A phase 1 study of vinflunine in combination with trastuzumab for the treatment for HER2-positive metastatic breast cancer.

OBJECTIVE: To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions. PATIENTS AND METHODS: In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m(2)) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity. RESULTS: The RD was 320 mg/m(2) according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m(2). When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1-87.7). The median progression-free survival was 11.3 months (95 % CI 9.4-21.0). At the dose of 280 mg/m(2), grade 3-4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %). CONCLUSION: The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m(2) every 3 weeks. No mutual PK drug-drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib.

BACKGROUND: The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. PATIENTS AND METHODS: We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). RESULTS: Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P<0.0001) and 19.5 versus 38.5 months (P<0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P<0.0001) and OS (P=0.001). CONCLUSION: The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.

[Initial management in oncology: results of CPRIM surveys on 2,583 patient's perceptions and expectations (outside Anticancer Centers)]. / Prise en charge initiale: résultats des enquêtes CPRIM sur le ressenti et les attentes de 2,583 patients (hors centres de lutte contre le cancer).

During the initial phase of management, the caregivers' role is particularly difficult. These two consecutive surveys have been conducted to cover three main aspects: 1) How the initial management took place; 2) What the perceived deficits were; 3) What improvements could be made. A self administered and anonymous questionnaire was given to the patients by physicians. Surveys were conducted in numerous institutions representative of all kinds of practice except for Anticancer Centres. Two thousand five hundred and eighty three adult patients have completed the questionnaire (1366 and 1217 respectively in the first and subsequent survey): women (55%), age under 70 years (76%), breast cancer (32%). Results were rather encouraging. About sixty per cent of the patients are entirely satisfied by the given information and 95% are confident with the department of care. The mean level of global aid is 8.2/10 in the first survey and 8.6/10 in the second one. However, improvements remain needed, particularly for the 8% dissatisfied patients. In spite of the classical bias for these studies, this work gives several concrete responses for improving initial management, particularly for the first consultation in the centre, which has a major impact on the patient satisfaction.

[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.

Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network.

BACKGROUND: Xp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients. PATIENTS AND METHODS: Patients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified. Nuclear TFE3 positivity was confirmed by reviewing pathology slides. Responses according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Overall, 53 patients were identified; 23 had metastatic disease, and of these 21 had received targeted therapy (median age 34 years). Seven patients achieved an objective response. In first line, median PFS was 8.2 months [95% confidence interval (CI) 2.6-14.7 months] for sunitinib (n = 11) versus 2 months (95% CI 0.8-3.3 months) for cytokines (n = 9) (log-rank P = 0.003). Results for further treatment (second, third, or fourth line) were as follows: all three patients receiving sunitinib had a partial response (median PFS 11 months). Seven of eight patients receiving sorafenib had stable disease (median PFS 6 months). One patient receiving mTOR inhibitors had a partial response and six patients had stable disease. Median OS was 27 months with a 19 months median follow-up. CONCLUSION: In Xp11 translocation RCC, targeted therapy achieved objective responses and prolonged PFS similar to those reported for clear-cell RCC.

[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.

[Primary carcinoma of the head of the epididymis]. / Tumeur épithéliale primitive de la tête de l'épididyme.

The authors report the case of a 44-year-old man in whom a poorly differentiated primary carcinoma of the head of the epididymis was discovered incidentally. Due to the rarity of this diagnosis, a comprehensive assessment was performed looking for a primary tumour, but without success. Despite early surgical resection, the patient developed lymph-node metastases. This exceptional tumour showed low sensitivity to chemotherapy. Malignant tumours of the epididymis are exceptional and require investigations to detect a primary tumour. Treatment is based on surgical resection, ideally via an inguinal incision, combined with chemotherapy adapted to the histological type.

[Edifice program: analysis of screening exam practices for cancer in France]. / Le programme Edifice : analyse des pratiques de dépistage du cancer en France.

