Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial.

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

[Pulmonary blastoma in an adult]. / Le pneumoblastome de l'adulte.

The authors report the case of a 24-year-old woman in complete remission 4 years after treatment for a biphasic pulmonary blastoma. After a left lower lobectomy, the patient developed a local recurrence that was treated by chemotherapy. In the light of this case, the authors review the clinical, radiological and therapeutic features of this very rare malignant lung tumour.

[Second-line therapy in patients with malignant pleural mesothelioma. A French retrospective study (2005-2006)]. / Traitement de seconde ligne dans le mésothéliome pleural malin. Étude rétrospective française (2005-2006).

BACKGROUND: The role of second-line chemotherapy (SLC) has still not been established in malignant pleural mesothelioma (MPM) but SLC is increasingly used because many patients are still fit at the time of the progression of the disease. METHODS: In this retrospective study, the authors reviewed their experience with SLC in pemetrexed-pretreated patients with MPM at two French thoracic oncology units (institut Gustave-Roussy, Villejuif, and hôpital d'Instruction des Armées Percy, Clamart). RESULTS: Between January 2005 and December 2006, 84 consecutive patients with progressing MPM after pemetrexed chemotherapy were enrolled. Forty-four patients received an SLC. There were 30 men and 14 women. The median age was 58 years (range: 34 to 76 years). Most patients had a performance status (PS) less than or equal to 1 (82%) and an epithelial histological subtype (91 %). The median time to progression (TTP) after first-line chemotherapy was 6.1 months. The SLC was a pemetrexed therapy in 21 patients and a new regime in 20 patients (gemcitabine alone or with oxaliplatin). The other three patients were enrolled in a phase I study. According to the Recist criteria, a partial response was observed in four patients and the disease was stabilised in six patients after SLC. The median TTP after SLC was 3.8 months. The median survival was 12.2 months (range: 2 to 72 months). Four of these 44 patients then received third-line (4.8 %) and two received fourth-line therapy (2.4 %). CONCLUSIONS: This experience indicates the feasibility of administering SLC in patients with MPM who are healthy at the time of the progression of the disease. The optimal treatment has not been defined to date and prospective trials are needed.

[Evaluating the nutritional status of a lung cancer patient is an important element in patient management]. / L'évaluation du statut nutritionnel du patient suivi pour un cancer bronchique est un élément important de la prise en charge.

Nutritional status assessment during the comprehensive management of patients treated for cancer is becoming increasingly necessary. Various data are currently available which show a relationship between the nutritional status and certain morbidity-mortality parameters. In contrast, there is a paucity of data concerning lung cancer. A relationship between survival and the nutritional status has been found in the literature, exclusively in advanced stages of lung cancer. Unlike that observed in oncological digestive tract surgery, where artificial nutrition is recommended preoperatively in severely malnourished patients, no link has been evidenced between postoperative morbidity and mortality and the preoperative nutritional status in lung surgery. The scientific nutritional societies simply recommend preoperative nutritional assessment. Reflection on management of malnourished patients receiving chemotherapy is still "archaic" and recent studies and recommendations are lacking. Although largely prescribed, oral nutritional supplements have not proven efficient and patient compliance will probably have to be improved. According to "good nutrition practice" rules, the digestive tube should be used when it is functional and in theory, enteral nutrition is indicated in this situation. In addition to the lack of clinical studies, one of the obstacles to its use is cultural with the need to obtain not only patient approval but also that of the prescriber. Parenteral nutrition was discredited in earlier studies. It should probably be reevaluated in the context of new chemotherapeutic molecules and a different way of handling nutrition care. The physiological concept of omega-3 fatty acid modulation of inflammation is of interest in animal studies but the clinical modalities of use remain to be defined and determined. The role of nutrition in the management of lung cancer is still very limited but there are major expectations and many solutions are awaited in the coming years.

[Fever and infectious complications in patient with lung cancer]. / Fièvre et complications infectieuses chez un patient porteur d'un cancer bronchique.

The respiratory infections are very frequent during lung cancer. Their diagnosis is often difficult because of the various etiologies (cancer, chemotherapy, radiotherapy) and this complexity can make discuss a preliminary bronchial exploration before any therapeutics. When it is about a located infection, germs in cause are often the same that in the community respiratory infections, in particular bacilli Gram negative, and it is thus logical to treat by the penicillin A. In front of an interstitial syndrome, it is necessary to evoke the opportunist infections, which are increasing in patients with cancer because of the multimodality therapeutic and the elongation of the survival. The neutropenic patient must be distinguished because of its specificities. The pulmonary infections lead to an important mortality. According to the patient (advanced age, underlying chronic obstructive pulmonary disease [COPD]) and to the treatment (chemotherapy, pneumonectomy), prevention must be discussed as the pneumococcal and Haemophilus influenzae vaccination.

