Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

[Management of a progressing prostate cancer: results of a national study]. / Surveillance et adaptation de la stratégie thérapeutique en cas de progression de la maladie dans le cancer de la prostate avancé : résultats d'une enquête nationale.

INTRODUCTION: The introduction of new treatments in metastatic castration resistant prostate cancer (mCRPC) requires a close follow-up to detect a progression and then to adapt the treatment. In that context, a national survey was proposed to a group of experts and the aim was to identify the modalities of surveillance in different clinical situations. METHODS: A questionnaire was sent to 1464 urologists, medical oncologists and radiotherapists, about a clinical case; it was about a patient presenting a prostate cancer, evolving from a biologic progression after radical prostatectomy to a situation of metastasis resistant to the castration. The questionnaire contained ten questions about reasons of changing treatment because of progression, and about modalities of the follow-up. RESULTS: A total of 318 questionnaires were analyzed (response rate of 22%). The results showed comparable practices between the different types of specialists, even if a more frequent rhythm of surveillance was reported by medical oncologists and radiotherapists. At progression after radical prostatectomy, a clinical and biological surveillance was generally realized every 3 or 6 months, and imaging exams were done on demand. Then, as the cancer progresses, the surveillance became systematic and more and more close, with imaging done every 3 months or on demand. While the definition of progression was essentially based on PSA testing at the beginning of the castration resistance, it then combines different clinical, biological and radiological criteria. CONCLUSIONS: There are few recommendations available about follow-up of patients with a mCRPC. In that survey, the oncologists and urologists reported a more intensive rhythm of surveillance as the prostate cancer progresses. LEVEL OF EVIDENCE: 4.

Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer.

BACKGROUND: High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. METHODS: In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher's exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. RESULTS: In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67-positive CTC (p = 0.228), but OS was significantly reduced in the Ki67-positive CTC group (median 512 days vs 751 days, p = 0.0091). No changes in relative proportion of vimentin- or Ki67-positive CTCs were observed in post-treatment samples compared to baseline. CONCLUSIONS: Analysis of vimentin and Ki67 expression can straightforwardly be assessed in CTCs from patients with mCRPC. Poorer survival outcomes were observed in vimentin- and Ki67-positive CTC patients. TRANSLATIONAL STUDY PROTOCOLS: CEC-CTC (IDRCB2008-AOO585-50) and Petrus ( NCT01786031 ).

[Neuroendocrine carcinoma of the digestive tract: a literature review]. / Carcinome neuro-endocrine du tractus digestif : revue de la littérature.

Neuroendocrine carcinoma is a rare and agressive malignant tumor, mainly developing at the expense of the respiratory and of the digestive tract. Among the digestive tract, appendix, small bowel, and pancreas are the preferential sites of involvement, other locations have been more rarely reported. Neuroendocrine digestive tumors may present with various symptoms in relationship with their localization and a complex pathophysiology. Diagnosis is often made at an advanced stage, explaining partly the bad prognosis of these tumors. The optimal management of digestive neuroendocrine tumors is rendered difficult by their rarity and by a low number of randomized trials. We review the literature regarding epidemiologic and prognostic features of these rare tumors, their diagnostic and therapeutic care. Potential complications are also discussed.

[Fever and cancer: components of diagnosis for optimal management]. / Fièvre et cancer : éléments de diagnostic pour une prise en charge adaptée.

Fever is defined as a body temperature above 37.8°C in the absence of antipyretic drug. It is a frequent and potentially severe event and its interpretation can be difficult in patients with solid tumors. It is usually alleged that more than half of cancer patients will be affected by the occurrence of this event during the course of their disease. Underlying causes are multiple but most frequent and severe causes include infections, the most life-threatening causes being, firstly, febrile neutropenia and secondly, healthcare-associated infections and more particularly infections related to catheter. Opportunistic infections are much less frequent than in hematology oncology but clinicians should be aware of two severe opportunistic infections: systemic candidiasis and Pneumocystis jiroveci pneumonia. Fever related to paraneoplastic or tumor necrosis complicates the diagnosis process. Other common causes of fever include venous thromboembolic disease or more rarely treatment related fever. We aim at examining the optimal diagnostic and therapeutic strategies when facing a cancer patient with fever.

A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas.

BACKGROUND: Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay). METHODS: Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch according to the manufacturer's protocol and ISET by studying cytomorphology and immunolabelling with anti-cytokeratin or lineage-specific antibodies. RESULTS: Concordant results were obtained in 55% (11 out of 20) of the patients with breast cancer, in 60% (12 out of 20) of the patients with prostate cancer and in only 20% (4 out of 20) of lung cancer patients. CONCLUSION: Our results highlight important discrepancies between the numbers of CTC enumerated by both techniques. These differences depend mostly on the tumour type. These results suggest that technologies limiting CTC capture to EpCAM-positive cells, may present important limitations, especially in patients with metastatic lung carcinoma.

[Targeting KRAS pathway in NSCLC therapy]. / Stratégies thérapeutiques ciblant la voie KRAS dans le cancer bronchique non à petites cellules.

KRAS mutations are currently the most frequently mutated oncogenes in non-small cell lung cancers (NSCLC). A growing body of evidence suggests that targeting RAS could be an efficient strategy in NSCLC. Several approaches have been developed to target either RAS protein or downstream effectors such as RAF or MEK. First clinical trials evaluating farnesyltransferases inhibitors have led to unsuccessful results. However, targeting RAF and MEK could be a more efficient approach in NSCLC.

[Managing nausea and vomiting in thoracic oncology]. / Prise en charge des nausées et vomissements en oncologie thoracique.

