C.H.N. Veenhof

Taxanes: A New Class of Antitumor Agents

Taxanes belong to a new group of antineoplastic agents with a novel mechanism of action for a cytotoxic drug. They promote microtubule assembly and stabilize the microtubules. Paclitaxel, the first agent in this group to become available, was isolated from the Pacific yew, Taxus brevifolia, in 1971. In preclinical and clinical studies, paclitaxel and its semisynthetic analog docetaxel exhibit significant antitumor activity. This review deals with the physicochemical properties, pharmacology, and results of preclinical and clinical trials of the taxanes.

Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.

PURPOSE To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.

Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer.

PURPOSE To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients. PATIENTS AND METHODS Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study. RESULTS The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models. CONCLUSION The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.

Carboplatin in combination therapy for ovarian cancer

Cisplatin today is a cornerstone of combination chemotherapy for ovarian cancer. Carboplatin seems equal to cisplatin in antitumour activity, but has a different toxicity profile. After a feasibility study, a randomized phase III study in ovarian cancer stage II, III, and IV was undertaken, comparing carboplatin with cisplatin in combination with cyclophosphamide, doxorubicin and hexamethylmelamine. Preliminary analysis of this study reveals no statistically significant difference in response rate. Notwithstanding equal haematological toxicity, the other side effects evoked by carboplatin in combination treatment are much milder than those evoked by cisplatin. Further analysis will be necessary to draw definite conclusions about the results obtained.

PHASE-II STUDY OF HIGH-DOSE MEGESTROL-ACETATE IN PATIENTS WITH ADVANCED OVARIAN-CARCINOMA

The EORTC Gynaecological Cancer Cooperative Group conducted a phase II study of high dose oral megestrol acetate: 800 mg/day for 1 month followed by 400 mg/day as maintenance treatment, in heavily pretreated patients with ovarian cancer. Of 72 patients included in this study, 54 were fully evaluable for response and toxicity. The response rate was low with only 1 patient having a partial response, 9 patients with stable disease and 44 patients with progressive disease. The toxicity profile was low. However, 1 patient died after 2 months of treatment, and in 3 patients thrombo-embolic events occurred. Weight gain varied in 20 of the 61 patients from 0.5 to 16 kg. This study does not suggest that the overall 10% benefit from hormonal therapy for chemotherapy refractory ovarian cancer will improve by increasing the dose.

Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study.

The aim of this study was to investigate the tumour response rate and toxicity of a combination chemotherapy consisting of mitomycin-C and cisplatin in patients with disseminated squamous-cell carcinoma of the uterine cervix. Chemotherapy consisted of mitomycin, 6 mg/m(2) intravenously (i.v.), and cisplatin, 50 mg/m(2) given i.v., both administered on day 1 of each cycle. The regimen was repeated at 4-weekly intervals. Mitomycin-C/cisplatin were used to treat 33 evaluable patients aged 29-67 years (median: 50 years). All patients except 1 had previously been treated with either surgery, radiation or both. At the initiation of chemotherapy, 8 patients had loco-regional and disseminated disease and 25 women had only distant metastases. The overall response rate was 42% (95% confidence interval (CI): 26-61%). Five complete and nine partial responses were observed with a median duration of response of 7.9 months (95% CI: 3.7-23.5 months). 9 patients had stable disease and 10 developed progressive disease during mitomycin-C/cisplatin-treatment. World Health Organization (WHO) grade III/IV side-effects were documented in 15 women, of whom 10 had gastro-intestinal toxicity, 3 had haematological toxicity, 1 had alopecia and 1 developed an allergic reaction to cisplatin. There were neither drug-related deaths nor severe or irreversible renal or hepatic dysfunction or peripheral neuropathy. The median progression-free survival was 5.0 months (95% CI: 3.6-6.2 months) for all patients and 10.5 months (95% CI: 6.2-15.2 months) for the responders. The median overall survival was 11.2 months (95% CI: 6.5-18.4 months).The mitomycin-C/cisplatin combination showed antitumour activity in the treatment of advanced or recurrent squamous-cell carcinoma of the uterine cervix. The regimen was well tolerated and could be administered on an outpatient basis.

