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Curr Oncol. 2010 August; 17(4): 52–58.
PMCID: PMC2913830

The predictive value of pre-treatment inflammatory markers in advanced non-small-cell lung cancer

G. Kasymjanova, MD,* N. MacDonald, MD, J.S. Agulnik, MD,* V. Cohen, MD, C. Pepe, MD,* H. Kreisman, MD,* R. Sharma, MD,* and D. Small, MD*

Abstract

Background

Accurate prediction of outcome in advanced non-small-cell lung cancer (nsclc) remains challenging. Even within the same stage and treatment group, survival and response to treatment vary. We set out to determine the predictive value of inflammatory markers C-reactive protein (crp) and white blood cells (wbcs) in patients with advanced nsclc.

Patients and Methods

Patients were assigned a prognostic index (pi):

  • 0 for crp 10 mg/L or less and wbcs 11×109/L or less,
  • 1 if one of the two markers was elevated, and
  • 2 if both markers were elevated.

We then used chest computed tomography (ct) imaging to evaluate response after 2 cycles of chemotherapy treatment.

Results

Of 134 patients, 46 had a pi of 0; 60, a pi of 1; and 28, a pi of 2. Disease progressed in 41 patients. Progression was significantly more frequent among patients with a pi of 2 (p = 0.008). Median survival was 20.0 months for the pi 0 group, 10.4 months for the pi 1 group, and 7.9 months for the pi 2 group (p < 0.001). The pi was the only significant prognostic factor for survival even after adjustment for performance status, smoking, and weight loss (hazard ratio: 1.57; 95% confidence interval: 1.2 to 2.14; p = 0.004).

Conclusions

Inflammatory state correlates significantly with both chemotherapy response and survival in stage iv nsclc. The pi may provide additional guidance for therapeutic decision-making.

Keywords: Non-small-cell lung cancer, nsclc, predictive factors, prognostic factors, crp, response, survival

1. INTRODUCTION

Patients with nsclc have heterogeneous tumour and host biology that leads to wide predictive and prognostic variance. To improve medical decision-making and to deliver the most suitable treatment, predictive and prognostic factors are used to divide the nsclc population into subgroups. Most studies have focused on the clinical characteristics of tumour and host, such as disease stage and performance status 1. However, even within the same stage and with a similar performance status, response to treatment and survival varies from patient to patient.

Basic scientists have clearly demonstrated the importance of molecular and cellular pathways linking cancer and inflammation 25. Many blood markers, including acute-phase C-reactive protein (crp), were identified 513. The crp induced by a cytokine consortium in which interleukin-6 (il-6) is the dominant partner was shown to be an important adverse survival determinant—independent of stage and performance status—in advanced cancer, including non-small-cell lung cancer (nsclc) 10,14,15.

In an effort to further refine prognostic accuracy, a variety of indices based on inflammatory markers have been proposed 10,14,15. The Glasgow Prognostic Score (gps) was shown to be superior to a subjective assessment of Eastern Cooperative Oncology Group (ecog) performance status (ps) in predicting the survival of patients with advanced nsclc 16. However, little is known about the effect of underlying inflammation on the response of nsclc to chemotherapy 17.

In the present study, we evaluated the association between baseline systemic inflammation and two outcome measures in advanced nsclc: freedom from progression in response to chemotherapy, and survival.

2. PATIENTS AND METHODS

2.1. Participant Identification

This prospective study was conducted between January 1, 2005, and January 10, 2009, in a cohort of consecutive patients with newly diagnosed stage iv (per the 7th edition of the International Association for the Study of Lung Cancer staging system) nsclc who had been treated with 2 cycles of platinum-based double-agent chemotherapy.

Computed tomography (ct) imaging of chest and abdomen, followed by metabolic imaging using positron-emission tomography, was used for staging. The particular chemotherapy regimen prescribed was chosen according to protocols used at the Jewish General Hospital, Montreal, Quebec. Possibilities included cisplatin or carboplatin in combination with paclitaxel, gemcitabine, vinorelbine, docetaxel, or etoposide. The choice of the treatment regimen was at the discretion of the treating physician.

The study protocol was approved by the Institutional Review Board at the Jewish General Hospital, and all patients provided informed consent.

