The predictive and prognostic value of the Glasgow Prognostic Score in metastatic colorectal carcinoma patients receiving bevacizumab Marianne Mailleta, Johann Dréanica, Marion Dhoogea, Olivier Mirc, Catherine Brezaulta, François Goldwasserb, Stanislas Chaussadea and Romain Coriata The Glasgow Prognostic Score (GPS), based on C-reactive protein and albumin levels, has shown its prognostic value in metastatic colorectal carcinoma (mCRC) patients receiving conventional cytotoxic therapy. Bevacizumab, a monoclonal antibody to vascular epidermal growth factor, improves the overall survival in mCRC. The aim of the present study was to assess the prognostic value of GPS in mCRC patients receiving antivascular epidermal growth factor therapy. From August 2005 to August 2012, consecutive patients with mCRC who received chemotherapy plus bevacizumab were eligible for the present analysis. The clinical stage, C-reactive protein, albumin and the Eastern Cooperative Oncology Group performance status were recorded at the time of initiation of bevacizumab. Patients received 5-fluorouracil-based chemotherapy plus bevacizumab in accordance with the digestive oncology multidisciplinary staff proposal and in line with the French recommendations for the treatment of mCRC. Eighty patients were eligible (colon n = 59, rectum n = 21), with a median follow-up of 14 months (range 1–58 months). Chemotherapy given with bevacizumab and 5-fluorouracil was oxaliplatin (n = 41, 51%) or irinotecan (n = 27, 34%). At baseline, 56, 31 and 13% of patients had a GPS of 0 (n = 45), 1 (n = 25) and 2 (n = 10), respectively. The
Anti-Cancer Drugs 2014, 25:1215–1219 Keywords: bevacizumab, chemotherapy, Glasgow Prognostic Score, metastatic colorectal carcinoma, performance status a
Gastroenterology and Digestive Oncology Unit, Department of Gastroenterology, Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, Paris and cDepartment of Cancer Medicine, Gustave Roussy Cancer Institute, University of Paris-Sud, Villejuif, France b
Correspondence to Romain Coriat, MD, PhD, Gastroenterology and Digestive Oncology Unit, Department of Gastroenterology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, 27, Rue du Faubourg Saint Jacques, F75014 Paris, France Tel: + 33 158 411 952; fax: + 33 179 734 881; e-mail: [email protected] Received 16 January 2014 Revised form accepted 19 April 2014
Various clinical and biological factors, such as weight loss, the Eastern Cooperative Oncology Group performance status (ECOG PS) and lymphopenia can be used to estimate the survival, aiming not to initiate aggressive treatment in patients with a poor prognosis . Previous studies have established the prognostic importance of the systemic inflammatory response as evidence by an elevated circulated C-reactive protein (CRP) . The Glasgow Prognostic Score (GPS), based on albumin and CRP levels, has shown its prognostic value in mCRC patients receiving conventional cytotoxic chemotherapy [7,8]. McMillan et al.  highlighted that the systemic inflammation-based prognostic score, the GPS, identified patients at risk and also provided well-defined targets for future treatments. DOI: 10.1097/CAD.0000000000000129
Patients with a GPS of 2 had a median survival of 2 months, which suggests that these patients do not benefit from chemotherapy . We have previously shown that GPS is still effective, and more accurate than ECOG PS, to evaluate the survival in CRC patients receiving anti-EGFR monoclonal antibody cetuximab . The aim of the present analysis was to assess the prognostic value of GPS in mCRC patients receiving bevacizumab in addition to chemotherapy.
