The discovery of hormone receptors and tamoxifen has revolutionized the management of breast cancer in women as the existence of oestrogen receptors has improved the response rate to hormone treatment from 30 to 50-70% with a further increase in this efficacy if there are also progesterone-positive receptors. LH-RH analogs induce medical castration. Their efficacy in combination with tamoxifen was demonstrated in terms of survival in pre-menopausal women with metastatic cancer. In the adjuvant situation, a meta-analysis of the 1980s demonstrated a benefit in terms of survival without relapse confirmed by more recent studies showing a reduction in the relative risk of relapse. On radiotherapy or ovariectomy, which are radical treatments, medical castration with LH-RH agonist analogs in combination with tamoxifen is therefore an alternative, reversible therapy for outpatients in particular now that a possible direct anti-tumor effect has been suggested by in vitro studies. Nevertheless, at present in France, Marketing Authorisation has not yet been granted for metastatic cancer.

Although after the discovery of GnRH, research was initially directed towards the treatment of infertility, the development during the last twenty-five years of synthetic GnRH analogs has led to major advances in the diagnosis and treatment of endocrine disorders and cancer. Agonists are 50-100 times more potent than the natural neuropeptide and induce an intense and constant secretion of gonadotrophins, while their continuous administration induces hypophyseal desensitization with a fall in FSH and LH production leading to a reduction in sex hormones production and therefore chemical castration. This has been used for the treatment of precocious puberty, in vitro fertilization protocols and management of various hormone-dependent cancers such as prostate and breast cancer, a field where these indications are being continually extended. LHRH antagonists, used at doses higher than those of agonists, induce an immediate inhibition of gonadotrophin secretion and rapidly reduce sex steroid levels. Their development is more recent, and they have begun to find a role in prostatic diseases, cancer and benign prostatic hypertrophy. The discovery of GnRH receptors in various types of cancer has suggested a direct cytotoxic effect on cancer cells as well as the indirect hormonal effect. Research currently in the preclinical stage involves the use of combinations of ligand analogs and cytotoxic agents to increase the anti-tumoral specificity of chemotherapy and provide greater efficacy and reduced collateral toxicity. The management strategy of prostate, breast and ovarian cancers may therefore be considerably modified. Likewise, this concept of targeted chemotherapy using analogs acting as cytotoxic agent carriers up to the tumor site is the aim of research to evaluate somatostatin and bombesin.

The main intracellular pathway activated by stimulation of GnRH receptors is related to Gq protein which induces a cytoplasmic metabolic cascade responsible for activation of genes producing gonadotrophins and regulating their secretion. Two other activation pathways were identified, a Gs protein-mediated pathway involved in pulsatile secretion of GnRH and a Gi protein-mediated pathway with an inhibitory and apototic effect on tumor cells. Finally, GnRH receptors may directly interact with membrane integrins and generate other cytoplasmic signals. Hence, GnRH receptors are not only involved in pituitary secretion but also in tumoral disease. The inhibitory effect of GnRH analogs on the secretion of sex steroids is responsible for the indirect anti-tumoral action already used in routine practice for the treatment of hormone-dependent cancer. However, the presence of GnRH receptors in tumor tissues suggests that they are directly involved in cancerous disease. The conformational variability of these receptors permits certain ligands to stabilize them in a form privileging various intracellular signals with activation of metabolic pathways involving protein kinase systems and generating a direct antitumoral effect by inhibition of cell growth and\or apotosis. The absence of an intracytoplasmic C-terminal tail in the structure of these receptors is an essential condition for the anti-proliferative effect of various ligands, agonists or antagonists, with an anti-tumoral activity varying according to their specificity. This will make it possible in the future to establish a new classification of GnRH analogs. The discovery of this direct antitumoral effect has therefore opened up a new therapeutic approach for hormone-independant cancers with GnRH receptors and the direct cytotoxic effect reinforces the hormonal action in hormone-dependant cancers.

A multidisciplinary therapeutic approach has led to significant increase in survival of children with cancer, however often with a high rate of severe sequela. Better understanding in tumor cell biology and transformation process allowed to describe active tyrosine kinases (mainly growth factor receptors) as a new target for cancer treatment. This review presents 2 approaches to target receptor tyrosine kinase activity: on one hand, antibodies that target the extracellular domain, the natural ligand binding site, and on the other hand, small inhibiting molecules, such as imatinib, targeted against the activated intracellular receptor tyrosine kinase. We focus on their clinical development and current application in the treatment of childhood cancer. Targeted therapies are in full rise and new perspectives are explored, such as their association to other treatment modalities and the targeting of microenvironment. This new therapeutic approach necessitates well designed clinical trials that include relevant biomarkers to evaluate its real therapeutic potential.