2.2. Prognostic Index

Standard techniques were used to determine crp, albumin, white blood cell count (wbcs), hemoglobin, and lactate dehydrogenase. A particle-enhanced turbidimetric assay was used to measure crp 18. The upper limits of the normal ranges for crp (10 mg/L) and for wbcs (11×109/L) were used as cut-off points 19.

Based on previous work by our group, the crp and wbc results were used to categorize patients into 3 different “prognostic index” (pi) groups (Table i) 6:

  • pi 0 for crp 10 mg/L or less and wbcs 11×109/L or less,
  • pi 1 if one of the two markers was elevated, and
  • pi 2 if both markers were elevated.
TABLE I
Definition of the prognostic index (pi)

2.3. Response to Chemotherapy

Response to chemotherapy was evaluated by chest ct after 2 cycles of chemotherapy. The response was categorized as progressive disease or freedom from progression. Freedom from progression was defined as an absence of objective progression; it included patients with either a complete response, a partial response, or stable disease according to the Response Evaluation Criteria in Solid Tumors (recist) 20.

2.4. Statistical Analysis

The primary outcomes of the study were the response to 2 cycles of platinum-based chemotherapy (as defined earlier) and overall survival. The association between pi and freedom from progression was investigated by chi-square test. Using t-tests and chi-square tests as appropriate, baseline blood parameters and the covariates of interest (age, sex, ps, smoking history, stage, and weight loss at first presentation) for the 3 pi groups were compared to confirm the homogeneity of the groups. Contingency tables and the chi-square test were used for categorical variables; t-tests were used for continuous variables.

Overall survival was defined as the time in months from diagnosis to the end of the study. Patients alive at the time of the last observation (March 30, 2009) were censored. Survival analysis was performed using the Kaplan–Meier method. Differences were assessed using a log-rank test. A Cox proportional hazards model was used to estimate the predictive power of the pi. The potential baseline prognostic factors included in the model were age, sex, crp, hemoglobin, weight loss, smoking status (smokers and ex-smokers vs. never-smokers), ecog ps, and pi. The likelihood ratio was used to test the contribution of each variable to the model when added last (that is, after adjustment for all of the other covariates).

All statistical analyses were carried out using the SPSS software package (version 14.0: SPSS, Chicago, IL, U.S.A.). All statistical tests were two-tailed. Statistical significance was accepted at p values of 0.05 or less.

3. RESULTS

The study identified 303 patients with stage iv nsclc. Of those 303 patients, 206 received chemotherapy and 97 were offered palliative radiation or supportive care (Figure 1). Of the 206 patients given chemotherapy, 69 were treated with a single agent and 137 received double-agent chemotherapy. In 3 patients, crp data were missing. The remaining 134 patients who had received 2 cycles of therapy and whose records had no missing data were analyzed.

Figure 1
Cohort organization chart. nsclc = non-small-cell lung cancer; rt = radiotherapy; sc = supportive care; crp = C-reactive protein.

Table ii shows the characteristics of the patient cohort. Mean age was 62 years (range: 31–83 years). Most had adenocarcinoma, a good ps, and no weight loss. Sites of metastases included lung, lymph nodes, bone, liver, and adrenal glands. The group included 65 ex-smokers (48%) who had quit more than 1 year before diagnosis, 40 patients (30%) who were still smoking at the time of diagnosis, and 29 never-smokers (22%). The most common treatment regimens were carboplatin–gemcitabine and carboplatin–paclitaxel.

TABLE II
Clinical characteristics of the study patients

Most patients had normal hemoglobin, albumin, and lactate dehydrogenase levels. The median crp concentration before chemotherapy was 13.2 mg/L. In 77 patients (57%), crp exceeded 10 mg/L. Median wbcs were 9.4×109/L. Before chemotherapy, wbcs were elevated in 39 patients (29%).

We calculated the pi for each patient based on binary crp and wbc values. In 46 patients (34%), the pi was 0; in 60 (45%), the pi was 1; and in 28 (21%), the pi was 2. We observed no association of pi with age or ecog ps (Table iii); however, significantly more men, smokers and ex-smokers, and patients with a weight loss of 5% or more were in the pi 2 group.

