J.M.G.H. van Riel

Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer

A feasibility study was performed to assess the toxicity and efficacy of a combination of gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer (LAPC). 24 patients (15 females and 9 males) with measurable LAPC were included; the median age of the patients was 63 years (range 39-74 years). The performance status ranged from 0 to 2. Gemcitabine was administered at a dose of 300 mg/m(2), concurrent with radiotherapy, three fractions of 8 Gy, on days 1, 8 and 15. When compliance allowed, gemcitabine alone was continued thereafter, at 1000 mg/m(2), weekly times 3, every 4 weeks, depending on the response and toxicity. All patients were evaluable for toxicity and response. The objective response rate was 29.2% (1 complete remission+6 partial remissions); 12 patients had stable disease. However, 2 of the radiological partial remissions were shown to be complete remissions by pathology assessment. Median duration of response was 3 months (range 1-35+months). Median time to progression was 7 months (range 2-37+months). Median survival was 10 months (range 3-37+months). Dose reduction or omission of gemcitabine was necessary in 10 patients. Non-haematological toxicity consisted of 87.5% nausea and vomiting grade I-II, diarrhoea 54%, ulceration in stomach and duodenum 37.5% (20.8% ulceration with bleeding); 1 patient developed a fistula between the duodenum and aorta, 5 months after treatment. Anaemia grade III-IV was observed in 8.3% of the patients. Neutropenia grade III-IV was observed in 8.3%, thrombocytopenia grades III-IV in 16.7%. In 1 patient who underwent resection postchemoradiation, no viable tumour cells were found. In addition, in the patient who suddenly died of a fistula between the duodenum and aorta, no viable tumour cells were detectable at autopsy. Although the toxicity of this treatment was occasionally severe, the response and survival are encouraging and warrant further studies of this combination.

Rb, mcl-1 and p53 expression correlate with clinical outcome in patients with liver metastases from colorectal cancer

BACKGROUND Thymidylate synthase (TS) has been associated with clinical outcome in disseminated colorectal cancer. However, many patients with low TS expression still fail to respond to treatment. Therefore, we studied the cell cycle proteins, Rb, E2F2, Ki67, p21 and p53 and the apoptotic proteins, mcl-1, hax, bcl-xl, bcl-2, Fas receptor, Fas ligand, caspase-3, M30 and PARP as potential predictive factors. PATIENTS AND METHODS In biopsy specimens of liver metastases from 31 colorectal cancer patients, protein expression was retrospectively determined by immunohistochemistry and related to response to hepatic arterial or intravenous (i.v.) 5-fluorouracil (5-FU) treatment, time to tumour progression (TTP) and overall survival. RESULTS Expression of both p53 and Rb correlated with survival benefit after 5-FU treatment. A median survival time of 79 weeks was found in patients with high levels of p53 or Rb compared to 36 and 44 weeks for patients expressing low levels of p53 (P = 0.027) or Rb (P = 0.030), respectively. Multivariate analysis showed that p53 was the best predictor of survival independent of sex, age or prior treatment. Following 5-FU hepatic arterial infusion, patients with a high TS expression had a shorter survival time than those with a low expression (P = 0.025). The anti-apoptotic protein mcl-1 was the only factor, which correlated with response to 5-FU treatment. Thirty-five percent of patients with a diffuse mcl-1 expression responded whereas ninety percent of patients with a peri-nuclear expression responded (P = 0.041). CONCLUSIONS These results indicate that besides TS, also Rb, p53 and mcl-1 are correlated with clinical outcome in patients with liver metastases from colorectal cancer.

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

Background:We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients.Methods:Consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan–Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy.Results:Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49–2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy.Conclusion:Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.

Hepatic arterial 5-fluorouracil in patients with liver metastases of colorectal cancer: Single-centre experience in 145 patients

BACKGROUND Hepatic arterial chemotherapy for liver metastases of colorectal cancer is still under discussion. Mainly because of the technical complications of this mode of treatment and the lack of a survival benefit in randomized studies. We performed an analysis of hepatic arterial 5-fluorouracil (5-FU) chemotherapy in 145 consecutive patients treated at a single institution. PATIENTS AND METHODS One hundred forty-five patients with inoperable liver metastases from colorectal cancer were included. 5-FU, 1000 mg/m2/day continuous infusion for five days every three weeks, was delivered in the hepatic artery by percutaneous catheter or arterial access device. RESULTS The response rate was 34% for all patients, 40% in patients with extrahepatic disease, and 15% in patients with i.v. 5-FU-based pretreatment. TTP and OS for all patients were 7.5 and 14.3 months, respectively. In patients with extrahepatic disease or i.v. 5-FU-based pretreatment, OS was significantly shorter compared to patients without extrahepatic disease or 5-FU-based pretreatment (9.7 vs. 19.3 months and 10.1 vs. 17.4 months, respectively), forty-seven percent of patients stopped treatment because of a complication. Complications most often seen in patients with arterial ports were hepatic artery thrombosis (48%) and dislocation of the catheter (22%). CONCLUSIONS The results of our analysis are in line with previous phase III studies. Extrahepatic disease and i.v. 5-FU-based pretreatment were prognostic for reduced OS. The complication rate of hepatic arterial delivery was worrisome. although, no negative impact on survival could be established. There is a strong need for improvement of hepatic arterial delivery methods before further evaluation of hepatic arterial

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

BACKGROUND The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.

Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial

BACKGROUND The effect of extended adjuvant aromatase inhibition in hormone receptor-positive breast cancer after sequential endocrine therapy of tamoxifen followed by an aromatase inhibitor for a 5-year treatment period still needs clarification. To address this issue, we began the DATA study to assess different durations of anastrozole therapy after tamoxifen. METHODS DATA was a prospective, randomised, open-label, multicentre, phase 3 study done in 79 hospitals in the Netherlands. We randomly assigned postmenopausal women with hormone receptor-positive early breast cancer with no signs of disease recurrence after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole treatment (1 mg orally once a day) in a 1:1 ratio. We used TENALEA (Trans European Network for Clinical Trials Services) for the randomisation procedure. Stratification factors were nodal status, hormone receptor status, HER2 status, and tamoxifen treatment duration. The primary study endpoint of this analysis was disease-free survival starting beyond 3 years after randomisation (adapted disease-free survival). Here we report the final analysis from the DATA trial, which is registered with ClinicalTrials.gov, number NCT00301457. FINDINGS Between June 28, 2006, and Aug 10, 2009, we screened 1912 patients of whom 955 were assigned to the 3-year group and 957 to the 6-year anastrozole treatment group. 1860 patients were eligible (931 in the 6-year group and 929 in the 3-year group) and 1660 were disease free 3 years after randomisation. The 5-year adapted disease-free survival was 83·1% (95% CI 80·0-86·3) in the 6-year group and 79·4% (76·1-82·8) in the 3-year group (hazard ratio [HR] 0·79 [95% CI 0·62-1·02]; p=0·066). Patients in the 6-year treatment group had more adverse events than those in the 3-year treatment group, including all-grade arthralgia or myalgia (478 [58%] of 827 in the 6-year treatment group vs 438 [53%] of 833 in the 3-year treatment group) and osteopenia or osteoporosis (173 [21%] vs 137 [16%]). INTERPRETATION We cannot recommend the use of extended adjuvant aromatase inhibition after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer. FUNDING AstraZeneca.

Real-world and trial-based cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer patients : a study of the Southeast Netherlands Breast Cancer Consortium

INTRODUCTION The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. METHODS A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. RESULTS In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained. CONCLUSION According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.

First line tailored chemotherapy in advanced colorectal cancer (ACRC) with 5-fluouracil/leucovorin (5FU/LV) or oxaliplatin/irinotecan chosen by the expression of thymidylate synthase (TS) and dihydropyrimidine (DPD)

3624 Background: Treatment of ACRC with 5FU/LV has a response rate (RR) < 25%. In a retrospective study both low TS and low DPD gene expression levels in metastases of ACRC were positive predictive factors of a response to 5FU (Salonga et al: CCR 2000). In contrast, the efficacy of oxaliplatin and irinotecan is supposedly independent of TS and DPD. METHODS Gene expression levels of TS and DPD using a quantitative RT-PCR assay were determined in pretreatment needle biopsies of metastatic tissue in previously untreated pts with ACRC. The cut-off values for TS and DPD relative to B-actin were 5 x 10 -3 and 45 x 10 -3, respectively. Chemotherapy consisted in arm A (low TS and low DPD) of weekly bolus 5FU/LV 500mg/m2 and in arm B (high TS and/or DPD) of 3-weekly oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. After progression, cross-over to the other regimen was allowed. Toxicity and response were evaluated every 3 and 9 weeks, respectively. Statistics using X2 test (one-sided, p<.05, 80 % power) required 20 evaluable pts in arm A to detect a significant increase of RR > 50%. RESULTS 47 out of 54 pts with a biopsy were treated in arm A (n=26) or arm B (n=21). 7 pts were not allocated to arm A or B due to deteriorating condition (3), other chemotherapy (2) and metastectomy (2). All pts in arm A were evaluable for response, and partial response (PR) was observed in 11 (RR 42 %) and stable disease (SD) in 9 pts. All but 1 pt in arm B were evaluable, with a PR in 5 (RR 25%) and SD in 9 pts. No responses were observed in 11 pts with a high TS/DPD after crossover to 5FU/LV, while crossover to the other regimen (n=10) resulted in 1 PR and 4 SD. No neutropenic fever or toxic deaths occurred. CONCLUSIONS This study shows a higher efficacy of monotherapy with 5FU/LV in pts with a low level of TS and DPD than expected in unselected pts. As the need for fresh metastatic tumor tissue hampers this approach, investigation of alternative methods for TS and DPD assessment and other predictive markers is warranted. [Table: see text].

5-Fluorouracil Induction of Fas and Apoptosis in Colon Cancer Patients: Relation of Clinical Outcome with Thymidylate Synthase, Mcl-1 and Rb

Thymidylate synthase (TS), catalyses the methylation of dUMP to dTMP with 5,10-methylene-tetrahydrofolate (CH2-THF) (1, 2). The active metabolite of 5-fluorouracil (5-FU), FdUMP forms a ternary complex with TS and CH2-THF leading to TS inhibition, growth arrest and cell death (1), which is stimulated by leucovorin (LV) (3, 4). Resistance to 5-FU is not only related to high TS levels, but also to mechanisms involved in cell growth inhibition or programmed cell death (3, 4, 5). Cell cycle progression is controlled by p53 (6), p21 (7), Rb and E2F (8). Drug treatment induces DNA damage, and p53 activates p21 to initiate cell cycle arrest. The tumor suppressor gene Rb forms a complex with E2F inhibiting their transcriptional activity (8). After phosphorylation of Rb by specific kinases, cell cycle progression can be activated by release of E2F1 and E2F2.