The purpose of our investigation was to evaluate the pharmacokinetic profile of doxorubicin administered by a new schedule. Nine non-pretreated young women with high risk breast cancer (mean age: 38, range: 29-45) entered this trial and received, cyclophosphamide (600 mg/m2) given as a 30-min infusion followed by doxorubicin (120 mg/m2) as a continuous infusion over 6 h. Chemotherapy was combined with hematopoietic factor support (G-CSF or GM-CSF). Blood was sampled over the 0-54 h period and 14 cycles were studied for pharmacokinetics. Doxorubicin as well as its major metabolite doxorubicinol were assayed in plasma specimen by high performance liquid chromatography. Mean doxorubicin plasma concentration peak was 42.6 ng/ml (standard deviation (SD): 13.3). The mean terminal half-lives were 32.6 h (SD: 22.0) and 39.2 h (SD: 21.6) for doxorubicin and doxorubicinol, respectively. Mean areas under the plasma concentration-time curve (AUC) were 413 ng/h-1 ml (SD: 103) and 1,707 ng/h-1 ml (SD: 815) for doxorubicin and doxorubicinol respectively. Consequently, the ratio of the AUC of doxorubicinol to that of doxorubicin was high (mean: 4.1 (SD: 1.6)) contrasting with previous studies reporting ratios less than 1 in patients with normal liver function. The systemic clearance of doxorubicin was 5.23 l/min/m2 (SD: 1.91). The inter- and intra-patient variability for AUC was low for both drugs. Hence the coefficients of variation were 24.6% for doxorubicin, 26.2% for doxorubicinol (inter-individual variation) and less than 10% for both compounds (intra-individual variation). In conclusion, the pharmacokinetic profile of doxorubicin (120 mg/m2) administered as a 6 h-continuous infusion is characterized by a greater exposure to doxorubicinol. This could be explained by a saturation in the biliary excretion process during the period following the end of the infusion.

Study of the antitumour effects of erythropoietin on metastatic renal cell carcinoma.

Taxol is a relatively new antineoplastic agent whose classification as either vesicant, non-vesicant, or irritant remains under debate. This case study is presented to follow a large-volume Taxol extravasation. The article illustrates assessment, follow-up, intervention and outcome of this situation. This case suggests the drug is a vesicant with the potential to cause moderate soft tissue injury.

Effectiveness of chemotherapeutic treatment is limited by multidrug resistance (MDR) phenomenon mediated by the overexpression of P-glycoprotein 170 termed Pgp which serves as an efflux pump removing several types of cytostatic drugs from the MDR cells. Several small molecules, frequently lipophilic cations and weak bases, are able to reverse in vitro this resistance. Several studies have shown that MDR modulators interact with Pgp. However, some molecules do not interact with Pgp but are able to completely restore drug sensitivity (e.g., quinine). Bennis et al. (1995) have shown recently that in contrast to verapamil and S9788, quinine increases nuclear doxorubicin accumulation without modifying its intracellular concentration. From this work, the authors concluded that quinine has essentially intracellular targets involved in drug distribution (cytoplasm to nucleus) from sequestration compartments. Their results have been obtained using spectrofluorometry on cell populations and fluorescence microscopy. By using confocal laser microspectrofluorometry, we investigated restoration of nuclear THP-DOX accumulation and sensitivity by verapamil, S9788 and quinine in 2 variants of the Chinese hamster ovary cells LR73, selected for resistance to doxorubicin (LR73D) and transfected with the mdr1 gene (LR73R), as well as in the sensitive ones (LR73S). Results show that verapamil and S9788 were able to restore THP-DOX sensitivity in resistant cells by increasing nuclear THP-DOX accumulation. This restoration is the consequence of Pgp inhibition and redistribution of the anticancer drug from the cytoplasm to nucleus. Quinine, in contrast, restores the sensitivity of MDR cells to THP-DOX and decreased their resistance index, but has no effect on THP-DOX nuclear accumulation. This suggests that quinine modifies the molecular environment of anthracyclines and/or their binding to cytoplasmic targets involved in another mechanism of anthracycline action.

Gemcitabine is a novel pyrimidine nucleoside whose activity has been demonstrated on solid tumors. We report here the results of a multicentre phase II trial of gemcitabine in chemonaive patients with inoperable non small cell lung cancer (NSCLC). Gemcitabine was given weekly at a dose of 1,250 mg/m2 administered as a 30 min intravenous infusion, for 3 weeks followed by 1 week of rest (1 cycle). All the 161 patients included were evaluable for toxicity and 151 of them were evaluable for efficacy. The majority of patients had a stage IIIb (31.1%) or stage IV (64.6%) disease; 10.6%, 83.2% and 6.2% of patients had a WHO performance status (PS) 0, 1, and 2, respectively. Adenocarcinoma accounted for 52.2% of cases and squamous cell carcinoma for 43.5% of cases. Three complete responses and 30 partial responses gave an objective response (OR) rate of 21.8% (95% confidence interval; 15.5-29.3%). All responses were validated by an independent Oncology Review Board. Median duration of response was 7.6 months. Median time to progression was 4.6 months (3.3 months in non responders and 7.6 months in responders). Median survival was 7.3 months in non responders and 13.4 months in responders (p < 0.001), which gave an overall median survival of 8.9 months (95% CI: 0.1-21.9 months) in the entire study population. An improvement of symptoms and personal state was also observed. Treatment was well tolerated. Neutropenia was the only dose limiting toxicity. WHO grade 3 or 4 neutropenia occurred in 19.6% and 5.7% of patients, respectively. With a 21.8% OR rate, this multicentre study confirms the activity of gemcitabine as a single agent in patients with inoperable NSCLC. Its good tolerance and original mode of action make gemcitabine a drug of choice in the therapeutic strategy of these tumors.