TABLE III
Clinical difference among the prognostic index (pi) groups

After 2 cycles of chemotherapy, 41 patients (31%) were found to have progressive disease. The pi and progression (Table iv) were weakly positively correlated (χ2 = 0.233,; p = 0.007). In the logistic regression analysis, the pi was the only significant predictor of progression. Age, sex, ecog ps, cancer stage, and smoking status were nonsignificant (Table v).

TABLE IV
Correlation of prognostic index (pi) with disease progression
TABLE V
Factors affecting rate of progression

Median follow-up was 10.3 months (range: 2.69–41.87 months). At the time of censoring, 86 patients (64%) had died. Overall median survival was 11.9 months [95% confidence interval (ci): 9.9 to 13.8 months]. Median survival for the pi 0 group was 20.0 months (95% ci: 9.50 to 30.5 months); for the pi 1 group, it was 10.4 months (95% ci: 8.3 to 12.5 months); and for the pi 2 group, it was 7.9 months (95% ci: 4.2 to 11.7 months; p < 0.001; Figure 2).

Figure 2
Kaplan–Meier survival curves based on the prognostic index (pi).

Univariate analysis identified crp and wbcs as significant prognostic factors in addition to ps. We observed no interaction between crp and wbcs. When crp and wbcs were combined into the pi, the effect was even stronger.

In a multivariate analysis, using the backward logistic regression method in a Cox model with all the variables of interest included, only the pi retained significance (hazard ratio: 1.57; 95% ci: 1.2 to 2.14; p = 0.004). The hazard for death was 2.5 for pi 1 and 3.9 for pi 2.

4. DISCUSSION

To our knowledge, this is the first prospective study aimed at evaluating the predictive value of pre-therapeutic inflammatory markers in nsclc.

We found that, combined into a pi, elevated plasma crp and wbcs at the time of nsclc diagnosis are independently associated with disease progression in response to 2 cycles of first-line treatment and with shorter overall survival in advanced nsclc. A lower pi score was associated with a reduction in the probability of disease progression after chemotherapy. The hazard for death was elevated by a factor of 2.5 for the pi 1 group and by a factor of 3.9 for the pi 2 group as compared with the pi 0 group. The development of the pi provides improved prediction accuracy for progression after 2 cycles of first-line treatment.

Despite advances in the accuracy of clinical staging, predictive and prognostic modeling for patients with advanced nsclc is still not satisfactory 1. A search is underway for molecular factors that might account for variation in tumour biology and its effect on survival 3,2124. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process 25. This environment promotes proliferation, survival, and migration of tumour cells and results in increased tumour aggressiveness. Some lung cancer cell lines have been shown to produce il-6. Indeed, there is evidence that il-6 is strongly related to crp and that crp, a routinely available and well-standardized clinical laboratory measurement, is a useful surrogate measure of tumour biology in patients with nsclc 14.

An increased serum crp level has been recognized as an ominous prognostic factor for several malignant tumours, including lung cancer 9,11,2631. In a prospective cohort study, Siemes et al. hypothesized that crp level and crp gene variation are associated with an altered risk of colorectal, lung, breast, and prostate cancer 32. In addition, crp is known to modulate both innate and adaptive immunity 33,34.

Other biologic factors such as baseline leucocytes and polynuclear cells have been less frequently studied in cancer patients in terms of their significance as predictive factors. A few studies demonstrated that in addition to ps, wbcs are an independent prognostic factor for poor survival in advanced nsclc 3539.

These insights are encouraging new anti-inflammatory therapeutic approaches to cancer treatment 6,40. However, the association between elevated inflammatory markers and chemotherapy response has not been clearly established 17,41.

The success of chemotherapy in esophageal and prostate cancer may relate to crp status 27,29,42,43. Wilop et al. correlated changes in crp over time with response to treatment in lung cancer patients receiving chemotherapy 44. Those authors reported that normalization of crp was associated with a low risk for progression, but that patients with an increase in crp of more than 25% showed progressive disease in most cases. However, their retrospective study was underpowered, given the small sample size and lack of control for stage and ps.

Several prognostic indices based on inflammatory factors have recently been described in nsclc 11,12,45. The most widely recognized is the gps, which uses a combination of crp and albumin 46. When compared with ps and wbcs, gps was superior in predicting survival 47. However, we found that serum albumin at diagnosis was occasionally low in our population and that adding wbcs to crp resulted in superior stratification of the resulting subgroups.

