1 site and liver versus other, as these seem to have the greatest prognostic importance. Molecular profiling of tumours may identify patients who are more likely to benefit from therapy, and predictive genomic markers for CRC have been identified [30].

Laboratory prognostic factors

Recent studies have confirmed the importance of abnormal laboratory values as prognostic factors in mCRC, although it is unclear why abnormal values develop and what they reflect. Median or mean laboratory values are less relevant than the proportion elevated above a cut-off level.

Haematological values

Haemoglobin level has been reported to affect chemotherapy outcomes in a number of malignancies, and a low pre-treatment haemoglobin level (usually <11g/l) has been identified as a negative prognostic factor for survival in mCRC patients [1,19-21,23,25]. How anaemia may affect treatment outcome is not clear. One possible mechanism is through accumulation of hypoxia-inducible factor-1, which is a key transcription factor that regulates many pathways including angiogenesis, growth-factor signalling, tissue invasion and metastasis [25]. There is increasing evidence that the presence of a systemic inflammatory response has an important role in predicting survival in patients with mCRC [31]. It has repeatedly been reported that elevated white blood cell count (>10 x [10.sup.9]/l) or neutrophil count are related to a poor prognosis in mCRC patients [1,3,9,14,15,20,21,23,27,29,32]. Elevated platelet count (>400 x [10.sup.9]/l) negatively affects prognosis and its impact on survival can be substantial. In one study, survival was 20 months if the platelet level was normal, but only 10 months if the platelet level was elevated [2].

Serum enzymes

The ALPs comprise a heterogeneous group of enzymes that are widely distributed in mammalian cells. They are often associated with cell membranes, but their exact physiological function is unknown. An elevated baseline level of ALP ([greater than or equal to] 300 U/l, or 2-3 times upper normal limit) prior to chemotherapy treatment is one of the strongest prognostic factors for poor survival of mCRC patients [1-3,9,16,18-20,22,24,27,32]. ALP level may reflect tumour bulk; however, a number of physiological and pathological factors influence the serum ALP level. At the start of first-line chemotherapy, ALP level predicts whether second-line chemotherapy will be given or not [13]. Lactate dehydrogenase (LDH) catalyses the reversible transformation of pyruvate to lactate under anaerobic conditions. Upregulation of LDH ensures an efficient anaerobic/glycolytic metabolism for tumour cells and reduced dependence on oxygen. Preclinical and clinical data suggest that a high serum LDH level is a biomarker for highly angiogenetic tumours. Patients with a high LDH level have increased intratumoral expression of genes involved in angiogenesis [33]. An elevated LDH level predicts a poor prognosis in mCRC patients [15,22,24,26,32]. Two studies have examined the effect of PTK/ZK, an oral anti-angiogenetic compound, in first- and second-line treatment of mCRC patients [34]. A pooled analysis showed that progression-free survival was significantly improved only in PTK/ZK-treated patients with high LDH levels (>1.5 times upper normal limit) [34]. Other

An elevated bilirubin level has been associated with a poor prognosis [15,29]. Patients with a high carcinoembryonic antigen (CEA) level appear to have a poor prognosis too [11,17,22].


Clinical, laboratory and tumour-related factors are prognostic for patients with mCRC, and can influence survival to a greater extent than any available chemotherapy treatment. The most important negative prognostic factors are PS 2, elevated levels of ALP, LDH or white blood cell count, reduced haemoglobin level and more than one metastatic site. It is important that prognostic factors between treatment groups in a clinical trial are comparable in order to ensure that any observed treatment effect is appropriately attributed to the treatment itself. An international consensus on study reporting of patient characteristics and stratification in mCRC trials should be developed.


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Halfdan Sorbye

Department of Oncology, Haukeland University Hospital, Bergen, Norway

Correspondence to: Halfdan Sorbye (email:
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Author:Sorbye, Halfdan
Publication:Advances in Gastrointestinal Cancer
Geographic Code:4EXNO
Date:Mar 1, 2008
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