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- Hagman, Helga
(författare)
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A targeted approach to maintenance of tumour response. Clinical and translational studies in metastatic colorectal cancer.
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In metastatic colorectal cancer (mCRC) chemotherapy +/- targeted therapy with palliative intent aims at prolonging survival with sustained quality of life. Maintenance of tumour response by a period of less intense treatment maydelay progression and accumulation of unacceptable toxicity. We studied the combination of targeted treatment with the angiogenesis inhibiting antibody bevacizumab (bev) and the epidermal growth factor tyrosine kinase inhibitorerlotinib (erlo) as maintenance treatment in two clinical trials.The Nordic ACT trial (paper I) included 249 mCRC patients. Following first line induction doublet chemotherapy plus bev, responding patients were randomised to maintenance treatment with bev or bev+erlo. We found no significant difference in survival outcomes between the arms. We then hypothesized that KRAS mutation of the tumour would have a negative impact on the erlo effect.In the Nordic ACT2 trial (paper II, N=233), the KRAS wildtype (wt) patients were randomised in the same manner as in Nordic ACT. The KRAS mutated (mut) patients recieved bev alone or metronomic low dose capecitabine and arms were compared without significant difference in effect or safety. The KRASwt patient cohorts from the both Nordic ACT trials were pooled in an analysis of survival outcomes (N=126) with no statistically significant gain from the addition of erlo to bev as maintenance.There are no validated biomarkers of anti-angiogenic therapy. Treatment induced hypertension has been associated with better response to angiogenesis inhibition. The vasoactive peptides (VPs) atrial natriuretic peptide, adrenomedullin, and copeptin are linked to regulation of blood pressure and angiogenesis. In paper III, the stablepro-peptides of each VP were analysed in plasma from ACT2 study patients with documented progressive disease (N=97). IncreasingVP levels during the first six weeks of induction chemotherapy + bev were significantly associated with better clinical outcome. In paper IV, we collected serum samples at start of induction, start of maintenance and at progression from ACT2 patients (N=22). Analyses of 55 circulating, angiogenesis-related proteins were performed at each time point byantibody array membrane technology. Levels of some, mostly pro-angiogenic, proteins decreased significantly during response and/or increased at progression.In summary, these studies demonstrate that mCRC patients may not benefit from bev+erlo as maintenance therapy in terms of efficacy, and that the clinical benefit can be further questioned due to tocixity concerns. KRAS status is not likely a predictive biomarker for erlo in mCRC. Microarray methodology for simultaneous detection of multiple proteins in serum is convenient for exploration of signalling patterns related to the response and resistance to angiogenesis inhibition. Our translational results support the evidence of an interaction between host-related vascular effects and response to chemotherapy plus bev. Both VPs and other counterbalancing pro-angiogenic factors are promising biomarkers that warrant further studies in this setting.
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| 2. |
- Hagman, Helga, et al.
(författare)
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Protein array profiling of circulating angiogenesis-related factors during bevacizumab containing treatment in metastatic colorectal cancer
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Background Prolonged angiogenesis inhibition may improve treatment outcome in metastatic colorectal cancer (mCRC) patients. However, due to the complexity of the angiogenic pathways there is a lack of valid predictive biomarkers for anti-angiogenic agents. Here, we describe and optimize a procedure for simultaneous dynamic profiling of multiple angiogenesis related proteins in patient serum to explore associations with the response and acquired resistance to anti-angiogenic therapy. Materials and methods Patients (n=22) were selected from a clinical trial investigating maintenance treatment with bevacizumab alone after response to induction chemotherapy + bevacizumab in mCRC. Serum samples were analysed for 55 unique angiogenesis related proteins using a commercial proteome profiler array and a publicly available image analysis program for quantification. Samples were collected at baseline before induction treatment start, at start of maintenance treatment, and at end of treatment after tumour progression. Main results and conclusion For eight proteins, the antibody array signals were below detection range in all patient samples. None of the proteins showed levels at baseline or at start of maintenance with strong evidence for correlation to time to progression (lowest nominal p-value 0.03). The dynamic ranges of protein levels measured during the induction treatment period and during the maintenance period were analysed separately for time trends. Evidence for changing trends (up/down) in the levels of MMP-8, TIMP-4 and EGF was observed both during response to induction treatment and at progressive disease, respectively. For three of the proteins (IL-8, Activin A and IGFBP-2), weak evidence for correlation between increasing protein levels during induction with chemotherapy and bevacizumab and time to progression was observed. In conclusion, semi-quantitative profiling of angiogenesis related proteins in patient serum may be a versatile tool to screen for protein patterns aiming at identifying resistance mechanisms of anti-angiogenic treatment in patients with mCRC.