INTRODUCTION: The practices of screening and the parameters influencing these practices are not well known in France. The objectives of the Edifice study were to analyze a large cohort of patients and doctors in order to further characterize these parameters. PATIENTS AND METHODS: The study was performed by the Institute TNS Healthcare-SOFRES, and included 2 parallel studies: 1) on 1 609 healthy persons representative of the global French population and aged 40 to 75 years (N = 1 509), with an over representation of patients aged 50 to 74 years living in the 22 pilot French departments pilots; 2) on 600 generalist practitioners. Data were collected and analyzed by the expert panel... RESULTS: Ninety-three, 25, 36 and 6% of the patients in the general population declared to have performed at least one a screening exam for breast, colon, prostate, and lung carcinoma respectively. Seventy, 20, 60 and 4% of GP declare to propose systematically to a 40-75-year-old patient a screening test for breast, colon, prostate, or lung cancer. For breast cancer screening the adhesion of the GP is independent of the date of implementation of a general screening in their own regions, while for colorectal screening, 34 and 20% of the patients living in the pilot versus other departments were screened. Overall, prostate cancer screening is recommended by the GP panel for 77.1% of patients aged 50 to 75 years. CONCLUSIONS: This study shows a good adhesion of screening procedures for GP and patients, shows that screening is improved by general screening policy in colorectal cancer, but that prostate cancer screening practices exceed what is recommended according to evidence based medicine.

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.

[Regression of vena cava tumour thrombus in response to sorafenib]. / Régression d'un thrombus cave néoplasique sous traitement par sorafénib.

Ten percent of patients with kidney cancer have associated vena cava thrombus, which is associated with a high operative morbidity. Up to now, no medical treatment has allowed regression of vena cava tumour thrombus. The authors report the case of a 62-year-old patient with left kidney cancer associated with vena cava tumour thrombus. After surgical resection, the patient relapsed in the form of vena cava thrombus associated with right renal vein thrombus, responsible for renal insufficiency requiring dialysis. Sorafenib therapy allowed regression of the vena cava thrombus, suspension of haemodialysis and local disease control with a follow-up of one year. This case report justifies a review of the place of anti-angiogenic therapy in the treatment of kidney cancer.

Breast cancer screening in France: results of the EDIFICE survey.

BACKGROUND: The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter. METHODS: This nationwide observational survey was carried out in France from 18 January to 2 February 2005 among representative samples of 773 women aged between 40 and 75 years and 600 general practitioners (GPs). Information collected included socio-demographic characteristics, attitude towards cancer screening and actual experience of cancer screening, as well as GPs' practice regarding screening. The precision of the results is +/- 4.3% for a 95% confidence interval. RESULTS: Among the 507 participating women aged between 50 and 74 years, 92.5% (469/507) had undergone at least one mammography: 54.6% (256/469) underwent this test on their own initiative and 44.6% (209/469) of women performed it in the framework of a systematic screening plan. Most women participating in the systematic screening (89.0% i.e. 186/209) had a mammography within the last dating from less than 2 years versus 73.8% (189/256) of those who performed it outside the screening program (Chi(2) test; p<0.01). Interestingly, 422 women (61.9% i.e. 422/682 women aged between 40-75 years with at least one mammography) had performed a mammography before the recommended age for screening. There was a significant correlation (p = 0.009) between the existence of a first mammography before 50 years of age and subsequent screening on women's own initiative (54.6% of 469 screened women). Main reasons for not performing the screening test every second year (77 women aged between 50-74 years) included: feeling unconcerned and/or unmotivated (p = 0.0001), no cancer anxiety (p = 0.020) and no recommendation by the GP (p = 0.015); Of the 600 participating GPs, 68.6% (412/600) systematically recommended a mammography to their patients. GPs' perceptions of the reasons for women's avoidance of the screening test were unwillingness to be aware of mammography results (44.4% - 266/600) and the belief that mammography was painful (52.5% - 315/600). CONCLUSION: The main result of the EDIFICE survey is the high rate of women's attendance at mammography screening. The EDIFICE survey pointed out that systematic and organized screening played a major role in the regularity of screening tests for breast cancer every second year. GPs and gynaecologist are key actors in heightening public awareness.

Identification of a functional EGF-R/p60c-src/STAT3 pathway in colorectal carcinoma: analysis of its long-term prognostic value.