[Malignant pleural mesothelioma: interrogations and hopes concerning the expected epidemic]. / Le mésothéliome pleural malin: incertitudes et espoirs face à une épidémie annoncée.

Malignant pleural mesothelioma (MPM) is a rare incurable tumor. Interest in MPM has increased in recent years due to a steadily increasing incidence subsequent to the intensive use of asbestosis, the main causal agent, but also due to better awareness in the political and scientific communities faced with a serious public health issue. Our knowledge of MPM has improved regularly in terms of pathologic diagnosis and the mechanisms underlying the mesothelial carcinogenesis. MPM is also the subject of many technological innovations as illustrated by the recent identification of new biological markers, access to metabolic imaging, and clinical research on targeted treatments. Proper management implies the participation of the general population since the implementation of administrative procedures for social indemnities. In 2007, a more aggressive therapeutic approach is becoming common practice with the use of radiotherapy and the emergence of the concept of multimodal care centered on wide pleuropneumonectomy. These advances create real hope for improvement, but also many interrogations since no standard treatment protocol has been clearly identified.

[Thymic tumors]. / Tumeurs épithéliales thymiques.

Thymomas and thymic carcinomas are rare and slow-growing tumors, which develop within the anterior mediastinum. Thymomas are often associated with autoimmune disorders and most particularly myasthenia gravis. The treatment of choice remains a complete surgical resection. Postoperative radiotherapy is often combined in case of invasive thymoma invading into adjacent organs. Postoperative radiotherapy in stage II with invasion into capsule has been more controversial lately. In inoperable locally advanced, or metastatic thymic tumors, neoadjuvant cisplatin-based followed by surgery and radiotherapy has given interesting results in the past years.

[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.

[Modalities of radiotherapy in small cell lung cancer: thoracic radiotherapy and prophylactic cerebral irradiation]. / Modalités de la radiothérapie dans les carcinomes bronchiques à petites cellules: radiothérapie thoracique et irradiation prophylactique cérébrale.

Small cell lung cancers (SCC) represent 20% of all lung cancers. After the initial control of the extension, only one third of the patients with SCC will finally have limited disease. The treatment of limited SCC currently relies on chemo-radiotherapeutic combinations that have improved overall survival and survival without metastases over the last few years. Nevertheless, even in limited forms, survival at 5 years varies from 10 to 15% and rarely exceeds 25% in the best series. The risk of relapse is high: although around 70% of patients with a limited form will have complete response, only 15 to 20% of them will exhibit prolonged survival. Indeed, most patients relapse, and the risk of cerebral dissemination for example is particularly high, reaching 50% at 2 years even in complete responders. After the results of a meta-analysis evaluating prophylactic cranial irradiation (PCI) among SCC complete responders, demonstrating 5% enhancement of survival at 3 years, PCI is part of the standard management of SCC in complete response. Despite the improvement in overall survival with the combined treatments, the mediocre results observed in terms of long-term survival warrant further clinical trials in order to define the optimal polychemotherapeutic and radiotherapeutic modalities, the best means of combining these two therapies and the place for new therapies.

The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option?

Due to their rarity, only few trials have studied the role of the doxorubicin-streptozotocin (DS) combination in advanced well-differentiated pancreatic endocrine carcinomas (AWDPEC). However, the published results are inconsistent. We reviewed all AWDPEC (5-year period, 45 patients) treated in our institution with the DS combination for: objective response rate (ORR), progression-free survival, overall survival (OS) and toxicity. An ORR of 36% (95% Confidence Interval (CI) 22-49) was obtained, with 16 partial responses (PR). The mean duration of PR was of 19.7 months. Two and 3-year OS rates were 50.2 and 24.4%, respectively. Toxicities were mainly digestive (grade > or =3 vomiting, 13%) and haematological (grade > or =3 neutropenia, 24%). Previous systemic chemotherapy and malignant hepatomegaly were associated with a poorer ORR (P=0.033, P=0.016) and OS (P=0.008, P=0.045). Multivariate analysis demonstrated previous chemotherapy as the only independent predictive-factor for survival (P=0.013). In conclusion, our data confirm the sensitivity of AWDPEC to the DS combination, with an ORR of 36% and a remarkable median response duration of 19.7 months, and suggests that it could be considered as a valid option in first-line therapy.

Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study.

