Phase II trial of PTK787/ZK 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC).

BACKGROUND: The objective of this multicenter, prospective uncontrolled phase II trial was to determine efficacy, safety and tolerability of vatalanib, an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor receptors, in the second-line treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC-proven tumor progression during or after one platinum-based chemotherapy regimen received a fixed dose of 1250 mg vatalanib either once-daily dosing (QD) or two divided daily dosing (TDD: 500 mg a.m. + 750 mg p.m.) until disease progression or unacceptable toxicity. Primary end point was the disease control rate (DCR) at 12 weeks. RESULTS: Fifty-four and 58 patients were enrolled to the QD and TDD arms. DCR at 12 weeks was 35% in the QD and 37% in the TDD arm. The best overall response included one (2%) patient with confirmed partial response with QD and three (5%) with TDD. Median progression-free survival and overall survival were 2.1/7.3 months in the QD arm and 2.8/9.0 months with TDD arm. This therapy showed a moderate toxicity profile for the majority of patients. CONCLUSIONS: In the chosen patient population, vatalanib QD and TDD dosing demonstrated potential benefits in tumor size reduction, DCR, and survival.

Intensive induction chemotherapy without methotrexate in adult patients with localized osteosarcoma: results of the Institut Gustave-Roussy phase II trial.

PURPOSE: To improve outcomes in localized osteosarcoma and to reduce the duration of preoperative chemotherapy, we conducted a phase ii trial assessing the efficacy of an intensive protracted regimen without methotrexate (api-ai regimen) in adolescent and adult patients with newly diagnosed disease. PATIENTS AND METHODS: Induction chemotherapy consisted of 2 cycles (4 courses) of doxorubicin 60 mg/m(2) (days 1 and 15), cisplatin 100 mg/m(2) (day 1), and ifosfamide 5 g/m(2) (days 2 and 15). The primary endpoint was good histologic response [ghr (≤5% identifiable tumour cells)]. RESULTS: From March 1993 to March 2000, 32 patients [median age: 21 years (range: 15-49 years)] were administered 126 induction courses. The median time between chemotherapy courses was 15 days (range: 12-32 days). All but 3 patients underwent conservative surgery. Toxicity was mainly hematologic, with febrile neutropenia occurring in 35% of patients and grades 3-4 thrombocytopenia in 35%. The ghr rate was 47%. The median follow-up was 64 months (range: 30-115 months). The 5-year event-free and overall survivals were 65% [95% confidence interval (ci): 48%-79%] and 69% (95% ci: 50%-83%) respectively. Two secondary hematologic malignancies occurred: 1 acute myelocytic leukemia (M5) in a poor responder with concomitant relapse, and 1 myelodysplastic syndrome in a patient achieving ghr. CONCLUSIONS: Despite hematologic toxicity, the results observed with the api-ai regimen compare favourably with those observed during previous induction chemotherapy containing methotrexate in adult patients and the pediatric population treated at our institution. These promising results have to be validated by an ongoing national multicentre trial coordinated by the French Sarcoma Group.

[New therapeutics strategies in renal cell carcinoma]. / Les nouvelles cibles thérapeutiques dans le cancer du rein.

New medical strategies have emerged over the past decade for the treatment of advanced renal cell carcinoma based on the discovery of specific molecular abnormalities. However, molecular targeted therapeutics including anti-angiogenics have demonstrated significant limits (limited impact on overall survival, development of potential severe toxicities). We review the future directions for drug development based on specific interaction with cellular and extra-cellular pathways. Both von Hippel-Lindau alterations and high immunogenicity profile represent two remarkable characteristics identified in clear cell carcinoma. The new generation of anti-angiogenics (including HIF, Notch, or angiopoietin inhibitors) and recent developments in immunotherapy also provide opportunities to modify the prognosis of advanced renal cell carcinoma.

[Angiogenesis: a new therapeutic target of thoracic and laryngopharyngeal carcinoma]. / L'angiogenèse: une nouvelle cible thérapeutique des cancers thoraciques et ORL.

