| 1. |
- Browall, Maria, et al.
(författare)
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A prospective exploration of symptom burden clusters in women with breast cancer during chemotherapy treatment
- 2017
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Ingår i: Supportive Care in Cancer. - : Springer. - 0941-4355 .- 1433-7339. ; 25:5, s. 1423-1429
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThe aim was to prospectively map symptom clusters in patients with stage I–IIIa breast cancer during standard chemotherapy treatment in a randomised study.MethodsParticipants completed the Memorial Symptom Assessment Scale (MSAS) at baseline, day 12 after the first and third cycle of FEC 75 or FEC 100, and day 12 after the last cycle of Taxotere. Cut-off values for symptom scores, a mean value based on each individual reporting a symptom including occurrence, frequency, severity and distress for inclusion in analysis, were determined.ResultsThe symptom burden cluster analysis was conducted in two steps and included symptoms with high frequency and high levels of distress. The factor analysis revealed three symptom clusters; physical, gastro (phys/gastro) and emotional, with core symptoms that remained stable over time. The most prevalent symptoms for the total sample during all cycles were as follows: lack of energy (range between 48 and 90%), feeling sad (48–79%), difficulty sleeping (54–78%), difficulty concentrating (53–74%), worrying (54–74%) and pain (29–67%).ConclusionIn summary, we have prospectively established that symptom clusters remain stable over time with a basis of core symptoms. This knowledge will aid in the development of effective core symptom-focused interventions to minimise symptom burden for patients treated with chemotherapy for breast cancer.
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| 2. |
- Kornalijnslijper-Altena, Renske, et al.
(författare)
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PREDIX II HER2 : Improving pre-operative systemic therapy for human epidermal growth factor receptor 2 (HER2) amplified breast cancer (BC)
- 2020
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:15 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy.Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007.
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| 3. |
- von Stedingk, Hans, et al.
(författare)
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Validation of a novel procedure for quantification of the formation of phosphoramide mustard by individuals treated with cyclophosphamide
- 2014
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 74:3, s. 549-558
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Tidskriftsartikel (refereegranskat)abstract
- Use of the patient's body surface area (mg m(-2)) as a basis for dosing does not take individual variation in metabolic capacity and rate of clearance into account. Here, we evaluated a novel approach for individual monitoring of short-lived cytotoxic agents formed from cytostatic drugs such as cyclophosphamide (CP). The accumulated blood dose of the cytotoxic active agent phosphoramide mustard (PAM) formed from CP was measured as a reaction product with hemoglobin (Hb adduct). This adduct, N-[2-(2-oxazolidonyl)ethyl]-valyl Hb (OzVal-Hb), was detached from Hb with the adduct FIRE procedure (TM), and the formed analyte was quantified using LC-MS/MS. This dose biomarker for PAM and the analytical procedure was evaluated in accordance with the guidelines on bioanalytical method validation formulated by the European Medicine Agency. The evaluated method was applied to quantify blood dose levels of PAM in female breast cancer patients (n = 12) before and after three cycles of polychemotherapy regimes containing CP. OzVal-Hb, a specific and stable biomarker, could be measured with great sensitivity (lower limit of quantification = 33 pmol g(-1) Hb), high accuracy (within +/- 20 %) and good repeatability (CV < 20 %). The inter-individual variability in the blood level of this adduct in women with breast cancer (n = 12) who received three doses of CP in combination with one or two other cytostatic drugs was 250 % following the first dose and approximately 150 % after each subsequent dose. Measurement of the biomarker OzVal-Hb can be used to quantify the short-lived cytotoxic agent PAM in a single blood sample drawn several days after therapy. This procedure may aid in individualizing doses of CP, thereby improving efficacy while both reducing the risk of and increasing the predictability of side-effects.
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| 4. |
- Xie, Hanjing
(författare)
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Pharmacogenetic and pharmacokinetic studies of cyclophosphamide : in cell, animal and human
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cyclophosphamide (CPA) is widely used anti-cancer drug that has to be catalyzed by the cytochrome P450 (CYP) enzyme 2B6 as well as some other CYPs to exert its cytotoxic activity. A high degree of interindividual variation in CPA kinetics has been reported in both children and adult patients, which may be due to several factors such as concomitantly used drugs, variation in physiological status of individual patients and genetic polymorphism of the CYP enzymes. The general aim of the present thesis was to study the pharmacogenetic and pharmacokinetic aspects of the mutual interactions between CPA and CYPs, the role of polymorphic CYP enzymes on CPA bioactivation and the effect of CPA on CYP expression in order to better understand the mechanisms underlying the variation in CPA kinetics. In the HL-60 cell line and its multi-drug resistant (MDR) phenotype HL-60R that was exposed to CPA, no measurable CYPs were induced by CPA exposure. this indicates that the CYP inducibility in cells is poor. CYP1B1, which is predominantly expressed in these cells, was suppressed after CPA treatment in a con centration-dependent manner. The beta-actin gene was suppressed when cells were exposed to CPA suggesting a possible mechanism that contributes to CPA cytotoxicity. The HL60R was shown to be sensitive to CPA treatment, demonstrating that the MDR phenotype is not involved in the mechanism of resistance to CPA. Ciprofloxacin administration prior to cyclophosphamide in the rat resulted in a significant decrease in the metabolic rate of CPA as expressed as the ratio AUC 4-Hydroxy-cyclophosphamide/ AUC CPA (AUC4OH-CPA/AUC CPA). Moreover, a significant suppression of the gene expression of CYP2C11 and CYP3A1 was observed. These results may have a great clinical relevance when choosing antibiotic treatment to patients receiving CPA. In rats treated with cyclophosphamide, the mRNAs specific for rat CYP2B1, 2B2, 3A2, 2C11, and proteins of CYP2B 1/2 and CYP3A were significantly induced after the administration of single intravenous dose of CPA. The microsomal activities of CYP2B, CYP3A and 2C11 were significantly increased accordingly. These results demonstrated that CPA has a marked inducing effect on CYP2B1, 2B2. 2C11, and 3A2. In particular, CPA showed a dramatic regulatory effect on CYP2B1 mRNA. We have evaluated the role of the polymorphic human CYP2B6 in CPA bioactivation using sixty-seven human liver specimens that were genotyped with respect to the CYP2B6*5 and CYP2B6*6 allelic variation. We found that carriers of the *6 allele tended to have relatively lower protein expression compared to non-*6 carriers, and significant higher CPA 4-hydroxylation capacity (p<0.05). A significant correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation was observed (p<0.0001). CPA 4-hydroxylation significantly correlated with CYP2B6 specific reactions (p<0.0001). The results demonstrate that the polymorphic CYP2B6 is an important enzyme in the bioactivation of CPA and that the CYP2B6 *6 allele has a strong impact on CPA 4-hydroxylation. The pharmacokinetics of CPA and its active 4-OH-CPA metabolite were determined in patients with hematological malignancies and related to the genotype of the CYP2B6, CYP2C9 and CYP2C19 genes. The interindividual variability in exposure to cycklophosphamide as expressed as the ratio of 4-OHCPA/CPA was 5.8-, 3.3- and 10.3- fold, respectively. In the population pharmacokinetic analysis the clearance contribution of the CYP2B6 G516T variant allele was about twice compared to the wild type gene while the genotype of CYP2C9 and CYP2C19 did not influence CPA clearance. A negative correlation was observed between bilirubin level and CPA bioactivation, showing the importance of the liver function for the metabolism of CPA.
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