There are several possible explanations to account for the association between crp and chemotherapy response. Chronic inflammation results in excessive cell proliferation and activation of a cascade of cellular actions that can lead to induction of irreversible dna damage and subsequent tumour progression 48. Chronic inflammation might also be responsible for activation, in peripheral leucocytes, of messenger rnas for nuclear factor κB inhibitor and for the effect of that inhibitor on cytochrome systems 49,50. A tumour-associated inflammatory response involving crp and il-6 downregulates the CYP3A4 gene and correlates with suppression of drug metabolism 5153, resulting in increased toxicity during chemotherapy.

Incorporated into a pi, crp and wbcs identified 3 subgroups of stage iv nsclc patients with distinct risks of progression and death. This information might be pertinent to treatment decision-making and might also influence a revised staging system. If the objective is prognostic stratification, then using anatomic features alone for staging is no longer sufficient.

The major strength of the present study is the uniformity of the patient population with respect to diagnosis, stage, and treatment. The study is limited by the relatively small cohort and the weak correlation between pi and freedom from tumour progression.

5. CONCLUSIONS

Based on widely available, inexpensive, and easy-to-perform measurements, we developed a novel pi. The proposed pi may improve the accuracy of predictions of freedom from progression and of survival in response to first-line treatment. It may also provide information to complement other prognostic models, such as those based on gene profiling. The biologic markers that form the pi could be incorporated into the more traditional anatomic methods of staging.

6. ACKNOWLEDGMENTS

The work presented here was supported by the Mona Zavalkoff Fund for Pulmonary Oncology, by an unrestricted grant from Sanofi–Aventis, and by the Angel Ball.

Footnotes

7. CONFLICT OF INTEREST DISCLOSURES

All authors declare that there are no financial conflicts of interest.