Nausea and vomiting are frequent symptoms that deteriorate the quality of life of lung cancer patients. They are most often iatrogenic and related to chemotherapy based on platinum salts; they can also be evidence of metastasis to the brain or hypercalcemia. Understanding the physiopathological mechanisms at work can make it possible to adopt effective therapeutic measures that are specific to each etiological context.

[Prostate cancer and disseminated intravascular coagulation: review of the literature]. / Cancer de prostate et coagulation intravasculaire disséminée: une revue de la littérature.

Disseminated intravascular coagulation is a rare complication of prostatic cancer evolution. Occurring on hormonorefractory phase, it remains most often infraclinic. Cases of acute, severe intravascular disseminated coagulation at first presentation are life-threatening because of hemorragic and thrombotic complications, justifying emergency medical treatment. In the light of a review of literature, we insist on epidemiological features, physiopathology and therapeutics of intravascular disseminated coagulation. In spite of a pejorative prognosis, this could help to achieve a period of remission.

[Cancer chemotherapy of the upper aerodigestive tract]. / Chimiothérapie des cancers des voies aérodigestives supérieures.

Tumours of the upper aerodigestive tract represent the sixth most frequent kind of cancer in France and throughout the world. If the localised forms may be controlled in the long run in two thirds of cases by surgery or radiotherapy, only one third of locally advanced forms are accessible to a cure after association from radiotherapy and chemotherapy. Besides, with a median of survival less than six months, metastatic tumours present a catastrophic spontaneous prognosis among patients with a medical ground that is often heavily deteriorated by prolonged exposure to alcohol and tobacco. Thus, there is a necessity to implement adapted therapeutic strategies to each patient and based on satisfactory proof levels of effectiveness. Optimisation of existing chemotherapy protocols and development of new therapies, in particular of targeted therapies, remain an important objective in the hope to improve results of treatments in locally advanced and metastatic cancers of the oral cavity.

[Favorable outcome of gemcitabine-induced acute respiratory distress syndrome]. / Syndrome de détresse respiratoire aiguë à la gemcitabine d'évolution favorable.

Gemcitabine is a new important drug used to treat solid tumors including non-small cell lung cancer, pancreatic, bladder and breast cancers. Myelosuppression is the most common adverse effect. Pulmonary toxicity is rare and usually mild and self-limiting with acute dyspnea. Severe pneumonitis and potentially fatal acute respiratory distress syndrome (ARDS) have been described in patients treated for a non-small cell lung cancer. We report a case of gemcitabine-induced ARDS in a 72-year old patient treated with gemcitabine and cisplatin for a bladder cancer without lung metastasis. Administration of high doses of corticosteroids led to a prompt symptomatic improvement.

[Combined chemotherapy and radiation therapy for intracranial germinomas. The Val-de-Grace hospital experience]. / Intérêt de la chimiothérapie néoadjuvante dans le traitement des séminomes purs intracérébraux: expérience de l'hôpital du Val-de-Grâce.

Optimal management of intracranial germinomas remains controversial. Focal irradiation to the primary tumor followed by prophylactic craniospinal radiotherapy represents the traditional treatment resulting in excellent long-term survival but potential late effects. To decrease late effects related to extensive fields of radiotherapy, combined chemotherapy and irradiation has been tested with reduced volumes and doses of radiation therapy. We report our experience about four patients successfully treated by neoadjuvant chemotherapy with carboplatin and etoposide followed by radiotherapy delivering 26 to 36 Gy to the whole brain and 36 to 50 Gy to the initial tumor volume.

[Spinal cord compression from a malignant pleural mesothelioma]. / Compression médullaire par extension intra-canalaire d'un mésothéliome pleural malin.

Thoracoscopy-talc led to the diagnosis of epithelial pleural mesothelioma in a 58-year-old man who presented with pleurisy. The course was rapidly unfavorable despite systemic chemotherapy. Dorsal pain revealed invasion of the spine and spinal canal leading to cord compression three months after the diagnosis of mesothelioma.

[Radiotherapy in stage I testicular seminoma: retrospective study and review of literature]. / Radiothérapie des séminomes testiculaires de stade I : étude rétrospective et revue de la littérature.

INTRODUCTION: Seminoma accounts for about 40% of germ cell tumours of the testicle. In this retrospective analysis, we review literature concerning management of stage I seminoma. MATERIALS AND METHODS: Between March 1987 and April 2001, 65 patients with stage I pure testicular seminoma received adjuvant radiotherapy with a 25 MV linear accelerator. RESULTS: Median age was 33 years. Testicular tumour has been found on the right testis in 39 patients and on the left one in 24 patients. Patients have been treated using an anterior-posterior parallel pair and have received 20-25 Gy in 10-14 fractions. The target volume consisted of paraaortic, and paraaortic + homolateral iliac lymph nodes in 17 and 46 patients, respectively. Acute toxicity was mainly digestive, 38% of patients presenting nausea and vomiting. Median follow-up time was 37 months. All patients are alive in complete remission. DISCUSSION: Because of good radio-sensitivity of seminoma, radiotherapy is regarded as standard adjuvant treatment (5 years relapse rate: 3-5%). Acute toxicity is dominated by moderate gastro-intestinal side effects. Secondary neoplasia represents one of the worst possible long-term complications of therapy. Waiting for ongoing randomised trials, the modern literature for seminoma reflects a trend toward lower radiation doses (20-25 Gy) and smaller treatment volumes (paraaortic field). Adjuvant chemotherapy with two courses of carboplatin, might be equivalent to radiotherapy but must be investigated in randomised trials. A surveillance policy is one of the other management options less recommended.