Punt, C.J.A.

Comparison of treatment outcome in metastatic colorectal cancer patients included in a clinical trial versus daily practice in the Netherlands (Article)

2013-06-01T00:00:00Z

The external validity of trial results is a matter of debate, and no strong evidence is available to support whether a trial may have a positive or a negative effect on the outcome of patients. Methods. We compared the results of stage IV colorectal cancer patients treated within a large Dutch phase III trial (CAIRO), in which standard chemotherapy and standard safety eligibility criteria were used, to patients treated outside the trial during the trial accrual period in a representative selection of 29 Dutch hospitals. Non-trial patients were identified by the Netherlands Cancer Registry (NCR), and were checked for the trial eligibility criteria. Results. The NCR registered 1946 stage IV colorectal cancer patients who received chemotherapy, of whom 394 patients were included in the CAIRO trial and 30 patients in other trials. Thus, the CAIRO trial participation rate was 20%. In the 29 hospitals, 162 patients received chemotherapy in the trial and 396 patients received chemotherapy outside the trial. Of the non-trial patients, 224 patients fulfilled the trial eligibility criteria. The overall survival of eligible non-trial patients was comparable to trial patients (HR 1.03, p = 0.70). However, non-eligible non-trial patients had a significantly worse outcome (HR 1.70, p < 0.01). Conclusion. These data provide evidence in a common tumor type that trial results have external validity, provided that standard eligibility criteria are being observed. Our finding of a worse outcome for patients not fulfilling these criteria strongly argues against the use of cancer treatments in other patient categories than included in the original trials in which these treatments were investigated.

Analysis of surrogate gene expression markers in peripheral blood of melanoma patients to predict treatment outcome of adjuvant pegylated interferon alpha 2b (EORTC 18991 side study) (Article)

2013-04-29T00:00:00Z

We analysed mRNA levels of interferon response genes (ISG15, STAT1, CXCL10) of inhibitors of the JAK/STAT pathway (STAT3, SOCS1, SOCS3) and of cytokines (TNFα, IL10, TGFß1) in peripheral blood of 91 stage III melanoma patients enrolled in EORTC 18991 trial to find biomarkers indicative for disease stage and predictive for efficacy of pegylated interferon alpha-2b (PEG-IFNα-2b) therapy. mRNA levels were analysed at baseline and after 6 months. Univariate and multivariate analyses were performed to estimate the prognostic and predictive role of mRNA levels for distant metastasis-free survival (DMFS) and relapse-free survival (RFS). Compared to healthy controls, melanoma patients showed significantly higher TGFβ1 mRNA levels. In a multivariate model, increasing SOCS1 and SOCS3 mRNA levels were associated with worse RFS (P = 0.02 and P = 0.04, respectively) and DMFS (P = 0.05 and P = 0.05, respectively) due to negative correlation between, respectively, SOCS1/SOCS3 mRNA levels and ulceration or Breslow thickness. No impact of PEG-IFNα-2b on mRNA levels was observed except for ISG15 mRNA levels, which decreased in the treatment arm (P = 0.001). It seems that patients with a decrease >60 % of ISG15 mRNA levels during 6 months PEG-IFNα-2b had inferior outcome.

Adjuvant chemotherapy in stage III colon cancer: Guideline implementation, patterns of use and outcomes in daily practice in the Netherlands (Article)

2012-01-01T00:00:00Z

Background. Little is known about how well guidelines about adjuvant chemotherapy in colon cancer are followed in daily practice. We evaluated the current guideline, which is based on the MOSAIC trial, by examining implementation, treatment patterns and disease-free survival. Material and methods. We analysed a population-based cohort of 391 patients treated with adjuvant chemotherapy for stage III colon cancer in 20052006. Data were gathered from the Dutch Cancer Registry and medical records of 19 hospitals. Patients were classified according to whether or not they fulfilled MOSAIC trial eligibility criteria. Results. The administered regimens were: fluorouracil-leucovorin (17 patients), capecitabine (93), fluorouracil- leucovorin plus oxaliplatin (145), and capecitabine plus oxaliplatin (136). After its inclusion in national guidelines, oxaliplatin was prescribed in 16 hospitals within six months. Patients receiving oxaliplatin were younger and had less comorbidity than other patients. Dose schedules corresponded well with guidelines. Two-year disease-free survival probability of oxaliplatin patients meeting MOSAIC eligibility criteria was 78.4% (95% CI 72.584.3), which was comparable to MOSAIC trial results. Conclusion. Guidelines for adjuvant chemotherapy in stage III colon cancer are generally well followed in daily practice. However, uncertainty remains regarding the optimal treatment of elderly patients and patients with comorbidities, which underscores the need for practical clinical trials including these patients.

The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (Article)

2011-12-16T00:00:00Z

Background: The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer. Methods/Design. Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response. Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol. Discussion. The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051).

Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: Final results of a randomised phase III study (EORTC 18032) (Article)

2011-07-01T00:00:00Z

Purpose: To compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. Patients and methods: A total of 859 patients were randomised to receive oral temozolomide at 150 mg/m2/day for seven consecutive days every 2 weeks or dacarbazine, administered as an intravenous infusion at 1000 mg/m2/day on day 1 every 3 weeks. The primary endpoint was overall survival (OS), using an intent-to-treat principle. EudraCT number 2004-000654-23 NCI registration number NCT00005052. Results: Median OS was 9.1 months in the temozolomide arm and 9.4 months in the dacarbazine arm, with a hazard ratio (HR) of 1.00 (95%confidence interval [CI]: 0.86, 1.17; P = 0.99). Median progression-free survival (PFS) was 2.3 months in the temozolomide arm and 2.2 months in the dacarbazine arm, with a HR of 0.92 (95%CI: 0.80, 1.06; P = 0.27). In patients with measurable disease, overall response rate was higher in the temozolomide arm than in the dacarbazine arm (14.5% versus 9.8%, respectively), but the median duration of response was longer for dacarbazine. The extended schedule, escalated dose temozolomide arm showed more toxicity than the standard dose, single agent dacarbazine arm. The most common non-haematological treatment emergent adverse events reported in both treatment arms were nausea, fatigue and vomiting and constipation. Conclusion: Extended schedule escalated dose Temozolomide (7 days on 7 days off) is feasible and has an acceptable safety profile, but does not improve OS and PFS in metastatic melanoma when compared to standard dose dacarbazine.

Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study) (Article)

2009-12-01T00:00:00Z

Aim: To evaluate the prognostic and predictive importance of detection of melanoma cells in peripheral blood using reverse transcriptase polymerase chain reaction (RT-PCR) in stage III cutaneous melanoma patients after sentinel or regional lymph node dissection. Patients and methods: Serial testing for tyrosinase and Mart-1/Melan-A transcripts in peripheral blood was performed every 6 months over a maximum period of 60 months in a subset of patients enrolled in EORTC 18991 phase 3 trial, comparing pegylated interferon-α-2b with observation. Univariate and multivariate analyses were performed to estimate the role of RT-PCR as prognostic and predictive factor for distant metastasis-free survival (DMFS). Results: Among 299 patients who underwent RT-PCR analyses, 109 (36.5%) had at least one positive sample, either at time of randomisation (N = 17) or subsequently (N = 92). The cumulative rate of positive results was similar in the two treatment groups, as the DMFS from first RT-PCR positivity. RT-PCR result, positive versus negative, at a given time point, had no prognostic impact on subsequent DMFS. Cox time-dependent analysis indicated a significantly higher risk of developing distant metastasis in patients with a positive sample as compared to those with a negative one: hazard ratio (HR) of 2.23 (95% confidence interval (CI), 1.40-3.55; p < .001). These results were comparable in the 2 treatment groups, indicating that RT-PCR assessment was not predictive for treatment outcome. Conclusion: Detection of circulating tumour cells by RT-PCR for tyrosinase and Mart-1/Melan-A was a time-dependent moderate prognostic factor for subsequent development of distant metastasis in stage III melanoma patients.

Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial (Article)

2008-07-14T00:00:00Z

Background: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. Methods: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 μg/kg per week for 8 weeks (induction) then 3 μg/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. Findings: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3·8-33·4) months. At 3·8 (3·2-4·2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0·82, 95% CI 0·71-0·96; p=0·01); the 4-year rate of recurrence-free survival was 45·6% (SE 2·2) in the interferon group and 38·9% (2·2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. Interpretation: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival. Funding: Schering Plough Research International.

A systematic review of economic analyses of pharmaceutical therapies for advanced colorectal cancer (Article)

2007-06-01T00:00:00Z

Colorectal cancer is one of the most common causes of cancer in the Western world. New drugs in the treatment of advanced colorectal cancer, such as irinotecan and oxaliplatin, have substantially increased the cost of treatment. A systematic literature review on the cost (-effectiveness) of pharmaceutical therapies for advanced colorectal cancer was conducted, in which 13 articles were included. The main topics were: orally versus intravenously administered fluoropyrimidine, raltitrexed, irinotecan and oxaliplatin. Additional information was collected on the cost (-effectiveness) of the monoclonal antibodies, cetuximab and bevacizumab. Only five articles had taken the societal perspective, in most articles no data on quality of life was presented, and only two reported the cost per quality-adjusted life year. As only a limited amount of information is available on the cost-effectiveness of pharmaceutical therapies for advanced colorectal cancer, there is a need for more cost-effectiveness studies. These studies are preferably performed by taking a societal perspective and including quality of life outcomes.