Wim W. ten Bokkel Huinink

Long-Term Risk of Cardiovascular Disease in 5-Year Survivors of Testicular Cancer

PURPOSE To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC). PATIENTS AND METHODS We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis. RESULTS After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. CONCLUSION Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel.

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol®) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m2, as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m2, at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

Coadministration of Cyclosporine Strongly Enhances the Oral Bioavailability of Docetaxel

PURPOSE Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2). RESULTS The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

Clinical pharmacokinetics of topotecan

SummaryTopotecan (Hycamtin®), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I in vitro and has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer. Now approved in the US, topotecan has completed single-agent phase I testing; phase II/III trials are ongoing.Under physiological conditions the lactone moiety of topotecan undergoes a rapid and reversible pH-dependent conversion to a carboxylated open-ring form, which lacks topoisomerase I inhibiting activity. At equilibrium at pH 7.4 the open-ring form predominates. Topotecan is stable in infusion fluids in the presence of tartaric acid (pH < 4.0), but is unstable in plasma, requiring immediate deproteinisation with cold methanol after blood sampling and storage of the extract at −30°C to preserve the lactone form.Topotecan has been administered in phase I trials in several infusion schedules ranging from 30 minutes to 21 days. The plasma decay of topotecan concentrations usually fits a 2-compartment model. Rapid hydrolysis of topotecan lactone results in plasma carboxylate levels exceeding lactone levels as early as 45 minutes after the start of a 30-minute infusion. The peak plasma concentrations and the area under the plasma concentration-versus-time curves (AUC) show linear relationship with increasing dosages. No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days.Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t½β) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability.The oral bioavailability of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed.Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition.Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.

Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer

Introduction. There is growing concern that some cytotoxic regimens for cancer affect cognitive functioning. This study examined the prevalence of cognitive complaints and deficits in testicular cancer (TC) patients treated with the worldwide standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. Materials and methods. Seventy TC patients treated with BEP chemotherapy after surgery (S+CT) were examined with interviews and neuropsychological tests. These patients were compared with 57 TC patients treated with radiotherapy after surgery (S+RT) and with 55 TC patients that received surgery only (S). Patients were examined a median of 3 years after completion of treatment. Results. Thirty two percent of the S+CT patients reported cognitive complaints compared with 32% of the S+RT patients and 27% of the S patients (p=0.85). No differences in mean cognitive test performance were observed between the groups. On individual impairment scores, more S+CT patients showed cognitive dysfunction compared with S patients, but not compared with S+RT patients (S+CT versus S [p=0.038, OR=4.6, CI=1.1–19.7], S+CT versus S+RT [p=0.70, OR=0.8, CI=0.3–2.4] and S+RT versus S [p=0.070, OR=3.7, CI=0.8–15.7). Cognitive complaints were not related to cognitive test performance, but to emotional distress and fatigue. Discussion. Cognitive complaints are common among TC patients, independent of treatment modality. These complaints are related to emotional distress and fatigue and not to formal cognitive deficits. The finding of a small group of TC patients treated with chemotherapy exhibiting cognitive deficits should be confirmed in a prospective study before we can decide on its cause and relevance.

Phase I and Pharmacokinetic Study of Oral Paclitaxel

PURPOSE To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). PATIENTS AND METHODS A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m(2) as a 3-hour infusion. RESULTS The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m(2). Dose escalation of oral paclitaxel from 60 to 300 mg/m(2) resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values +/- SD after 60, 180, and 300 mg/m(2) of oral paclitaxel were 1.65 +/- 0.93, 3.33 +/- 2.39, and 3.46 +/- 1.37 micromol/L.h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 +/- 3.26 micromol/L.h. CONCLUSION The MTD of oral paclitaxel was 300 mg/m(2). However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m(2), the oral paclitaxel dose of 180 mg/m(2) in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.

Phase I and Pharmacokinetic Study of Irinotecan Administered as a Low-Dose, Continuous Intravenous Infusion Over 14 Days in Patients With Malignant Solid Tumors

PURPOSE To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m(2)/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m(2)/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m(2)/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% +/- 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION The recommended dosage is 10 mg/m(2)/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

Cisplatin induced neuropathy : central, peripheral and autonomic nerve involvement

SummaryA prospective study was performed in patients treated with cisplatin to evaluate the occurrence and degree of central, peripheral and autonomic neuropathy and to determine the most accurate method to study this neuropathy. Twelve patients were examined before, during and after treatment. Evaluation included neurologic examination, conventional nerve conduction studies of the median and peroneal nerves and short latency somatosensory evoked potentials (SSER) after median and tibial nerve stimulation. Valsalva maneuvers before and during treatment were performed in 11 patients. Symptoms of peripheral neuropathy paralleled clinical signs. Conventional nerve conduction studies did not seem to be more accurate than clinical examination in determining peripheral neuropathy. SSER appeared to be the most sensitive method for the detection of peripheral nerve impairment. A slowing of central conduction velocity occurred after cumulative doses of 200–400 mg/m2 as measured by SSER. In two patients also some involvement of the autonomic nerves was suggested.

Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. An individual dosing strategy has been recommended to yield the most optimal exposure, expressed as the area under the concentration-time curve (AUC). The formula developed by Calvert et al. (dose = target-AUC × [GFR+25]) can be used to achieve this. However, due to the inconvenient [51Cr]-ethylenediaminetetraacetic acid ([51Cr]-EDTA)-based measurement of the glomerular filtration rate (GFR), its application in the clinic has thus far been limited. Chatelut and coworkers have recently proposed a formula to estimate carboplatin clearance using the serum creatinine concentration. We retrospectively tested the Chatelut equation and the Calvert formula using either the creatinine clearance based on 24-h urine collection or the creatinine clearance based on the formula of Cockcroft and Gault. The latter equations were shown to predict the carboplatin clearance reasonably well, although systematic overprediction and underprediction occurred. However, the formula proposed by Chatelut and co-workers had no significant bias and was precise. It is proposed that this formula be used to calculate the optimal carboplatin dosage after prospective validation has been performed.

Safety and Efficacy of Patupilone in Patients With Advanced Ovarian, Primary Fallopian, or Primary Peritoneal Cancer: A Phase I, Open-Label, Dose-Escalation Study

PURPOSE To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with resistant or refractory ovarian, fallopian, or peritoneal cancer. PATIENTS AND METHODS Patients received patupilone (6.5 to 11.0 mg/m(2)) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m(2)/week; N = 53; OR, 5.7%). CONCLUSION Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m(2). Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m(2) dose.