CA 19-9 and the Management of Pancreatic Cancer
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a retrospective analysis of a single institution's experience with CA 19-9 as a marker in patients with pancreatic cancer, the absolute level prior to therapy, and the drop after treatment, was shown to be an independent prognostic factor for survival.
Source: Reni M, et al. Carbohydrate antigen 19-9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer. 2009;115:2630-2639.
Although there has been some improvement in the management of advanced pancreatic cancer, prognosis remains poor, as does the need for a robust research agenda addressing optimal treatment. Although chemotherapy doublets have demonstrated only marginal benefit when compared to single-agent gemcitabine,1-3 four drug regimens have been shown to be more effective.4,5 Nonetheless, for patients with pancreatic cancer, assessment of clinical response is sometimes problematic. Imaging studies are often unreliable because of the vigorous desmoplastic reaction, including inflammation and fibrosis within and around the tumor.6 Thus, additional markers have been explored as an adjunct to radiological studies and, in this context, there has been considerable interest and experience with serum levels of carbohydrate antigen 19-9 (CA 19-9). This molecule is a sialylated Lewis blood group, tumor-associated antigen that is not synthesized by individuals who lack the Lewis antigen glycosyltransferase. Several retrospective studies have identified a correlation between a decline in serum CA 19-9 value and prolonged survival.7,8 However, because of the limited numbers of patients in those studies and the various definitions of CA 19-9 response, a consensus was not reached about the frequency with which tests should be performed, or about the meaningful cutoff level of marker change. Furthermore, a recent retrospective analysis of prospectively collected data from a randomized phase III trial concluded that a decrease in CA 19-9 during chemotherapy (analyzed by correcting for guarantee-time bias) is not a valid surrogate endpoint for survival in clinical trials.9 Data from the latter trial are difficult to interpret because of the high percentage of missing values (72 of 247 patients; 29%) and because a decline in CA 19-9 concentration of > 50% was related significantly to survival in the analysis that was not corrected for guarantee time bias and in the Cox regression model.
Thus, Reni et al from Milan undertook a retrospective analysis to assess the correlation between a decline in CA 19-9 value and survival in a large cohort of patients treated at a single institution and pooled from five consecutive trials that examined the role of first-line therapy in patients with advanced pancreatic cancer. The objective of this study was to evaluate the correlation between a decline in carbohydrate antigen 19-9 (CA 19-9) and survival in patients with advanced pancreatic cancer who received up-front chemotherapy.
CA 19-9 serum basal values were measured in 247 patients with advanced pancreatic cancer who were enrolled in five consecutive trials between 1997 and 2007. Survival curves were compared among patients who had a predefined CA 19-9 nadir difference (< 50%. Group 1; 50% to 89%, Group 2; or > 89%, Group 3). To eliminate guarantee-time bias, survival analysis was repeated using the landmark method.
In both univariate and multivariate analysis, the basal CA 19-9 value significantly predicted survival. The median survival was 15.5 months for 34 patients who had normal basal CA 19-9 values (group 1), 11.9 months for 108 patients who had basal values between 38 U/mL and 1167 U/mL (group 2), and 8 months for 105 patients who had basal values > 1167 U/mL (group 3). At least one CA 19-9 follow-up value was available for 204 patients who had baseline values greater than normal. When considering the nadir CA 19-9 level, there was a significant, stepwise increase in overall and progression-free survival by both univariate and multivariate analyses for those whose level did not decline 50%, for those whose decline was 50%-89%, and for those whose decline was > 90%. Further statistical analysis using the landmark method to eliminate guarantee-time bias confirmed these findings.
Commentary
Thus, in this study, baseline CA 19-9 was confirmed as an independent prognostic factor for progression-free and overall survival for patients with advanced pancreatic cancer. Reni et al suggest that the role of CA 19-9 may be expanded in clinical investigation as a complementary measure to radiologic measures to provide a better assessment of chemotherapy activity.
CA 19-9 represents an ideal endpoint for clinical studies because it is quick, safe, and easy to measure, and allows the assessment of patients with "unmeasurable'' disease. However, it should be recalled that CA 19-9 is not expressed in 10%-15% of patients with pancreatic cancer who are negative for the Lewis blood group antigen; therefore, the current considerations cannot be applied to that subset of patients. The level of CA 19-9, or the change in level, may also be useful in clinical practice to drive treatment decisions in critical situations, such as whether to continue with palliative chemotherapy in patients who have radiologically stable or progressive disease.
References
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2. Herrmann R, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25:2212-2217.
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6. Brambs HJ, Claussen CD. Pancreatic and ampullary carcinoma. Ultrasound, computed tomography, magnetic resonance imaging and angiography. Endoscopy. 1993;25:58-68.
7. Halm U, et al. Decrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer. Br J Cancer. 2000;82:1013-1016.
8. Maisey NR, et al. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer. 2005;93:740-743.
9. Hess V, et al. CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol. 2008;9:132-138.
In a retrospective analysis of a single institution's experience with CA 19-9 as a marker in patients with pancreatic cancer, the absolute level prior to therapy, and the drop after treatment, was shown to be an independent prognostic factor for survival.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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