8. REFERENCES

1. Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of progress. Chest. 2002;122:1037–57. [PubMed]
2. Apetoh L, Tesniere A, Ghiringhelli F, Kroemer G, Zitvogel L. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 2008;68:4026–30. [PubMed]
3. Deans C, Rose–Zerilli M, Wigmore S, et al. Host cytokine genotype is related to adverse prognosis and systemic inflammation in gastro-oesophageal cancer. Ann Surg Oncol. 2007;14:329–39. [PubMed]
4. Hilmy M, Campbell R, Bartlett JM, McNicol AM, Underwood MA, McMillan DC. The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration and cox-2 expression and survival in patients with transitional cell carcinoma of the urinary bladder. Br J Cancer. 2006;95:1234–8. [PMC free article] [PubMed]
5. Watine J. Comments on: haemostatic abnormalities in lung cancer: prognostic implications, Buccheri et al., Eur J Cancer, 33, pp. 50–55, 1997. Eur J Cancer. 1998;34:430. [PubMed]
6. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res. 2009;15:425–40. [PubMed]
7. Bonnefoy M, Ayzac L, Ingenbleek Y, Kostka T, Boisson RC, Bienvenu J. Usefulness of the prognostic inflammatory and nutritional index (pini) in hospitalized elderly patients. Int J Vitam Nutr Res. 1998;68:189–95. [PubMed]
8. Brown DJ, Milroy R, Preston T, McMillan DC. The relationship between an inflammation-based prognostic score (Glasgow Prognostic Score) and changes in serum biochemical variables in patients with advanced lung and gastrointestinal cancer. J Clin Pathol. 2007;60:705–8. [PMC free article] [PubMed]
9. Casamassima A, Picciariello M, Quaranta M, et al. C-Reactive protein: a biomarker of survival in patients with metastatic renal cell carcinoma treated with subcutaneous interleukin-2 base immunotherapy. J Urol. 2005;173:52–5. [PubMed]
10. Clinchy B, Fransson A, Druvefors B, et al. Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma. Cancer. 2007;109:1742–9. [PubMed]
11. Kelly L, White S, Stone PC. The B12/crp index as a simple prognostic indicator in patients with advanced cancer: a confirmatory study. Ann Oncol. 2007;18:1395–9. [PubMed]
12. MacDonald N, Kasymjanova G, Dobson S, et al. Prognostic value of baseline inflammatory markers in inoperable non-small cell lung cancer (nsclc) [abstract 17035] Proc Am Soc Clin Oncol 2006. 24[Available online at: www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=40&abstractID=31987; cited June 10, 2010]
13. Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. The anticancer immune response: indispensable for therapeutic success? J Clin Invest. 2008;118:1991–2001. [PMC free article] [PubMed]
14. McKeown DJ, Brown DJ, Kelly A, Wallace AM, McMillan DC. The relationship between circulating concentrations of C-reactive protein, inflammatory cytokines and cytokine receptors in patients with non-small-cell lung cancer. Br J Cancer. 2004;91:1993–5. [PMC free article] [PubMed]
15. Heikkila K, Harris R, Lowe G, et al. Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control. 2009;20:15–26. [PubMed]
16. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer. 2003;89:1028–30. [PMC free article] [PubMed]
17. Koch A, Fohlin H, Sorenson S. Prognostic significance of C-reactive protein and smoking in patients with advanced non-small cell lung cancer treated with first-line palliative chemotherapy. J Thorac Oncol. 2009;4:326–32. [PubMed]
18. Schwartz MW, Schifreen RS, Gorman E, Tuhy PM, Bienvenu J, Warkentin DL. Development and performance of a fully automated method for assay of C-reactive protein in the aca discrete clinical analyzer. Clin Chem. 1988;34:1646–9. [PubMed]
19. Jewish General Hospital, Department of Diagnostic Medicine . Normal Reference Range Table. Montreal, QC: Jewish General Hospital; 2008.
20. Julka PK, Doval DC, Gupta S, Rath GK. Response assessment in solid tumours: a comparison of who, swog and recist guidelines. Br J Radiol. 2008;81:444–9. [PubMed]
21. Armaiz–Pena GN, Lutgendorf SK, Cole SW, Sood AK. Neuroendocrine modulation of cancer progression. Brain Behav Immun. 2009;23:10–15. [PMC free article] [PubMed]
22. Apetoh L, Obeid M, Tesniere A, et al. Immunogenic chemotherapy: discovery of a critical protein through proteomic analyses of tumor cells. Cancer Genomics Proteomics. 2007;4:65–70. [PubMed]
23. Ullrich E, Ménard C, Flament C, et al. Dendritic cells and innate defense against tumor cells. Cytokine Growth Factor Rev. 2008;19:79–92. [PubMed]
24. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59–73. [PubMed]
25. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;7:1073–81. [PubMed]
26. Geissbühler P, Mermillod B, Rapin CH. Elevated serum vitamin B12 levels associated with crp as a predictive factor of mortality in palliative care cancer patients: a prospective study over five years. J Pain Symptom Manage. 2000;20:93–103. [PubMed]
27. Guillem P, Triboulet JP. Elevated serum levels of C-reactive protein are indicative of a poor prognosis in patients with esophageal cancer. Dis Esophagus. 2005;18:146–50. [PubMed]
28. Karakiewicz PI, Hutterer GC, Trinh QD, et al. C-Reactive protein is an informative predictor of renal cell carcinoma–specific mortality. Cancer. 2007;110:1241–7. [PubMed]