Patients and methods We performed a retrospective medical record review of consecutive patients with mCRC who initiated first-line or second-line treatment with 5-fluorouracil-based chemotherapy and bevacizumab (Avastin; Genetech, South San Francisco, California, USA) in our institution from August 2005 to August 2012. Eligibility criteria were advanced pathologically proven mCRC, age 18 years or more and ECOG PS, CRP and albumin evaluation before treatment initiation. Cancer staging was performed on the basis of clinical findings and thoracic and abdominopelvic computed tomography scans, according to the American Society TNM classification. The tumour response was assessed after every six cycles with repeat computed tomography according to Response Evaluation Criteria in Solid Tumors . PFS and OS were measured from the date of first administration of bevacizumab to the date of disease progression or death. This retrospective study was conducted in agreement with good clinical practice and applicable laws and the Declaration of Helsinki, and was approved by the local ethics boards. Routine laboratory measurement of CRP and albumin concentrations was carried out. The coefficient of variation was less than 5%, as established by the routine quality control procedure. GPS was constructed as described previously: patients with both elevated CRP (>10 mg/l) and hypoalbuminemia (< 35 g/l) were allocated a score of 2 . Patients in whom the CRP level was elevated (>10 mg/l) or patients who had hypoalbuminemia less than 35 g/l were allocated a score of 1 . Patients in whom the CRP level was not elevated (< 10 mg/l) and who had a normal albumin level were allocated a score of 0. Statistical analysis
Descriptive statistics were used to report patients and disease characteristics. Qualitative data were expressed as number and percentage. The quantitative descriptive analysis was presented as median (interquartile range). Survival analyses were performed using the Kaplan– Meier method with the log-rank test. Multivariate analysis was performed using the Cox regression analysis. A P value of less than 0.05 was considered statistically significant. Statistical analysis was performed using
GraphPad 6.0 (GraphPad Software Inc., San Diego, California, USA) software. Deaths up to 1 June 2013 were included in the analysis.
Results A total of 80 patients were included in the present analysis. Patients and disease baseline characteristics are summarized in Table 1. Most patients (median age 65 years, range, 36–83 years) had normal albumin levels (n = 62, 78%) and normal CRP levels (n = 51, 64%). The chemotherapy regimen used in addition to bevacizumab was mainly FOLFOX (n = 41, 51%) and FOLFIRI (n = 24, 30%). At the time of diagnosis, 56, 31 and 13% of patients had a GPS of 0 (n = 45), 1 (n = 25) and 2 (n = 10), respectively. The median follow-up duration was 14 months (range 1–58 months). At the time of analysis (1 June 2013), eight patients remained under treatment with bevacizumab. By univariate survival analysis, CRP, haemoglobin, GPS and ECOG PS were significant predictors of OS, but not PFS (Table 1). The median PFS was 10.1, 6.5 and 5.6 months in the GPS 0, 1 and 2 groups, respectively Table 1 Clinical characteristics and univariate overall survival analysis in patients with metastatic colorectal cancer receiving 5-fluorouracil and antivascular epidermal growth factor-based chemotherapy (n = 80) Patients (N = 80) [n (%)] Age (years) < 65 38 (48) ≥ 65 42 (52) Sex Male 45 (56) Female 35 (44) ECOG performance statusa 0 13 (16) 1 51 (64) ≥2 16 (20) a GPS 0 45 (56) 1 25 (31) 2 10 (13) C-reactive protein (mg/l)a < 10 51 (64) ≥ 10 29 (36) Albumin (g/l) < 35 18 (22) ≥ 35 62 (78) Type Colon 59 (74) Rectum 21 (26) Number of metastatic sites 1 42 (52) 2 26 (33) ≥3 12 (15) Lymphocytes 13 (16) < 1000/mm3 > 1000/mm3 67 (84) Haemoglobina < 10 × 103/l 3 (4) ≥ 10 × 103/l 77 (96)
GPS and bevacizumab in colorectal cancer Maillet et al. 1217
Clinical characteristics and univariate overall and progression-free survival analysis in patients with metastatic colorectal cancer receiving 5-fluorouracil and antivascular epidermal growth factor-based chemotherapy (n = 80)
n (%) 45 (56) 25 Age (years) < 65 22 (48) 11 ≥ 65 23 (52) 14 Sex Male 23 (52) 15 Female 22 (48) 10 Number of metastatic sites 1 24 (53) 11 2 13 (29) 10 ≥3 8 (18) 4 a C-reactive protein (mg/l) < 10 39 (87) 6 ≥ 10 6 (13) 19 Albumin (g/l) < 35 0 8 ≥ 35 45 17 ECOG performance status 0 8 (18) 5 1 30 (67) 12 ≥2 7 (15) 8 Overall survival (months)a Median 20.1 (11.4–29.3) 11.4 Progression-free disease (months) Median 10 (5.8–14.9) 6.5
5 (50) 5 (50)
8 (80) 2 (20)
(44) (40) (16)
7 (70) 3 (30) 0
1 (10) 9 (90)
10 (100) 0
(20) (48) (32)
0 9 (90) 1 (10)
Considering two groups (PS = 0 vs. ≥ 1), the median OS were significantly different (P = 0.003; Table 1). By multivariate analysis with ECOG PS (0 vs. ≥ 1), haemoglobin and the GPS (0–1 vs. 2) entered as covariates, only the GPS (P = 0.03) remained a significant predictor of OS.
