Population Pharmacokinetics of Cabozantinib in Metastatic Renal Cell Carcinoma Patients: Towards Drug Expenses Saving Regimens.

INTRODUCTION: Cabozantinib is one of the preferred treatment options in the latest metastatic renal cell carcinoma (mRCC) guidelines. Cabozantinib is also associated with high drug expenses irrespective of the used dose, because a flat-prizing model has been implemented. In addition, concomitant intake with a high-fat meal increases its bioavailability on average by 57%. Combined with the long terminal half-life of cabozantinib (99 h), this creates possibilities to extend the dosing interval to reduce drug expenses whilst maintaining equivalent exposure. OBJECTIVES: The primary objective was to evaluate the population pharmacokinetic (POPPK) model of cabozantinib developed for its registration using real-world patients' therapeutic drug monitoring (TDM) data. The secondary objective was to design, simulate, and evaluate alternative dose regimens with the aim to reduce drug expenses whilst maintaining comparable exposure. METHODS: Retrospective TDM data from mRCC patients treated with cabozantinib were obtained. The data were evaluated using the published Food and Drug Administration (FDA) cabozantinib POPPK model, a two-compartment disposition model with a dual (fast and slow) lagged first-order absorption process derived from FDA registration documents, as a basis. Subsequently, simulations of alternative drug expenses saving regimens were evaluated. RESULTS: Twenty-seven mRCC patients with 75 pharmacokinetic observations were included. Patients were treated for a median of 75 days with a median dose of 40 mg. Model evaluation results showed that the cabozantinib TDM concentrations were adequately predicted by the published FDA cabozantinib POPPK model, except for a slightly higher clearance (CL) of 3.11 L/h compared to the reported value (2.23 L/h). The simulation study indicated that an alternative dose regimen that consists of taking 60 mg of cabozantinib for 2 days and then skipping 1 day results in comparable average exposure when compared with a 40 mg daily dose, both without food interaction, while saving 33.3% of the total drug expenses per month. The food effect of a high-fat meal was also taken into account when simulating other alternative dose regimens; 40 mg every 72 h combined with a high-fat meal resulted in comparable exposure when compared with a 20 mg daily dose fasted, while saving 66.7% in drug expenses. CONCLUSIONS: In this study, the optimized cabozantinib POPPK model resulted in adequate prediction of real-world cabozantinib pharmacokinetic data. Alternative dosing regimens with and without using known food interactions were proposed that resulted in potential strategies to significantly reduce cabozantinib drug expenses.

[Influenza vaccination of patients with solid tumours during chemotherapy: efficacy and safety]. / Griepvaccinatie tijdens chemotherapie bij patiënten met solide tumoren.

- Adult patients with solid tumours receiving chemotherapy have reduced immunity against infections and are at increased risk of influenza infection and its complications. However, many of said patients are not vaccinated for influenza.- Limited observational research in this patient group has given some indication of the protective effects of the influenza vaccine on clinical outcome measures.- Serological studies have shown that the antibody response following influenza vaccination is often less pronounced in patients with solid tumours compared to healthy individuals. Nonetheless, in most cases a timely protective antibody response can be achieved.- The inactivated influenza vaccine is safe in immunosuppressed patients, irrespective of the moment at which it is administered. Side-effects are similar, both in nature and number, to those seen in healthy individuals.- Influenza vaccination can be offered to all adult patients with solid tumours, preferably before chemotherapy is commenced. Vaccination during chemotherapy, however, usually also generates sufficient vaccination response and can reduce the risk of influenza-related complications. Therefore, chemotherapy should not preclude patients from being administered the influenza vaccine.

Clinical validation study of genetic markers for capecitabine efficacy in metastatic colorectal cancer patients.

BACKGROUND AND AIM: Pharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine. PATIENTS AND METHODS: Germline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival. RESULTS: In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup. CONCLUSION: With the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy.

[A woman with paraneoplastic dermatoses; signs of recurrent malignancy]. / Een vrouw met paraneoplastische huidafwijkingen; voorbode van een recidief van een maligniteit.

BACKGROUND: Paraneoplastic dermatoses may be the first manifestation of a malignancy. Rapid recognition is therefore important. CASE DESCRIPTION: A 72-year-old woman who had been treated in the past for metastasised neuroendocrine carcinoma and had undergone curative treatment for stage-1c endometrial carcinoma developed three paraneoplastic dermatoses over a 2-year period: acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa. Half a year later, cutaneous metastases derived from the endometrial carcinoma treated 12 years prior were discovered. CONCLUSION: The development of three paraneoplastic dermatoses in a short period of time is rare. Acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa can develop in association with both neuroendocrine and endometrial carcinoma. The sudden development of paraneoplastic dermatoses is frequently a forewarning of progression of the malignancy.

Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer.

BACKGROUND: To evaluate the efficacy and tolerability of preoperative short-course radiotherapy followed by capecitabine and oxaliplatin treatment in combination with bevacizumab and subsequent radical surgical treatment of all tumor sites in patients with stage IV rectal cancer. PATIENTS AND METHODS: Adults with primary metastasized rectal cancer were enrolled. They received radiotherapy (5 × 5 Gy) followed by bevacizumab (7.5 mg/kg, day 1) and oxaliplatin (130 mg/m(2), day 1) intravenously and capecitabine (1000 mg/m(2) twice daily orally, days 1-14) for up to six cycles. Surgery was carried out 6-8 weeks after the last bevacizumab dose. The percentage of radical surgical treatment, 2-year survival and recurrence rates, and treatment-related toxicity was evaluated. RESULTS: Of 50 included patients, 42 (84%) had liver metastases, 5 (10%) lung metastases, and 3 (6%) both liver and lung metastases. Radical surgical treatment was possible in 36 (72%) patients. The 2-year overall survival rate was 80% [95% confidence interval (CI) 66.3%-90.0%]. The 2-year recurrence rate was 64% (95% CI 49.8%-84.5%). Toxic effects were tolerable. No treatment-related deaths occurred. CONCLUSIONS: Radical surgical treatment of all tumor sites carried out after short-course radiotherapy, and bevacizumab-capecitabine-oxaliplatin combination therapy is a feasible and potentially curative approach in primary metastasized rectal cancer.

[A man with blisters on hand and feet]. / Een man met blaren op handen en voeten.

A 41-year-old man with metastases of a gastrointestinal stroma tumour was treated with an angiogenesis inhibitor. He presented with a distinct painful erythematous hyperkeratotic bullous hand-foot skin reaction. This was thought to be caused by the oral angiogenesis inhibitor and resolved after discontinuation of the therapy. This is a known adverse effect of angiogenesis inhibitors and is dose dependent.

A study of the importance of fine needle aspiration cytology in the diagnosis of the solitary thyroid nodule.

The results of 287 fine needle aspirations (FNAs) of the thyroid, performed between 1 January 1982 and 31 December 1986, were retrospectively analysed with respect to clinical history, physical examination, scintigraphy and echoscopy, and compared with the results of the histological examination of thyroid tissue removed from the 65 patients who were operated. Except for the follicular tumour group, FNA examination proved to be the best method for differentiating benign and malignant lesions. The specificity was found to be 48%, the sensitivity 86%. The only value of scintigraphy and echoscopy appears to be in their supporting role. Based on these results a new strategy for the evaluation of thyroid nodules is proposed, in which the FNA examination has a more important place in the diagnosis than before.