AIMS: The Epidermal Growth Factor-Receptor (EGF-R) is frequently overexpressed in colorectal carcinoma (CRC) and patients can benefit from anti-EGF-R therapy. Yet, the relationship, within tumours, between EGF-R and the activity of downstream effectors such as the non-receptor tyrosine kinase p60c-src and the signal transducer and activator of transcription 3 (STAT3) has not been extensively analyzed. METHODS AND RESULTS: We evaluated EGF-R, tyrosine 416-phosphorylated p60c-src (P-p60c-src), STAT3 and tyrosine 705-phosphorylated STAT3 (P-STAT3) on Tissue Micro Array (TMA) from 126 patients with CRC. Composite immunohistochemistry scores based on the intensity of labelling and the percentage of positive cells were determined on TMA for EGF-R, P-p60c-src, STAT3 and P- STAT3. A high score was found in 56%, 61%, 62% and 27% of the cases for EGF-R, P-p60c-src, STAT3 and P-STAT3 respectively. There was a significant correlation between EGF-R and P-p60c-src (p=0.006) and between P-p60c-src and P-STAT3 (p=0.0009). STAT3 was significantly correlated with vascular emboli (p=0.03) and perineural invasion (p=0.02). CONCLUSIONS: The correlations between EGF-R, P-p60-src and P-STAT3 and some stage-related pathological features point to a critical role for a EGF-R-connected p60c-src-kinase-mediated pathway involving STAT3 and contributing to cell survival and proliferation within CRC tumours.

[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.

[Hormone-refractory prostate cancer]. / Cancer de la prostate hormonorésistant.

Hormone-refractory prostate cancer is an advanced stage of the metastatic disease; it has a poor prognosis and a short median survival, about 9 to 18 months. The current article is based on a literature review regarding the prognostic factors and medical treatments, with a focus on recent advances in chemotherapy. With the use of docetaxel that increases the median survival of this disease and improves the symptoms, new clinical protocols have been developed, with promising results; these protocols propose a combination with calcitriol or antiangiogenic agents. Supportive care is also an important part of the treatment due to the high level of bone involvement and its consequences. Such recent advances constitute a real progress in the management of prostate cancer, namely the pharmacological combinations with a promising efficacy and little toxicity.

[Choroidal metastasis revealing pulmonary adenocarcinoma]. / Métastase choroïdienne révélatrice d'un adénocarcinome bronchique.

Lung cancer is the first cause of choroidal metastasis in man. Generally, its discovery is made at end-stage of the disease. It can be uncommonly the presenting sign as in our case. We report a case of a 28-year-old patient with no prior medical history. He presented with visual decrease and metamorphopsia that lead to the diagnosis of a metastatic adenocarcinoma of the lung (bone, liver, choroid, nodles). Chemotherapy permitted to improve visual acuity, in parallel with disappearance of choroidal metatasis. Discovery of choroidal tumor should evoke in first line metastasis. Chemotherapy can improve visual acuity and the quality of life.

[Skin signs associated with epidermal growth factor inhibitors]. / Manifestations cutanées des inhibiteurs du récepteur du facteur de croissance épidermique.

BACKGROUND: Inhibitors of epidermal growth factor receptors (EGFR) constitute a new alternative treatment for patients presenting certain advanced stage solid cancers (bowel, breast, ovary). Adverse cutaneous effects of these drugs are now starting to be described. OBSERVATIONS: Our study involved 2 men and 2 women with no previous history of acne included in a treatment protocol comprising EGFR inhibitors. Mean age was 52 years. The primary cancers were breast, ovary, bowel and unidentified. The EGFR inhibitors used were gefitinib (ZD1839) (2 cases), carnetinib (Cl1033) and cetuximab (IMC-C225). Skin lesions appeared after 7 days and included erythematous papules and follicular pustules of the face, back and upper chest. No comedons were seen, and there were no nodules or cysts. The severity of the rash resulted in discontinuation of treatment in 2 patients with complete disappearance of skin lesions in both cases. In one patient, reduction of the dosage of gefitinib (IMC-C225) led to gradual resolution of the rash. Histological examination of papules and pustules concluded on an acute suppurative folliculitis. Smears and cultures ofa nasal lesion and pustules revealed coagulase-positive Staphylococcus aureus in 2 patients. Combined doxycycline 100 mg daily and benzoyl peroxide was prescribed for 3 months and a favourable outcome was achieved after a mean 2 weeks. DISCUSSION: EGFR inhibitors act by inhibiting mechanisms oftumour proliferation in certain cancers at advanced stages or refractory to other treatments. Our findings in these four patients are similar to the published cases in terms of rapid onset of monomorphous, papulopustular, follicular eruption without comedons. Rapid response to cyclines and benzoyl peroxide is also reported in literature. This treatment must be instituted rapidly and patients must be informed about the cutaneous side-effects of EGFR inhibitors before the start of therapy. The pathophysiology of these eruptions is still unknown. Skin signs are probably due to interaction with EGFR functions, including overexpression of EGFR in keratinocytes and hair follicles.

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.