Carboplatin Dosage Formulae Can Generate Inaccurate Predictions of Carboplatin Exposure in Carboplatin/Paclitaxel Combination Regimens

SummaryCarboplatin is a frequently used antitumour agent recommended to be administered according to the Calvert formula: dose = AUC × (GFR+25), where GFR is the glomerular filtration rate as measured by 51Cr-EDTA clearance and AUC is the targeted area under the carboplatin concentration versus time curve. In several modified Calvert formulae, the GFR is estimated on the basis of serum creatinine levels. We compared AUCs of carboplatin that were predicted by modified Calvert formulae with actual measured AUCs in 75 courses in patients with non-small cell lung cancer or ovarian cancer who were treated with the combination of carboplatin-paclitaxel. Predictions were made using two modified Calvert formulae, in which the GFR was calculated by serum creatinine level-based equations, according to Jelliffe (Eq. 1) and Cockroft-Gault (Eq. 2). We also studied the performance of a formula for the clearance of carboplatin, as proposed by Chatelut (Eq. 3). The actual measured mean AUC was 4.6 mg/ml·min (range 1.9 to 10.4 mg/ml·min, SD 1.7). Equation 1 overestimated the AUC by 32.9% with an imprecision of 43.0%, and equation 2 overestimated the AUC by 27.6% with an imprecision of 33.4%. For equation 3, an AUC overestimation of only 10.2%, but with an imprecision of 25.3%, was observed. In conclusion, all three equations overestimated the carboplatin AUCs and had poor precisions. We concluded that the real carboplatin AUCs were lower than calculated, using the three tested formulae. This may have important consequences for ongoing and future phase II and III studies with carboplatin-paclitaxel combinations, utilising these formulae to calculate the carboplatin dose. Thus far, the original Calvert dosage formula remains the ‘golden standard’.

Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.

The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol® (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (Cl=37.8-134 ml/h/m2; t½=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (VSS=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.

A pilot study of CHAC-1

Cisplatin is considered to be a cornerstone in the treatment of ovarian cancer. Neij t et al. ( 1)) recently published the results of a randomized phase III trial comparing the antitumor activity of a cisplatin containing regimen CHAP-5, with a non-platinum containing regimen HexaCAF, which was standard treatment in 1979. In Figure 1 survival curves of the treatment arms are given. Survival of patients treated with the platinum containing regimen is better than that obtained for patients treated with a non-platinum containing regimen. The treatment was given in conjunction with aggressive primary cytoreductive surgery or as interventive surgery. Since a subgroup of patients of the GOG study (Omura, personal communication) and a study from Mount Sinai (5) seems to indicate that cisplatin containing treatment regimens may result in better survival of patients suffering from ovarian cancer, the Dutch group, integrating with the Gynecological Cancer Cooperative Group of the EORTC is trying to

Clinical Pharmacology of Carboplatin Administered in Alternating Sequence with Paclitaxel in Patients with Non-Small Cell Lung Cancer: A European Cancer Centre (ECC) Study

The clinical pharmacology of carboplatin, co-administered with paclitaxel, was investigated in a dose-finding and sequence-finding study in 56 previously untreated patients with non-small cell lung cancer (NSCLC). Carboplatin was administered over 30 minutes and paclitaxel over 3 hours every 4 weeks. Patients were randomized for the administration sequence, being first carboplatin (C) then followed by paclitaxel (P) or vice versa. Each patient received the alternate sequence during the second and subsequent courses. Total platinum concentrations in plasma and plasma ultrafiltrate (pUF) were measured applying flameless atomic absorption spectrometry. Ninety-five concentration-time curves were obtained in plasma and pUF.