research
Modulation of docetaxel treatment
- Publication date
- 12 November 1997
- Publisher
- The taxanes are a new class of drugs that exert antitumor activity
through a unique mechanism. As early as in the late 1960s paclitaxel,
extracted from the bark of the Pacific Yew Taxus Brevifolia, was the first
compound with a taxene ring that exhibited antitumor activity.
Because of the difficulties in drug isolation, extraction and formulation, the
development of this antitumor agent has been relatively slow. In 1986
docetaxel, the second drug in this new class of compounds, was
developed. Docetaxel is synthesized from 10-deacetyl baccatin III, a
noncytotoxic precursor extracted from the European Yew Taxus Baccata.
Taxanes promote the polymerization of tubulin into stable
microtubules and inhibit microtubule depolymerization. This leads to a
disruption of the equilibrium within the microtubule system and ultimately
leads to cell death. The activity of docetaxel was studied in many
murine tumor models that showed that docetaxel was active against
subcutaneous B16 melanoma, MX-1 mammary cancer, C38 colon
carcinoma, CX-1 colon carcinoma, LX-1 lung carcinoma, P03
pancreatic carcinoma, SK MEL-2 melanoma and OVCAR,3, HOC 8, HOC
10 and HOC 22 ovarian carcinomas.
In phase I studies on single agent docetaxel responses were reported
in various tumor types such as breast cancer, ovarian cancer,
adenocarcinoma of unknown primary, pancreatic cancer, small cell and
non-small cell lung cance. The major dose limiting toxicity was an
early-onset, short-lasting, dose-dependent, schedule-independent and noncumulative
neutropenia. Other side effects were generally mild and
consisted of alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity,
infrequent hypersensitivity reactions, fluid retention and skin- and
nailtoxicity. For phase II studies the recommended dose and schedule was
100 mg/m2 given as a 1-hour infusion every 3 weeks.
Phase II studies on docetaxel among others showed activity in breast
cancer. non-small cell lung cancer, head and neck cancer, gastric cancer, melanoma, soft tissue sarcom), and pancreatic cancer.
In view of the fact that docetaxel is effective in a variety of solid
tumors, it was considered important to study the combination of the drug
with other potent antitumor agents. This thesis includes phase I studies on
the combination of docetaxel with cisplatin and ifosfamide, respectively.
Fluid retention and neurotoxicity, occurring in relation to the cumulative
docetaxel dose, are besides activity important features. At high
cumulative doses of docetaxel these side effects may become severe and
disabling and lead to treatment discontinuation. It is important to try to
alleviate these side effects in view of the single agent use but also in view
of expected increased toxicity in case of combination chemotherapy.
Therefore we performed a prospective study on the incidence of
neurotoxicity induced by the combination of docetaxel and cisplatin, two
potentially neurotoxic drugs.
Despite corticosteroid comedication fluid retention still occurs. In
view of case reports suggesting amelioration of this side effect by
venotonic drugs, we performed a prospective study on the venotonic drug
hydroxyethylrutosiden in patients treated with docetaxel.
The neurotoxicity induced by docetaxel was previously reported in
studies where corticosteroid comedication was not given routinely.
Although introduced to reduce docetaxel-related fluid retention, it was yet
unknown if corticosteroids also had an effect on neurotoxicity. This was
assessed prospectively in the last chapter.