Hydroxyurea is an antineoplasic agent usually used in myeloproliferative syndromes, but also in other benign pathological circumstances. Several dermatological manifestations have been recognized as being secondary to its prolonged use, of which the leg ulcer. We report an observation. Mrs. L.D, 47 years, were hospitalized on July 14, 2004 for an ulcer of left ankle in a feverish context. She was followed since 2001 for a chronic myelogenous leukaemia, and took hydroxyurea at a rate of 1500 mg per day, with a good clinical and hematologic answer. She presented a painful ulcer compared to the left external malleolus, with purulent bottom, without signs of vascular attack. The hemogram showed a hyperleucocytosis with 24.000 white elements/mm3 with neutrophilic polynucleosis. Pus sample on the ulcer showed Pseudomonas aeruginosa, and the blood culture was negative. The cure was obtained two months after stopping hydroxyurea. The ulcer of leg related to hydroxyurea is a seldom described pathology. Its occurrence imposes the final stop of the treatment.

Clinical implications associated with polymorphisms in drug-metabolizing genes involved in the chemotherapy of colorectal cancers (5-flurorouracil, oxaliplatin and irinotecan) are reviewed.

The first report of jaw osteonecrosis in patients treated with bisphophonates was published in 2003. Since then, not a week goes by without new cases being described in the literature. The vast majority of patients treated with IV bisphosphonates are oncology patients, although numbers of patients with osteonecrosis treated for osteoporosis and Paget's disease are also rising. In the absence of any established treatment, it is generally agreed that initiating pretherapeutic prevention strategies in oncology patients is advisable. Treatment of a recognised osteonecrosis is discussed, with preference being given for a conservative approach rather than aggressive surgical procedures. Our team suggests classifying affected patients into two categories according to the lesions: disabling or non-disabling. An appropriate treatment plan can then be put into place.

Bisphosphonates prevent bone complications induced by cancer. Their low toxicity promoted their extensive use supported by different international recommendations. However the prescription of these therapies is now seriously questioned because of their late and severe toxicity, the osteonecrosis of the jaw, and the growing efficiency of the oncologic therapies. No monitoring method is now available for bisphosphonates therapy. Therefore only a stricter selection of the patients, based on established and well-proven indications, as well as limitation of the administration durations could maintain an adequate risk/benefit ratio.

Prognosis of breast cancer women has been dramatically improved by the adjuvant therapies. As the vast majority of patients are cured, the importance of long-term quality of life is growing. The question of the maternity is an essential concern for the young women who have to receive chemotherapy or several years of endocrine therapy. This problem is often underestimated and may lead to emotional distress, depression or anxiety. A regional multidisciplinary working group was set up in order to offer optimal information about fertility and cancer as to propose specific therapeutic reproduction options, when applicable. Specificity of the young patients' breast cancer, the treatment approaches and their impact on fertility are discussed in this paper.

Metastatic renal cell carcinoma remains a main therapeutic challenge in oncology. Interferon-alpha and Interleukin-2 have been the sole available drugs for decades. Allogeneic bone marrow transplantation is an interesting but experimental therapeutic approach. The von Hippel-Lindau disease is a rare genetic disorder predisposing to the development of renal cell carcinoma. Its molecular elucidation paves the way for novel therapeutic approaches based, mainly but not exclusively, on the inhibition of angiogenesis.

Survival rates for cancers that occur in childhood and adolescence have improved over the last decades, and preservation of future fertility in these patients has become a relevant issue. Premature ovarian failure is a consequence of exposing women to chemotherapeutic drugs and ionizing radiation. Ovarian cryopreservation is an alternative to cryopreservation of embryos or oocytes for theses patients. Ovarian cryopreservation aims to reimplant ovarian tissue after complete remission into the pelvic cavity (orthotopique site) or a heterotopic site like the abdominal wall or the forearm. In vitro folliculogenesis, that aims at the maturation of ovarian cortex primordial follicles cryopreserved for a FIV, is still in an experimental research stage. In this review, the objective was to evaluate the real hopes of pregnancy after ovarian cryopreservation. Indeed, many teams offer ovarian cryopreservation at present time, although only two pregnancies have been achieved to date. In both cases, it can be discussed whether the fertilized oocyte originated from the transplant or from the native ovary. Furthermore, the potential for reintroduction of cancerous cells may limit this technique in cancers that are known to have a risk of ovarian dissemination. The hopes engendered by ovarian cryopreservation, but also its limits, must be explained to the patients before an ovarian surgery for cryopreservation.

