Advanced pancreatic cancer - how to choose an adequate treatment option.

The prognosis of pancreatic adenocarcinoma is poor, making it one of the leading causes of cancer-related death. The 5-year overall survival rate remains below 5% and little progress is made during the past decade. Only about 10%-20% of patients are eligible for curative-intent surgery and the majority end up having recurring disease even after radical surgery and postoperative adjuvant chemotherapy. Chemotherapy in metastatic disease is palliative at best, aiming at disease and symptom control and prolongation of life. Treatment always causes side effects, the degree of which varies from patient to patient, depending on the patient's general condition, concomitant morbidities as well as on the chosen treatment modality. Why is pancreatic cancer so resistant to treatment? How to best help the patient to reach the set treatment goals?

Disease outcome of patients with pancreatic cancer in a cohort treated outside clinical trials.

This retrospective study included 92 consecutive patients with locally advanced or metastatic pancreatic cancer treated in the Turku University Hospital in 2010. The diagnosis of pancreatic cancer was verified by either histological samples (adenocarcinoma) or by imaging or both, excluding other known histological types of tumours. Median patient survival was 11 months. Smokers had a better median overall survival (20 months) than non-smokers (10 months) (p=0.029). Patients with carcinoma of the head of pancreas had the best survival rates (15 months), whereas those with cancers of the tail of pancreas reached a median survival of only 3 months. The importance of this small trial resides in its retrospective and non-randomized nature, analyzing real-life patients, as encountered in daily practice, out of which, unfortunately, a substantial proportion would not be eligible for any randomized clinical trial.

ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer.

The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) associates with treatment resistance and adverse outcome in several human cancers. We studied ALDH1 expression in rectal cancer, with special emphasis on its association with treatment response and disease outcome. Immunohistochemical staining for ALDH1 was conducted for 64 biopsies and 209 operative samples from rectal cancer patients treated with short- (n = 89) or long-course (n = 46) (chemo)radiotherapy plus surgery, or with surgery only (n = 74). The staining results were compared to clinicopathological variables, tumor regression grade (TRG) and disease outcome. Nuclear ß-catenin expression pattern was analyzed from 197 operative samples. Positive ALDH1 expression was present in 149 operative samples (71%), correlating with deficient nuclear ß-catenin regulation (P = .018). In a pairwise comparison of respective biopsy and operative samples, ALDH1 expression remained stable or increased after preoperative (chemo)radiotherapy in most of the cases, while it decreased in few cases only (P = .02 for positive/negative category; P <.001 for intensity). ALDH1 expression did not, however, relate to tumor regression grade. In node-negative rectal cancer, ALDH1 expression was an independent predictor of short disease-free and disease-specific survival (P = .044; P = .049), specifically among patients treated with adjuvant chemotherapy. We conclude that ALDH1 associates with deregulated ß-catenin signaling, supporting the role of ALDH1 in rectal cancer stemness. ALDH1 expression relates to poor outcome in early stage rectal cancer, a group where new prognostic tools are particularly needed, and may indicate chemo- and radioresistance.

Carbonic anhydrase IX, hypoxia-inducible factor-1α, ezrin and glucose transporter-1 as predictors of disease outcome in rectal cancer: multivariate Cox survival models following data reduction by principal component analysis of the clinicopathological predictors.

Strong expression of carbonic anhydrase IX (CAIX), hypoxia-inducible factor-1α (HIF-1α), ezrin and glucose transporter-1 (GLUT-1) was previously shown to be related to adverse disease outcome in rectal cancer. In this study, operative samples of 178 rectal cancer patients 77 treated with short-course and 47 with long-course preoperative radiotherapy (RT), and 54 with no preoperative treatment, as well as 80 preoperative biopsies from the RT group patients were analyzed for these markers. For data reduction, principal component analysis (PCA) was used to extract a set of factors from the original clinicopathological variables that would explain as much as possible of their variance. After extraction and promax rotation, this set of five first-order factors (F1-F5) was used in multivariate (Cox) modeling together with the four biomarkers. In model 1 (biomarkers in operative samples), F1 was the only independent determinant of disease-free (DFS) (p=0.043) and disease-specific survival (DSS) (p=0.029). In model 2 (biomarkers in preoperative biopsies), none of the five factors or biomarkers were significantly associated with DFS. However, HIF-1α (p=0.024), ezrin (p=0.034), F1 (p=0.011), and F3 (p=0.001) were significant independent predictors of DSS. Similarly, in model 3 (ezrin in preoperative biopsies and others in operative samples), none of the factors or biomarkers were significant predictors of DFS. However, CAIX (p=0.028), and F1 (p= 0.017) were significantly associated with DSS. Preoperative RT markedly modifies the expression of these four biomarkers and also interferes with the original clinicopathological prognosticators (loaded to F1-F5), emphasizing the complexity of prognostication in rectal cancer.