High-dose methotrexate has been used as a therapeutic strategy in osteosarcoma for 20 years. Cerebral neurotoxicity is frequent.

Ifosfamide is one of the most efficient antimitotic in soft tissue sarcoma. To try to find a possible dose-effect, 10 patients with advanced pretraited relapsed soft tissue sarcoma received 15 g/m2/cycle ifosfamide in continuous infusion during 5 days. A pharmacokinetic study was done for 2 patients. All patients received growth factors, ondansetron and 8 clonazepam. Renal toxicity was evaluated after the first and the second cycle. Twenty two cycles were delivered to patients who have been already treated with ifosfamid (10 patients with 15 g/m2 to 54 g/m2, median 27 g/m2) or cis platinum (2 patients). No major renal or neurologic toxicity was observed; only subclinical modifications of urinary enzymes excretion were found. Two patients had visual hallucinations at the end of a cycle and just in the 2 following days; another presented a neuropathy of inferior limbs. Hematological toxicity was very limited. Pharmacokinetic study did not show induction mechanism at this dosage and with this type of administration. So ifosfamide 3 g/m2 during 5 days is feasible. The few level of complications observed is perhaps linked to the daily dose of 3 g/m2 instead of 4 g/m2 or more used in the other studies.

The constant aging of the population has a profound impact on future health policies regarding cancer treatment, because age is the main single determinant for developing cancer. A new specialty is now emerging: geriatric oncology. So far, the very few data available indicate that elderly patients are often misstaged and therefore mistreated, as a result of the lack of appropriate instruments for the evaluation of the individual life expentancy. New instruments should be developed given the emergency situation created by the explosive increase in cancer incidence.

Cardiotoxicity is not a well-known complication of the administration of vinorelbine (Navelbine). We report a case of cardiogenic shock with pulmonary edema after administration of vinorelbine within an association of radiotherapy and chemotherapy.

The study of a homogeneous series of 215 cases of prostatic cancer, 175 of which received first-line treatment with diethylstilbestrol (DES) clearly demonstrated that: 1. practically all well differentiated prostatic cancers, regardless of their stage, responded remarkably well to first-line treatment with sufficient doses of DES, as, when correctly monitored, practically none of these cancers escaped and early stages of escape can be salvaged. 2. true escape occurs all the earlier and evolves all the more rapidly for advanced, poorly differentiated cancers, but this is not constant. 3. to our knowledge, confirmed true metastatic escape to effective doses of DES cannot be salvaged by another treatment, while DES has been successfully used as salvage therapy in several cases of escape to LHRH agonists. 4. the thromboembolic risks must be thoroughly evaluated and prevented by associated anticoagulant treatment. They do not constitute a formal contraindication to treatment when it is closely monitored. However, the best treatment for these cases, when accepted by the patient, appears to be a combination of castration with a daily dose of 1 to 2 mg of DES. 5. The low cost of this treatment must also be taken into account in the assessment of this treatment modality.

Photodynamic therapy of cancerous cells is a technique relying upon the irradiation of tumorous cells after selective incorporation of a photosensitizer. The bis (tri n-hexylsiloxy) silicon phthalocyanine is a second generation photosensitizer. Anti-cancerous potentialities of this molecule have been evaluated against the melanotic M6 cell line. Results have evidenced a high phototoxicity at low concentration and no dark toxicity under the same conditions. EPR studies on the photochemical pathways involved in phototoxicity processes have been realised in solvent and model membranes (liposomes). Results provide evidences for the production of singlet oxygen (1O2) as well as superoxide (02(o)-) and hydroxyl radicals (0OH).

Haematopoietic growth factors are glycosylated proteins involved in the differentiation of pluripotent stem cells into committed progenitor cells, which eventually give rise to distinct haematopoietic cell lineages. Three recombinant hematopoietic growth factors--G-CSF, GM-CSF and erythropoietin--are currently commercially available for clinical use. G-CSF and GM-CSF are lineage-specific growth factor that regulate the production and function of granulocytic and monocytic cells. They have been shown to reduce the incidence of febrile neutropenia. Primary prophylactic administration is reserved for patients in which the expected incidence of febrile neutropenia is greater than 40% without haematopoietic growth factor. After a documented occurrence of febrile neutropenia in an earlier cycle, the secondary prophylactic administration of G-CSF or GM-CSF may be considered. However, in the absence of clinical data supporting maintenance of chemotherapy dose-intensity, dose reduction should be considered as an alternative to the use of haematopoietic growth factors. G-CSF and GM-CSF also shorten the period of neutropenia in patients undergoing high-dose chemotherapy with autologous bone marrow support. Erythropoietin is currently approved for treatment of anemia associated with cisplatin-based chemotherapy with the aim to reduce transfusion requirements.

Oxaliplatin is a new cytotoxic drug, with a mechanism of action nearly similar to that of cisplatin. However, in vitro and in vivo studies showed an interesting activity in colorectal cancer. This article summarizes the main data available for patients with advanced colorectal cancer concerning phase I studies, pharmacokinetic, single agent phase II studies, combinations with 5-fluorouracil (5-FU), and tolerance. 10% response rate in second-line therapy, 20 to 25% in first-line, and 26 to 45% in combination with 5-FU in second-line have been reported. The limiting toxicity is a reversible sensitive neuropathy. Oxaliplatin combined with 5-FU should be considered as one of the best therapeutic options in second-line colorectal cancer patients. Further studies will indicate the role of oxaliplatin in less advanced disease, such as metastatic first-line or adjuvant therapy.