Early increase in circulating carbonic anhydrase IX during neoadjuvant treatment predicts favourable outcome in locally advanced rectal cancer

Abstract

Background: Locally advanced rectal cancer (LARC) comprises heterogeneous tumours with predominant hypoxic components. The hypoxia-inducible metabolic shift causes microenvironmental acidification generated by carbonic anhydrase IX (CAIX) and facilitates metastatic progression, the dominant cause of failure in LARC.

Methods: Using a commercially available immunoassay, circulating CAIX was assessed in prospectively archived serial serum samples collected during combined-modality neoadjuvant treatment of LARC patients and correlated to histologic tumour response and progression-free survival (PFS).

Results: Patients who from their individual baseline level displayed serum CAIX increase above a threshold of 224 pg/ml (with 96 % specificity and 39 % sensitivity) after completion of short-course neoadjuvant chemotherapy (NACT) prior to long-course chemoradiotherapy and definitive surgery had significantly better 5-year PFS (94 %) than patients with below-threshold post-NACT versus baseline alteration (PFS rate of 56 %; p < 0.01). This particular CAIX parameter, ΔNACT, was significantly correlated with histologic ypT0-2 and ypN0 outcome (p < 0.01) and remained an independent PFS predictor in multivariate analysis wherein it was entered as continuous variable (p = 0.04).

Conclusions: Our results indicate that low ΔNACT, i.e., a weak increase in serum CAIX level following initial neoadjuvant treatment (in this case two cycles of the Nordic FLOX regimen), might be used as risk-adapted stratification to postoperative therapy or other modes of intensification of the combined-modality protocol in LARC.

Trial registration: ClinicalTrials.gov NCT00278694.

Figures

Fig. 1

Serum carbonic anhydrase IX (CAIX) levels during neoadjuvant treatment of patients with locally advanced rectal cancer. Using a commercially available immunoassay, CAIX was measured in serum sampled from the study patients at baseline (n = 66), following four weeks of neoadjuvant chemotherapy (post-NACT; n = 66), at completion of a 5-week course of chemoradiotherapy (post-CRT; n = 54) and at evaluation of the neoadjuvant therapy four weeks later (n = 50). CAIX values are depicted by boxes (25th, 50th and 75th percentiles), bars (10th and 90th percentiles) and circles (outlier values). Distribution of CAIX values during the neoadjuvant course was different from baseline (* p < 0.05, ** p < 0.001; calculated by Mann-Whitney U-test)

Fig. 2

Serum carbonic anhydrase IX (CAIX) levels and progression-free survival in locally advanced rectal cancer. Progression-free survival was analysed (by the Kaplan-Meier method) for the population of 66 study patients with paired serum sample measurements of CAIX following neoadjuvant induction chemotherapy versus baseline (a variable termed ΔNACT), divided into two groups above (solid line) and below (dashed line) an estimated optimum cut-off ΔNACT value of 224 pg/ml. Difference between the two groups was significant (p < 0.01)