29. Graff J, Lalani AS, Lee S, et al. C-Reactive protein as a prognostic marker for men with androgen-independent prostate cancer (aipc): results from the ascent trial [abstract 5074] Proc Am Soc Clin Oncol 2007. 25[Available online at: www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=31092; cited June 10, 2010]
30. Suh SY, Ahn HY. A prospective study on C-reactive protein as a prognostic factor for survival time of terminally ill cancer patients. Support Care Cancer. 2007;15:613–20. [PubMed]
31. Hara M, Matsuzaki Y, Shimuzu T, et al. Preoperative serum C-reactive protein level in non-small cell lung cancer. Anticancer Res. 2007;27:3001–4. [PubMed]
32. Siemes C, Visser LE, Coebergh JW, et al. C-Reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol. 2006;24:5216–22. [PubMed]
33. Du Clos TW, Mold C. C-Reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res. 2004;30:261–77. [PubMed]
34. Peisajovich A, Marnell L, Mold C, Du Clos TW. C-Reactive protein at the interface between innate immunity and inflammation. Expert Rev Clin Immunol. 2008;4:379–90. [PubMed]
35. Panek B, Chyczewska E, Ossolińska M, Naumnik W, Izycki–Herman T, Korniluk M. Evaluation of some functions of polymorphonuclear granulocytes in lung cancer patients during chemotherapy [Polish] Pneumonol Alergol Pol. 2005;73:167–71. [PubMed]
36. Teramukai S, Kitano T, Kishida Y, et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer. 2009;5:1950–8. [PubMed]
37. Tibaldi C, Vasile E, Bernardini I, Orlandini C, Andreuccetti M, Falcone A. Baseline elevated leukocyte count in peripheral blood is associated with poor survival in patients with advanced non-small cell lung cancer: a prognostic model. J Cancer Res Clin Oncol. 2008;134:1143–9. [PubMed]
38. Kato K, Hitsuda Y, Kawasaki Y, et al. The value of serum C-reactive protein as a survival determinant in patients with advanced non-small-cell lung cancer [Japanese] Nihon Kokyuki Gakkai Zasshi. 2000;38:575–80. [PubMed]
39. Mignot G, Ullrich E, Bonmort M, et al. The critical role of il-15 in the antitumour effects mediated by the combination therapy imatinib and il-2. J Immunol. 2008;180:6477–83. [PubMed]
40. MacDonald N. Cancer cachexia and targeting chronic inflammation: a unified approach to cancer treatment and palliative/supportive care. J Support Oncol. 2007;5:157–62. [PubMed]
41. Wilop S, Crysandt M, Bendel M, Mahnken AH, Osieka R, Jost E. Correlation of C-reactive protein with survival and radiographic response to first-line platinum-based chemotherapy in advanced non-small cell lung cancer. Onkologie. 2008;31:665–70. [PubMed]
42. Beer TM, Ryan CW, Venner PM, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ascent investigators. J Clin Oncol. 2007;25:669–74. [PubMed]
43. Qin TJ, An GL, Zhao XH, et al. Combined treatment of oxaliplatin and capecitabine in patients with metastatic esophageal squamous cell cancer. World J Gastroenterol. 2009;15:871–6. [PMC free article] [PubMed]
44. Al Murri AM, Bartlett JM, Canney PA, Doughty JC, Wilson C, McMillan DC. Evaluation of an inflammation-based prognostic score (gps) in patients with metastatic breast cancer. Br J Cancer. 2006;94:227–30. [PMC free article] [PubMed]
45. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dagg K, Scott HR. A prospective longitudinal study of performance status, an inflammation-based score (gps) and survival in patients with inoperable non-small-cell lung cancer. Br J Cancer. 2005;92:1834–6. [PMC free article] [PubMed]
46. Ackerman WE, 3rd, Zhang JM. Serum hs-crp as a useful marker for predicting the efficacy of lumbar epidural steroid injections on pain relief in patients with lumbar disc herniations. J Ky Med Assoc. 2006;104:295–9. [PubMed]
47. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Comparison of an inflammation-based prognostic score (gps) with performance status (ecog) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. Br J Cancer. 2004;90:1704–6. [PMC free article] [PubMed]
48. Taieb J, Chaput N, Ménard C, et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med. 2006;12:214–19. [PubMed]
49. Bisoendial RJ, Birjmohun RS, Akdim F, et al. C-Reactive protein elicits white blood cell activation in humans. Am J Med. 2009;122:582.e1–9. [PubMed]
50. Assenat E, Gerbal–Chaloin S, Maurel P, Vilarem MJ, Pascussi JM. Is nuclear factor kappa-B the missing link between inflammation, cancer and alteration in hepatic drug metabolism in patients with cancer? Eur J Cancer. 2006;42:785–92. [PubMed]
51. Robertson GR, Liddle C, Clarke SJ. Inflammation and altered drug clearance in cancer: transcriptional repression of a human CYP3A4 transgene in tumor-bearing mice. Clin Pharmacol Ther. 2008;83:894–7. [PubMed]
52. Kacevska M, Robertson GR, Clarke SJ, Liddle C. Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol. 2008;4:137–49. [PubMed]
53. Sharma R, Kacevska M, London R, Clarke SJ, Liddle C, Robertson G. Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies. Br J Cancer. 2008;98:91–7. [PMC free article] [PubMed]

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