Angiogenesis or new blood vessel formation is a complex and fundamental event in the process of tumor growth and metastatic dissemination. Actually, most of antiangiogenic agents target the VEGF considered like the most potent proangiogenic factor. These molecules directly inhibit VEGF or the kinase activity of its receptor (VEGFR) and represent a significant therapeutic progress in several solid tumors types. First clinical studies of antiangiogenic agents in thoracic and laryngopharyngeal carcinomas have shown promise mainly in combination with other therapies (chemotherapy, other targeted therapies or radiotherapy). Besides common antiangiogenic therapies-induced adverse events, risks of bleeding caused by tumor necrosis mainly in squamous cell lung carcinomas have been observed during early clinical trials. Assessment of surrogate markers of target inhibition could allow a better selection of patients able to benefit from antiangiogenic treatments eventually combined with chemotherapy or molecules targeting others metabolic pathways.

Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib.

Sunitinib, a multitargeted tyrosine-kinase inhibitor, extends survival of patients with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumours. Between October 2005 and March 2007, we retrospectively reviewed blood glucose level variations associated with sunitinib therapy in patients treated for mRCC. Nineteen of the patients had type II diabetes. All 19 patients had a decrease in blood glucose level (mean 1.77 mmol l(-1)) after 4 weeks of treatment. This was followed by re-elevation in the 2-week rest period. After two cycles of sunitinib administration, two patients had stopped blood glucose-lowering drugs whereas five other patients had normalised their blood glucose level. On the basis of pre-clinical data, we hypothesise that several mechanisms could be involved in this process, such as capillary regression of pancreatic islets, IGF-1 modulation through HIF1-alpha or NF-kappaB activation. In addition, a decrease of glucose uptake in the context of concomitant gastrointestinal toxicity cannot be excluded. Glycaemic control should be carefully evaluated in diabetic patients treated with sunitinib, and routine monitoring is warranted.

[Neoadjuvant therapy for renal cancer]. / Traitement néoadjuvant du cancer du rein.

A 73-year-old man presented with renal cell carcinoma of the left kidney. Despite the absence of metastases, primary nephrectomy was not performed immediately due to the large tumour volume and the presence of large lymph node extension. The patient was treated with sunitinib for 10 months. Computed tomography at the end of treatment showed a significant reduction of the size of the tumour and the volume of lymph node extension. Radical nephrectomy was then performed. On histological evaluation, the primary renal tumour and, to a lesser degree, the lymph nodes were predominantly necrotic.

Comparison of the efficacy and safety of combinations of metopimazine or ondansetron with methylprednisolone in the prevention of delayed emesis in patients receiving chemotherapy.

BACKGROUND: Delayed emesis following chemotherapy in cancer patients remains an important challenge for treatment and contributes to poor quality of life and treatment compliance. OBJECTIVES: To compare the efficacy and tolerability of associations of metopimazine and ondansetron with methylprednisolone for the prevention of delayed chemotherapy-induced nausea and emesis. METHODS: A randomised, open-label, observational, cross-over design was used to compare two treatment strategies following two consecutive sessions of chemotherapy separated by at least 1 week. Patients were randomised to treatment with sublingual metopimazine (15 mg tid) or ondansetron lyophilisate (8 mg bid) for 5 days. All patients received oral methylprednisolone (48 mg). Patients reported episodes of nausea and emesis in a diary, and completed the Functional Living Index Emesis quality of life questionnaire. Adverse events were also evaluated. RESULTS: Ninety-nine patients were included in the study, 79.5% of whom were women, with a mean age of 52.7 years. Breast cancer was the most common individual cancer and most patients were receiving combinations of cytotoxic drugs. Treatment was successful at preventing delayed emesis in 73.6% of patients during treatment with the metopimazine-methylprednisolone association and 57.5% during the ondansetron-methylprednisolone association. Analysis of discordant pairs revealed a significant benefit in favour of the methopimazine-methylprednisolone association (p = 0.006). No significant difference was observed between treatments for the overall quality of life score. The incidence of gastrointestinal disorders, particularly constipation, was significantly higher during ondansetron-methylprednisolone treatment (p = 0.0112). CONCLUSION: Methopimazine is an effective and well-tolerated alternative to setrons for the treatment of delayed nausea and emesis in patients undergoing chemotherapy.

Evaluation of retroperitoneal and pelvic lymph node metastases with MRI and MR lymphangiography.