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| 4. |
- Kinos, Sampsa, et al.
(författare)
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Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study)
- 2024
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Ingår i: Acta Oncologica. - : Medical Journals Sweden. - 0284-186X .- 1651-226X. ; 63, s. 248-258
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study.Materials and methods: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients.Results: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs.Interpretation: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.
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| 5. |
- Taxbro, Knut, et al.
(författare)
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Clinical impact of peripherally inserted central catheters vs implanted port catheters in patients with cancer : an open-label, randomised, two-centre trial
- 2019
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Ingår i: British Journal of Anaesthesia. - : Elsevier. - 0007-0912 .- 1471-6771. ; 122:6, s. 734-741
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCentrally inserted totally implanted vascular access ports (PORTs) and peripherally inserted central catheters (PICCs) are widely used for the administration of chemotherapy. Our aim was to study the incidence of catheter-related deep venous thrombosis in patients with cancer receiving chemotherapy through either a PICC or a PORT.MethodsAdults with non-haematological cancer (mainly breast and colorectal) from two Swedish oncology centres were included and followed for up to 1 yr. Patients were randomly assigned to receive a single-lumen PICC or PORT. The primary end point was the occurrence of a clinically significant catheter-related deep venous thrombosis, and the secondary end point was a composite of adverse events related to the catheter: insertion complication, thrombosis, occlusion, infection, and mechanical problems.ResultsThe trial recruited 399 participants (PICC, n=201; PORT, n=198) between March 2013 and February 2017. The PICCs were associated with 16 (8%) deep venous thromboses compared with two (1%) in the PORT group (HR=10.2; 95% confidence interval, 2.3–44.6; P=0.002). The overall incidence of composite adverse events was higher for patients with a PICC compared with those with a PORT (HR=2.7; 95% confidence interval, 1.6–4.6; P<0.001).ConclusionsPICCs are associated with higher risk for catheter-related deep venous thrombosis and other adverse events when compared with PORTs. This increased risk should be considered when choosing a vascular access device for chemotherapy, especially in patients with solid malignancy.
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| 6. |
- Taxbro, Knut, 1973-, et al.
(författare)
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Cost analysis comparison between peripherally inserted central catheters and implanted chest ports in patients with cancer-A health economic evaluation of the PICCPORT trial
- 2020
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Ingår i: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 64:3, s. 385-393
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Tidskriftsartikel (refereegranskat)abstract
- Background A reliable central venous access device is a cornerstone in the treatment of cancer. Both peripherally inserted central catheters (PICC) and totally implanted chest ports (PORT) are commonly used for the delivery of chemotherapy. Both types of catheter can cause adverse events such as catheter-related deep venous thrombosis (CR-DVT), infection and mechanical complications. Method We conducted a randomized controlled trial including 399 patients with cancer and performed a health economic evaluation investigating the cost related to PICCs and PORTs using several clinically relevant dimensions from a healthcare perspective. The cost was determined using process and cost estimate models. Result PICCs are associated with a higher total cost when compared with PORTs. Combining the costs of all categories, the prize per inserted device was 824.58 EUR for PICC and 662.34 EUR for PORT. When adjusting for total catheter dwell time the price was 6.58 EUR/day for PICC and 3.01 EUR/day for PORT. The difference in CR-DVT was the main contributor to the difference in cost. The daily cost of PICC is approximately twice to that of PORT. Conclusion We have demonstrated that the cost from a healthcare perspective is higher in cancer patients receiving a PICC than to those with a PORT. The difference is driven mainly by the cost related to the management of adverse events. Our findings are relevant to anaesthetists, oncologists and vascular access clinicians and should be considered when choosing vascular access device prior to chemotherapy.
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