PURPOSE: The aim of this open-label phase II study was to evaluate the activity of raltitrexed (Tomudex; AstraZeneca, Cergy, France) and oxaliplatin combination therapy in patients with diffuse malignant pleural mesothelioma. PATIENT AND METHODSs: Fifteen pretreated and 55 chemotherapy-naive patients (median age, 60 years; World Health Organization performance status of < or = 2) were enrolled. Most patients (66%) had advanced disease. Patients received raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 3 weeks. RESULTS: Twenty-four patients (34%) were classified as having a poor prognosis. In the overall study population, 14 patients (20%) had a partial response, and 32 patients (46%) had stable disease. The symptomatic response rates were as follows: shortness of breath, 36%; pain, 30%; activity, 23%; appetite, 21%; and asthenia, 20%. Median time to disease progression was 18 weeks (95% confidence interval [CI], 13 to 22 weeks). In chemotherapy-naive patients, median survival was 31 weeks (95% CI, 23 to 40 weeks) from the start of treatment and 49 weeks (95% CI, 40 to 52 weeks) from diagnosis of mesothelioma. In pretreated patients, median survival was 44 weeks (95% CI, 24 to 40 weeks) from the start of treatment and 226 weeks (95% CI, 63 to 292 weeks) from the diagnosis of mesothelioma. Overall 1-year survival was 26% (95% CI, 15.5% to 36.4%), survival was 22% (95% CI, 10.9% to 33.2%) in chemotherapy-naive patients and 40% (95% CI, 15.2% to 64.8%) in pretreated patients. Hematologic toxicity was mild, and there was no alopecia. The most common adverse events were asthenia, nausea/vomiting, and paraesthesia, and no treatment-related deaths were reported. CONCLUSION: The raltitrexed and oxaliplatin combination is an active outpatient regimen in malignant mesothelioma and has an acceptable tolerability profile.

[Pulmonary carcinosarcoma with jejunal metastasis: complete response to chemotherapy]. / Carcinosarcome pulmonaire avec métastase jéjunale et réponse complète à la chimiothérapie.

We report a case of pulmonary carcinosarcoma with jejunal metastasis. The lung is an exceptional localization for carcinosarcoma, a tumor with carcinomatous and sarcomatous components. These two components are closely related but well-defined morphologically and immunohistochemically. Risk of metastasis and local recurrence is high. Surgery is the treatment of choice for localized forms. Prognosis depends on the sarcomatous component which is usually sensitive to chemotherapy, with at least doxorubicin and ifosfamide. This rare case illustrates the potential for jejunal metastasis and complete response to chemotherapy, proven histologically at 33 months.

Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma.

BACKGROUND: The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC). METHODS: Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m(2), respectively. RESULTS: Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m(2)) and oxaliplatin (85 mg/m(2)) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated (167 cycles) at that dose level. Thirteen cycles were associated with grade 3-4 non-febrile neutropenia in six patients, and eight cycles with grade 3-4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m(2) experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70-100 mg/m(2). Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients. CONCLUSIONS: The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m(2) and oxaliplatin 85 mg/m(2) every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

[Malignant pleural mesothelioma. From diagnosis to prognosis]. / Le mésothéliome pleural malin. Du diagnostic au pronostic.

EPIDEMIOLOGY: The incidence of malignant pleural mesothelioma has constantly increased over the past forty years. The recent measures of ban on the use of asbestos and the long latency of this tumor after exposure means that its peak incidence can be foreseen for the years 2010-2020. DIAGNOSIS: Various health professionals are involved in the care of this tumor, which benefits equally from progresses in clinical and fundamental research. Some progress has been made in understanding its oncogenesis as well as its histopathologic analysis. PROGNOSIS: Malignant pleural mesothelioma symptoms are rapidly invalidating and the patient's prognosis is bad at short-term. However, hope may come from the detection of early stages of the disease and from the individualization of good prognosis factors, permitting the selection of patients for whom some curative therapies are in course of evaluation.

[Malignant pleural mesothelioma. Present data and perspectives for treatment]. / Le mésothéliome pleural malin. Données actuelles et perspectives pour le traitement.

CHEMOTHERAPY: With regard to the efficacy of mono-chemotherapy and according to the literature, no cytotoxic substance, apart from methrotrexate at high doses, leads to a response rate of more than 20%. With regard to cyrotoxic associations, the published results show slightly betterresponse rates. IMMUNOTHERAPY: Interleukine 2 as well as various interferons have been tested alone or in association with chemotherapy. Fairly encouraging response rates have been reported. However, the possibility of severe adverse events must be taken into account. RADIOTHERAPY: The interest of prophylactic parietal radiation following invasive thoracic treatment has been demonstrated. Palliative use of radiotherapy is possible for pain, and more rarely for decompression. With curative aim, the results of isolated radiotherapy are disappointing. SURGERY: Palliative surgery is aimed at reducing the tumour and pleural symphysis. Curative surgery consists in wide extrapleural pneumonectomy, permitting total resection of the visceral pleura, or decortication pleurectomy leaving the lung in place. Mean survival of patients having undergone surgery is of 10 to 17 months with rates between 10 and 30% at 2 years ASSOCIATED THERAPY: For the first time, despite high morbidity rates, associated therapy has led to prolonged survival, whereas isolated therapy has not. This is the case with an association of radical surgery, radiotherapy and adjuvant chemotherapy. IN THE FUTURE: In the treatment of malignant pleural mesothelioma, genetic, anti-proliferative and immune therapy, that attempt to use the immune system of the patient to obtain an anti-tumour cytotoxic reaction, appear promising.