Local, regional lymph node involvement is an essential prognostic factor and an important determinant of treatment choices for patients with retroperitoneal and pelvic cancer. Current cross-sectional imaging modalities, including computed tomography and magnetic resonance (MR) imaging, use the nonspecific criterion of size and are limited in their ability to differentiate benign from malignant lymph nodes. MR lymphography is a promising imaging modality in differentiating benign from metastatic lymph nodes and provides information on lymph node morphology and function. Ultrasmall superparamagnetic iron oxide (USPIO) particles with a long plasma circulation time are suitable as an MR contrast agent for intravenous MR lymphography. They are taken up by macrophages in normally functioning nodes and reduce the signal intensity of tissue in which they accumulate because of T2 and susceptibility effects of iron oxide. In metastatic nodes, macrophages are replaced by cancer cells, which lack reticuloendothelial activity and cannot take up USPIO. The main mechanisms that might explain a heterogeneous node appearance after USPIO injection are discussed. In published reports, USPIO has shown high degrees of sensitivity and specificity for characterizing lymph nodes in cancer patients. We review the development of USPIO compounds, their imaging characteristics, and our clinical experience.

Metastatic malignant melanoma.

Malignant melanoma is one of the most worrisome tumors in terms of epidemiology, and incidence is increasing. The estimated lifetime risk in the United States is 1 in 75 people. As soon as the first distant metastasis appears, the disease becomes one of the most aggressive and chemoresistant tumors: 90-95% of patients do not survive more than 3 years. Results with chemotherapy are disappointing as few drugs have demonstrated an impact on survival. Drug combinations provide only a slightly higher response rate and do not overcome the natural chemoresistance of this tumor. Tamoxifen, which was widely investigated in the late 1980s and 1990s, has not added any benefit in terms of response rate or survival. Since their description as immunomodulating molecules, the cytokines interferon-alpha and interleukin-2 (IL-2) have been extensively tested in malignant melanoma. They seem to achieve higher response rates and survival rates than chemotherapy but undoubtedly lead to more long-term unmaintained remissions. Their combination with chemotherapeutic drugs, "chemoimmunotherapy", has been tested using various doses and schedules (one or two cytokines, single drug or combination chemotherapy). The combination of cisplatin and IL-2 plays a key role in this strategy. However, because of its higher toxicity, the real benefit of chemoimmunotherapy on patient survival still needs to be proven.

[Radiation-induced cataract: physiopathologic, radiobiologic and clinical aspects]. / Cataracte radio-induite: aspects physiopathologiques, radiobiologiques et cliniques.

Cataractogenesis is a widely reported late effect of irradiated crystalline lens. In this review the authors discussed the different aspects of radiation cataract pathogenesis, and the different mechanisms involved in the lens opacification, particularly the epithelium modifications such as epithelial cell death. The authors also reported the influence of radiation exposure on cataract formation following total body irradiation (TBI) and autologous or allogeneic bone marrow transplantation for hematologic malignancies. Moreover, the radiobiological parameters are not studied for the crystalline lens of human. We applied for the first time the linear-quadratic (LQ) and biological effective dose (BED) concept to TBI data. The calculated value of alpha/beta of 1 Gy is in the range of the values reported for the other late responding tissues. The other risk factors for cataract development after TBI such as age, gender, central nervous system boost, long-term steroid therapy and heparin administration are discussed. In terms of cataract or sicca syndrome prevention, numerous compounds have been successfully tested in experimental models or used for the prevention of radiation-induced xerostomia in patients treated for head and neck cancer. However, none of them has been clinically evaluated for ocular radiation late effects prevention. In this report the authors discussed some of the radioprotectors potentially interesting for radiation-induced cataract or sicca syndrome prevention.

[Zd 1839 "Iressa"]. / Le ZD 1839: "Iressa".

ZD 1839 is a highly specific EGF receptor tyrosine kinase inhibitor. Inhibition of EGF receptor transphosphorylation by ZD 1839 blocks the signal transduction at the first step, thus providing antiproliferative effects. Preclinical studies demonstrated efficacy and good bioavailability. The terminal half-life of the compound in patients is ranging from 27 to 41 hours, allowing single oral dosing. Tolerance in healthy volunteers was excellent. In phase I studies, toxicity was manageable. Most common side effects were skin rash, nausea, vomiting, and diarrhea. During those studies, clinical responses were observed in patients with various malignant tumors, in particular non small cell lung cancer. Phase II and III studies are ongoing.