Cystatin C is a protein freely filtered in the renal glomerulus, then reabsorbed and completely metabolised within the tubular cells. The possibility to predict the clearance of compounds eliminated by the kidneys (and then to control their interindividual variability) was evaluated for two cytotoxic drugs (carboplatin and topotecan) in adults and EDTA (ethylene diamine tetraacetic acid), a compound used to determine the glomerular filtration rate in children. The population pharmacokinetic approach based on NONMEM program was used. For each of the three compounds, the cystatin C serum level was better predictive of clearance than that of creatinine. Moreover, for carboplatin and EDTA, the best equation between clearance and patients' characteristics included both cystatin C and creatinine level. A generalisation of cystatin C assay would contribute to standardise the clinical practices in Oncology.

During last years, irinotecan has become registered as a major cytotoxic drug in several tumor types. Since the metabolism of this drug is predominantly made in the liver, administration to patients with liver dysfunctions remains a major problem. Hyperbilirubinemia has been shown to require dose reduction. In addition, gene polymorphism of UGT1A1 was shown to be associated with a higher risk of toxicity. However, studies are still required to optimise the use of irinotecan in patients with liver dysfunctions.

5-fluorouracil, (5-FU) is an antimetabolite used in many types of cancers. It has a narrow therapeutic index. More than 80% of administered 5-FU is detoxified in 5-fluoro-5,6-dihydrouracil (5-FUH2) by an enzyme: dihydropyrimidine dehydrogenase (DPD). Half life increased with DPD deficiency. Thus, patients presenting a partial or profound DPD deficiency have an increased risk of severe or lethal toxicity. DPD deficiency was estimated between 3 to 5% in the normal population. Different approaches have been developed: Pharmacogenetic on the DPD gene or pharmacologic measuring DPD activity. More than 30 mutations have been reported on this gene. The more common mutation is the slice-site mutation IVS14+1G>A. Analysis of the various mutations allowed to identify a population at risk with a DPD deficiency. DPD activity is determined in peripheral blood mononuclear cells. This assay offers the capability of identifying individuals who are completely deficient in DPD activity and those who are partially deficient. Assays to detect DPD deficiency are not used as a screening test to prevent 5-FU toxicity.

Numerous toxic side-effects, sometimes severe, are regularly reported in patients treated with 5-fluorouracil, and oral fluoropyrimidines, UFT and capecitabine, in metastatic and adjuvant setting. These toxic effects are due to a large interindividual variability of the metabolism, mainly depending on dihydropyrimidine dehydrogenase activity (DPD), the major enzyme of the catabolism of fluoropyrimidines. Thus, the patients with a DPD deficiency are at high risk of early severe acute toxicity, with this kind of drug. These toxic side-effects are potentially lethal. DPD deficiency frequencies, partial or complete, are about 3-5% and 0.2% respectively. They are most often due to a gene polymorphism. Different techniques for the detection of DPD deficiency before treatment have been reported: phenotypic, such as the plasma ratio of dihydrouracil/uracil, or genotypic, such as the detection of DPD gene variants, deleterious for enzyme activity. The pretherapeutic detection of DPD deficiency would permit to avoid almost every early acute toxic side-effects. We must emphasize that it is not merely a genetic result, since the detection of a deficiency most often does not contra-indicate the use of a fluoropyrimidine, but it must be combined with therapeutic advice.