Discussion In routine practice, the decision to initiate chemotherapy in mCRC patients is primarily based on ECOG PS, which is assessed subjectively, and related to anxiousness and depressiveness. Indeed, significant differences in the assessment of ECOG PS have been reported between oncologists, nurses and patients, oncologist being the most optimistic in their assessment and patients the least .
GPS has been shown to be a useful predictor of OS in patients with mCRC before the era of anti-VEGF treatments . GPS avoids any subjective assessment, being simply based on albumin and CRP levels. Here, we found that GPS maintains its prognostic value in the era of anti-VEGF therapy, and might even be superior to ECOG PS to predict OS in mCRC patients. Our results are consistent with the relationship between GPS and OS
PS = 0 PS = 1 PS > 2
GPS = 0 GPS = 1 GPS = 2
Progression-free survival in Glasgow Prognostic Score (GPS) groups 0, 1 and 2 (a) and in ECOG PS groups 0, 1 and > 2 (b) in patients with metastatic colorectal carcinoma.
(P = 0.16) (Table 2 and Fig. 1a). Otherwise, PFS did not differ according to ECOG PS (Fig. 1b). The median OS were 20.1, 11.4 and 6.5 months in the GPS 0, 1 and 2 groups, respectively (P = 0.03; Table 1 and Fig. 2a). The median OS in patients with an ECOG PS of 0, 1 and ≥ 2 were 17.1, 17.8 and 9.4 months, respectively (Fig. 2b).
observed in mCRC patients receiving capecitabine  and, more generally, conventional chemotherapy without targeted agents [18–20]. This may be in part because ECOG PS mostly reflects the functional status at a specific point in time, whereas the GPS predicts the progressive nutritional decline  that is associated with
Overall survival in Glasgow Prognostic Score (GPS) groups 0, 1 and 2 (a) and in ECOG PS groups 0, 1 and > 2 (b) in patients with metastatic colorectal carcinoma.
poor tolerance to chemotherapy . Meanwhile, the presence of inflammation and malnutrition are considered as prognostic factors, with decreased survival in patients with cancer . Mauricio et al.  identified that nutritional and inflammatory states are two prognostic factors that deserve more attention in future studies and in clinical practice. It is important to note that the present analysis showed a significant difference in OS according to the GPS but no difference in terms of PFS in patients receiving bevacizumab in addition to chemotherapy. This may be due to the fact that the benefit induced by the addition of bevacizumab to chemotherapy could overcome the impact of an altered nutritional and inflammatory status in patients with a GPS of 2. However, this difference in OS according to the GPS could also be related to a better tolerability and dose intensity of cytotoxic drugs in patients with a favourable nutritional and inflammatory status. Indeed, the tolerability of bevacizumab itself is not expected to be altered in mCRC patients with a GPS of 2, as it has shown a low rate of toxicity with hypertension being the sole bevacizumab-related toxicity that increased in this setting [3,4,25]. Moreover, hypertension is usually easily manageable with early and adequate treatment [3,4,26]. Finally, we observed a particularly small number of patients with all grade anaemia (4%). These could be explained by the widespread use of erythropoietin or transfusion before chemotherapy. Overall, our data suggest that bevacizumab improves PFS in mCRC patients regardless of the nutritional and inflammatory status, similar to what is seen with imatinib
in gastrointestinal stromal tumour patients with a poor general status . Conclusion
In the present study, a simple inflammation-based prognostic score, the GPS, based on routinely available well-standardized laboratory measurements, was an independent predictor of OS among patients with mCRC receiving 5-fluorouracil-based chemotherapy plus bevacizumab. Given the poor OS seen in patients with a GPS of 2, we postulate that the use of the GPS could help in better identifying mCRC patients who could derive benefit from intensive treatments.
Acknowledgements Conflicts of interest
Prof. Goldwasser has acted as a paid consultant for Roche, Amgen, Bayer Healthcare and Pfizer. Dr Mir has acted as an advisory board member for Roche, and a paid consultant for Roche, Servier and Pfizer. Dr Coriat has acted as an advisory board member for Roche, Sanofi and Merck. For the remaining authors, there are no conflicts of interest.
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