Over the last 2 decades, the role of apoptosis in anticancer agent cytotoxicity has become clear. Defects in the regulation of apoptosis (programmed cell death) make important contributions to the pathogenesis and progression of most cancers and leukemias. Apoptosis defects also have a key role in cell resistance to chemotherapy. Mitochondria play a central part in cell death in response to anticancer agents. Most of these agents target mitochondria via caspases or other regulator elements of the apoptotic machinery. Nevertheless, some anticancer agents, already in clinical use (paclitaxel, vinblastine, lonidamine, etoposide, arsenic trioxide) or in pre-clinical development (betulinic acid, MT21), directly target and permeabilize mitochondria. The acknowledgement of mitochondria as a new target for anticancer agents provides a new way to bypass cancer cell chemoresistance.

Strategies for the treatment of metastatic colorectal cancer must take into account the contribution of monoclonal antibodies. A group of new efficient tools in oncology, these drugs target tumor antigens. Bevacizumab recognizes VEGF. Vascular endothelial growth factor (VEGF) is a key mediator in angiogenesis. This antibody combined with chemotherapy increases the survival of patients treated for metastatic colorectal cancer. Median survival of patients treated with antibodies and chemotherapy is 20 months, compared with only 15 months for patients treated with chemotherapy alone. Cetuximab is a monoclonal antibody that binds competitively and with high affinity to the EGF receptor. Cetuximab is currently approved for use in patients with pretreated colorectal cancer. EGF is a major cell growth factor. The side effects of these new biotherapies are different from chemotherapy: bevacizumab affects vascular elements and the most common side effect of anti-EGFR treatment is acneiform skin rash.

Studies of biotherapy-induced physiological changes are few, and systematic monitoring for neurotoxic effects are lacking. The purpose of this exploratory pilot study was to determine the change in peripheral nerve function and symptom distress during treatment with biotherapy for malignant melanoma. A convenience sample of 11 participants with malignant melanoma receiving interferon-alpha had measures of peripheral nerve function measured at baseline, four and 12 weeks of treatment. Data were analyzed using plots and regression slopes to determine change over time in sensation, gait/balance, vision, hearing, vibratory sense, muscle strength, deep tendon reflexes, blood pressure, and symptom distress. Declines in hearing, sensation, vibration, and muscle strength were found. Changes in visual acuity, and orthostatic blood pressure were noted, while gait/balance remained stable. Additionally, neuropathy symptoms were associated with symptom distress. The characterization of such changes can increase our understanding of the nature of the physiological effects associated with high-dose biotherapy treatment and aid clinicians to better prepare patients for anticipated changes in function and subsequent lifestyle adjustments. These findings can be used to provide information in a larger study of this phenomenon regarding important outcomes and measurement time-points of therapy-induced neuropathy and decreasing symptom distress in patients receiving cancer treatment with biologic agents.

Rituximab (Mabthera) is used in the treatment of refractory low-grade non-Hodgkin's lymphoma or in case of relapse after chemotherapy. Among the different adverse reactions with this drug, the most common is a constellation of symptoms (fever, rigors and chills) that occur more frequently during administration of the first dose of drug. These symptoms could be related to a cytokine-release syndrome. We report the case of a 46 year-old patient, presenting a familial cardiomyopathy, deceased a few minutes after having developed this syndrome, at the time of the 2nd infusion of rituximab. Several hypothesis have been suggested to explain this sudden death: a cardiac failure following deterioration of the systolic function, potentially related to the negative inotropic effects of TNFalpha, and/or an impairment of the diastolic function following the volemic overload. The impact of the reflex "administration of monoclonal antibody/cytokine-release syndrome" was only little investigated under physiologic or pathologic conditions. In spite of a risk of adverse reactions apparently moderated compared to the other drugs used in this context, this case report underlines the need for a special attention when using rituximab among patients with cardiac risk factors (reassessment of the benefit-risk ratio, specific monitoring, pre medication). More generally, it underlines the need for a systematic and continuous identification and reporting of adverse drug reactions to the French network of regional pharmacovigilance centres.

Proteasome is involved in cell cycle and apoptosis regulation. Its deregulation could participate to oncogenesis.

Intensive use of radiochemotherapy has greatly improved the prognosis associated with cancer in young women patients. However, improvement of the vital prognosis is frequently associated with impairment of fertility and premature ovarian failure. Cryopreservation of ovarian tissues has been developed but effective secondary use of cryopreserved tissue by means of autograft or through in vitro follicular maturation need yet to be clarified even though first success seemed to be recently obtained. Infant ovaries have been considered to be less sensitive than adult ovaries, which has suggested that hypophysal blockage could protect adult ovaries against fertility impairment before and during radiochemotherapy. Non-randomized studies using LHRH agonists support such a hypothesis. However what we know about physiopathology of follicular destruction involving exaggerated apoptosis and several animal models do not fit with these results. By consequence randomized studies need to be performed to verify the benefit, which one could expect from such a systematic clinical use.