Securin identifies a subgroup of patients with poor outcome in rectal cancer treated with long-course (chemo)radiotherapy.

BACKGROUND: Securin is an oncogene with functions in cell proliferation, tumour initiation and progression. Its prognostic value in rectal cancer is somewhat unknown. Accordingly, we studied securin expression together with Ki-67 in rectal cancer in relation to preoperative (chemo)radiotherapy (RT) and disease outcome. MATERIAL AND METHODS: Biopsies (n = 65 for securin; n = 57 for Ki-67) and operative specimens (n = 207) from 211 patients treated with short-course RT (n = 87), long-course RT (n = 54) or surgery only (n = 70) were studied with immunohistochemistry (IHC) for securin and Ki-67 expression. In the long-course RT group, 45 patients received chemotherapy (5-fluorouracil or capecitabine) concomitantly with RT. The results of IHC were related to clinicopathological variables, disease outcome and tumour regression grade (TRG) after long-course RT. RESULTS: Both markers showed significant reduction after RT (p < 0.001). No differences in expression was seen in the long-course RT group between the patients with or without concomitant chemotherapy (p = 0.23 for securin; p = 0.31 for Ki-67). Low Ki-67 expression, but not that of securin, in operative specimens was significantly related to excellent TRG (p = 0.02 for Ki-67; p = 0.21 for securin). In univariate survival analysis, excellent TRG predicted longer disease-specific survival (DSS; p = 0.03). In multivariate Cox analysis, high securin expression after long-course (chemo)RT was an independent predictor of shorter DSS (p = 0.036) together with patient age (p = 0.043) and disease recurrence (local or distant; p = 0.009), whereas no similar appearance was seen in other treatment groups. CONCLUSION: Securin expression in rectal cancer is significantly reduced after RT. High securin expression and poor TRG after long-course (chemo)RT are indicators of unfavourable disease outcome.

Preoperative radiotherapy modulates ezrin expression and its value as a predictive marker in patients with rectal cancer.

The purpose of this study was to assess the value of ezrin expression as a predictor of disease outcome in rectal cancer treated by preoperative radio- or chemoradiotherapy. Operative samples from 176 rectal cancer patients and 76 diagnostic preoperative biopsies from the same cohort were analyzed for ezrin expression using immunohistochemistry. The patients had received short- (n = 76) or long-course radiotherapy with (n = 36) or without chemotherapy (n = 10) or no treatment preoperatively (n = 54). The direct effect of radiation on ezrin expression was studied in cultured cells by Western blot analysis. The biopsies and respective operative samples were significantly different (κ = -0.010 for 4-tier scoring and κ = 0.028 for dichotomized scoring) in their ezrin expression. Most preoperative biopsies (61/76, 80%) had negative/weak ezrin expression compared with 56% (43/76) of the corresponding operative samples. After preoperative treatment, negative expression in the biopsies of 18 (82%) of 22 patients turned positive, whereas positive expression in 6 (11%) of 54 biopsies turned negative in the operative samples. In univariate analysis, disease-free survival and disease-specific survival were significantly longer (P = .027 and P = .002) when ezrin expression in the preoperative biopsy was negative/weak compared with moderate/strong expression. Such prognostic association was lost in the radiated operative specimens. In multivariate regression model, ezrin was not a predictor of disease-free survival. No direct effect of radiation on ezrin expression was seen in vitro. In conclusion, radiotherapy increases ezrin expression in rectal cancer. In pretreatment biopsies, negative/weak ezrin expression correlates with favorable disease outcome, suggesting that ezrin expression modulates tumor aggressiveness and/or response to treatment.