Short summary

In a prospective pharmacokinetic study, we wish to investigate whether pharmacokinetics of paclitaxel (Ptx) differs between older and younger  women with ovarian or endometrial cancer receiving first line treatment with carboplatin and Ptx, and to investigate whether pharmacokinetics changes in subsequent treatment cycles. Further, we wish to examine neurons derived from pluripotent stem cells from patients with and without neurotoxicity to Ptx using state of the art methods.

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Rationale

Cancer incidence increases with age. It is a general problem, that older cancer patients are underrepresented in clinical studies. Thus in the studies, which established carboplatin and Ptx as the treatment of choice in epithelial ovarian cancer (EOC), the average age of the patients was approximately 56 years, whereas in Denmark, average age at diagnosis is approximately 65 years.

Very few ovarian cancer patients will be cured by surgery alone. Despite primary extensive and often macroscopically radical surgery, relapses are common. Neo-adjuvant and/or post-surgery chemotherapy is indicated in all patients except FIGO stage 1A/1B low grade  disease, and recommended treatment is combination chemotherapy with paclitaxel 175 mg/m² and carboplatin area under the concentration-time curve 5 mg·min·ml^-1 (AUC5) (TC) in three-week intervals. Addition of bevacizumab is recommended if surgery is not macroscopically radical and in all stage IV patients. TC also remains first choice of treatment in advanced, non-operable disease. TC is also the chemotherapy regimen of first choice in recurrent platinum-sensitive ovarian cancer and in endometrial cancer stage III-IV disease.

Ptx is a taxane registered for use in various malignant diseases, including ovarian cancer. Ptx provokes many types of adverse reactions in patients. Bone marrow toxicity and peripheral neuropathy are common and potentially serious adverse reactions to treatment with Ptx. Severe bone marrow toxicity is seen in approximately 10% of the patients, whereas grade 2-3 neuropathy has been reported in up to 50% of all patients. Symptoms are reversible in some, but not all patients. Clinical signs of chemotherapy induced peripheral neuropathy (CIPN) include sensory loss, paresthesia, dysesthesia, numbness and tingling and this often leads to neuropathic pain. CIPN can be severely debilitating, but even mild to moderate symptoms can significantly impair quality of life, and commonly persist for up to 2 years after treatment cessation.

The elimination of Ptx is highly dependent on hepatic function. Biotransformation is CYP mediated, primarily via CYP3A4 and CYP2C8. The most frequent and dose-limiting toxicity of Ptx is bone marrow depression with resulting neutropenia. Previous studies have shown that the time, in which the plasma concentration of Ptx is more than 0.05 µmol/L  (Tc > 0.05), is an important predictor of both neutropenia (18-20) and CIPN. However, concentration is also associated with treatment efficacy. The infusion time of Ptx is also associated with side effects such as bone marrow toxicity and CIPN. There are limited and conflicting data on age-related changes in the clearance and the area under the concentration-time curve (AUC) of Ptx. An association has been found between lower clearance (increased AUC) and neutrophil count. Clinical parameters such as comorbidity and co-medication might also influence Ptx clearance. It is clear that there is a significant inter- and intra-patient variability in Ptx PK, which in turn impacts on the risk of side effects. Genetic variability might account for a substantial part of this.

Recently, a large number of studies examined genetic variation of Ptx-induced peripheral neuropathy. Many such studies test genetic variants in genes responsible for neuronal function. While these studies provide important insight to this side effect, validation studies often fail to confirm results. Thus, efficient cellular models to examine the mechanistic basis of this side effect seem in high demand. Induced pluripotent stem cells are a type of stem cells that can be generated directly from adult cells. The advantage of these types of cells is that they can be used to generate patient-specific cells (neurons, cardiomyocytes and many others) that can be studied in vitro. In effect, this means that it is possible to develop and investigate patient-specific neurons. This technique allows for much more advanced and specific studies of Ptx induced neurotoxicity.

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Description of the cohort

This study will be a prospective pharmacokinetic and pharmacogenetic study in patients eligible for treatment with carboplatin AUC5 mg·min·ml^-1 and Ptx 175 mg/m² before or after surgery for epithelial ovarian, fallopian tube, peritoneal, or in advanced operable or non-operable endometrial cancer. Patients will receive the standard regimen of the above mentioned chemotherapy, i.e. 3-h intravenous infusion of Ptx followed by carboplatin, both administered every third week. Based on power calculations, 12 women aged 60 years or younger and 12 women aged 70 years or older will be included according to the following criteria.

Inclusion criteria:

• Histologically verified ovarian, Fallopian tube, peritoneal, or endometrial cancer
• Candidate for standard treatment with carboplatin and Ptx given every 3 weeks, either in a neo-adjuvant, adjuvant, or palliative setting.
• Age: 18 years or older and 60 years or younger or age 70 years or older
• Capable of giving informed consent

Exclusion criteria:

• Previous cancer diagnosis within the past 5 years
• non-melanoma skin cancer and carcinoma in situ of the cervix allowed
• Previous taxane and platinum treatment
• Planned concurrent other antineoplastic treatment
• Bevacizumab allowed in patients with EOC who have not had macroscopically radical surgery, according to standard treatment.
• Known hepatic disease (cirrhosis, hepatitis)
• Uncomplicated previous hepatitis A allowed.
• Known peripheral neuropathy
• Diabetes mellitus

Data and biological material

Patient and disease specific data will be obtained from the medical charts.

Blood will be drawn at baseline and after each treatment (hematology, creatinine, electrolytes, albumin, liver enzymes, and CA-125). After treatment cycle one and four with drawing of Ptx PK samples, plasma orosomucoid will also be measured. Whole blood will be drawn at baseline and DNA analyses made from the buffy coat. After the first course of TC, blood plasma will be sampled at 3h (just before end of Ptx infusion), at 5, 7, 9, and 24 h after start of Ptx infusion. After the fourth course of chemotherapy, this procedure will be repeated to investigate intra-individual changes in PK of Ptx. In order to determine individual genotypes in genes suspected of playing a role for development of neuropathy (e.g. EPHA family, XKR4, PIK1P1 and SGCC) and for distribution and elimination of Ptx (e.g. CYP2C8, CYP3A4, ABCB1 and related genes), patient DNA will be analyzed. 

Skin biopsies will be obtained at baseline from all patients who consent to this part of the study.

Collaborating researchers and departments

Department of Oncology, Odense University Hospital

• Postdoc Trine Lembrecht Jørgensen, MD, PhD
• Professor Jørn Herrstedt, DMSc

Clinical Pharmacology, University of Southern Denmark

• Cand.Scient Flemming Nielsen, PhD
• Postdoct Tore Bjerregaard Stage, MSc
• Professor Kim Brøsen, DMSc

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital and University of Southern Denmark

• Clinical Associate Professor Troels Korshøj Bergmann, MD