Imatinib (Glivec) is a specific inhibitor of tyrosine kinase receptor, in particular of the proto-oncogene c-kit. Proto-oncogene c-kit is expressed or mutated in stromal digestive tumors (GIST). Pharmacokinetic (PK) analysis showed that imatinib displayed linear PK in patients with advanced GIST. Imatinib is extensively metabolized by the cytochrome P450 enzyme system. Alpha-1-acid glycoprotein (AAG), a protein involved in the acute phase of inflammation, is implicated in protein binding of imatinib and seems to play a key role in imatinib PK.

Nowadays, more and more oral anticancer chemotherapies are developed either for cytotoxic or new targeted drugs. But this relatively new route of administration in oncology drives to new problems in treatment management and particularly to non-compliance, i.e. the deviance of the actual way patients take their treatment with the prescription. Population PK-PD models and Monte-Carlo simulations allow to study the impact of non-compliance on toxicities. After a brief review on recent developments about oral chemotherapies, this work presents a simulation where non-compliance, modelled with a two state Markov chain defining four compliance profiles from excellent to poor, is linked to two dose-toxicity (continuous or categorical) population models. Simulated patients with the lowest compliance level were less exposed to treatment and therefore experienced less toxicity with shorter events. Nevertheless treatment efficacy is also lower, and this loss of efficacy may compromise patient's outcome. These results foresee the necessity of global simulations, combining compliance, toxicity and efficacy modelling.

Paclitaxel (Taxol) is a drug derived from the bark of the Pacific yew tree and is widely used in cancer treatment, especially for breast, ovarian, and lung cancers. It has not previously been reported to induce lupus.

There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors.

Pemetrexed is a chemotherapeutic drug with good tolerance, used as first line treatment for malignant pleural mesothelioma in association with cisplatin, and alone as second line treatment in resistant or relapsing non-small cell lung cancer (NSCLC). However, cutaneous toxicity has been described, principally as a rash. Cutaneous toxicity of all grades has been observed in up to 14%, and grade 3 or 4 toxicity in 0.8-1.3% of cases.

For several decades, organometallic and organometalloid compounds have played an important part in anticancer chemotherapies, in particular those derived from platinum. Trivalent arsenic, in the form of arsenic trioxide (As2O3; Trisenox(R)) is currently used in the treatment of refractory leukemias, but at the cost of major adverse effects. Moreover, recent studies showed that the trypanocide melarsoprol, could be more effective than arsenic trioxide on myelogenous leukaemias. We have synthesized a series of derivatives from 2-phenyl-[1,3,2]dithiarsolan-4-yl)-methanol (AsIII). Our work shows that the substitution of the aromatic ring by an iodine atom in the ortho position or by an amino-dimethoxytriazin group in the para position increases very significantly the antileukemic activity and improves the therapeutic index (IT=LD50/IC50) of these melarsoprol-derivatives molecules, as compared to arsenic trioxide. However, one of the most promising compounds seems to be arsthinol, an old drug used in the past as an amebicide. Nanoparticle carriers of melarsoprol were also prepared for the purpose of modifying its tissue distribution reduce its brain toxicity.

Tyrosine kinase receptors are an important family of membrane receptors implicated in oncogenesis. Their activation triggers signaling cascades that activate cell growth, proliferation and controls cell death. Inhibiting these receptors leads to signaling impairments and favors antitumor activity. Different anti-receptor tyrosine kinases are proposed for therapy, mainly consisting in monoclonal antibodies impairing the fixation of ligands onto the receptors, and of tyrosine kinase inhibitors, blocking the phosphorylation of the receptors. These therapeutic agents are being extensively studied and supported by considerable scientific and financial investments in the pharmaceutical industry. In this paper, we will consider Human Epidermal Growth Factor Receptors (HERs). Therapeutic use of targeted therapy agents, directed against these receptors is conditioned by the detection of target receptor expression in the tumor tissues. However, it appears more and more clearly that additional diagnosis molecular markers as well as surrogate response prediction markers are needed to enable more efficacious therapeutics.