5-fluorouracil, an antimetabolite agent, has been widely used since 1957 for treatment of varied types of cancer such as gastro-intestinal, pancreas, breast, lung, head and neck malignancies. Cardiotoxicity of 5-fluorouracil is rare and was first described in 1975. It can induce severe complications and involve vital prognosis in the short-term. These complications are less known by cardiologists than medical oncologists. The following clinical case represents a potentially serious and rare case of completely reversible cardiogenic shock in a patient with a colo-rectal cancer. A better knowledge of these complications could reduce cases of death by an earlier diagnosis, and a better evaluation of patients with high cardiotoxicity risk.

The prognosis of glioblastoma remains extremely poor. Clinical research has been very active for thirty years, and has explored all the concepts developed in the laboratories of radiobiology. Radiosensitisation of hypoxic tumours, hyperfractioned radiotherapy, external beam radiotherapy plus stereotactic radiosurgery or brachytherapy boost, and intensity modulated radiation therapy failed to improve the results of the treatment of these patients. Concomitant chemoradiotherapy has just obtained a new success in the treatment of glioblastoma. The addition of temozolomide to radiotherapy resulted in a statistically significant survival benefit with minimal acute additional toxicity. The challenge remains to improve clinical outcomes further, and some new research pathways are open.

The present work focuses on the therapeutic efficacy and the toxicity of alpha interferon in patients younger than age 18 years. 5 patients younger than 18 years were treated and followed up between 1990 and 1999 at the department of haematology (Aziza Othmana Hospital) Hydroxyurea was given as initial treatment to all patients. After a median period of 8 months, these patients received alpha interferon (5 millions units/m2 once). Six months after the beginning of the alpha interferon a complete hematologic response was obtained in all patients. The median overall survival was of 66 months: 3 patients are still alive (2 patients in an advanced stage and one patient in chronic phase) and 2 patients died after transformation. The most common reported side effects of alpha interferon were asthenia, weight loss, fever, myalgia, chills and headaches--these toxic manifestations were mild and were noticed in all our patients. Myelosuppression was noted in two patients. Interferon is well tolerated in patients younger than age years 18 old, with CML. It may offer an alternative to bone marrow transplantation in children in the chronic phase of CML without histocompatible donor. The role of new agents such as STI 571 needs to be evaluated as well.

These last decades showed important progress in cancer systemic therapies. A better understanding of the differences between cancer cells and normal cells lead to the emergence of targeted therapies. These treatments interfere with different specific molecules playing a critical role in tumour growth or progression. On the other side, thanks to the development of new therapeutic substances, new modes of administration and to the improvement of supportive care, conventional chemotherapy is more effective and less toxic. The following review summarizes current progress with clinical impact observed these last years.

The management of elderly patients with cancer is not established. The use of antineoplastic agents (particularly of chemotherapy) raises a lot of questions. Efficiency and toxicity. Data come from subgroups of clinical trials and from selected populations. Chronological age itself does not contra-indicate chemotherapy. Pharmacokinetics. Physiologic and functional changes occur with aging but there is great inter-patient variability. Oral chemotherapy. Oral treatments underline the problem of compliance. Under-treatment. Elderly patients are under-represented in clinical trials. Relevant issues have to be defined individually and cancer's real place in patient's general situation has to be specified. Geriatric assessment. This tool has proved its usefulness in many domains for global management of elderly patients. A multidisciplinary team is necessary, under geriatrician coordination. The aim is to elaborate an individualized medico-social intervention program. Geriatric assessment in oncology. Its interest for cancer patients is shown by emerging reports but its routine use by oncologists is impossible. Treatment strategies. They are not validated.

The authors had for aim to assess the effectiveness and toxicity of a piperacillin-tazobactam-netilmicin combination, and the possibility of avoiding using glycopeptide, in children with febrile neutropenic episodes induced by chemotherapy.

The requirement for safe and optimal administration of cytotoxic drugs led us to test a new product manufactured by Codan. The transfer set (CONNECT SET) and the administration set (CYTO-AD-SET) were assessed successively by pharmacist assistance within a centralized unit for cytotoxic drug preparation and by the nursing staff in an ambulatory unit. Transfer sets can be handled in the centralized units without using needles, but with an increased sterilization load and production cost. Assessment of the administration sets demonstrated time saving for the nursing staff. These materials require significant expenditures, careful training, and a change in treatment routine, but provide important time savings for the nursing staff and considerable improvement in the safety of handling cytotoxic drugs.