Reduced risk of secondary primary extra pulmonary cancer in advanced/metastatic lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Lung cancer survivors are at high risk of developing a second primary cancer (SPC). We explored the Unicancer Epidemiology Strategy Medical-Economics for advanced or metastatic lung cancer (AMLC) database to assess the impact of immune checkpoint inhibitors (ICI) on the risk of SPC in patients with advanced/metastatic lung cancer. PATIENTS AND METHODS: This retrospective study used data from patients with AMLC, with treatment initiated between January 1st 2015 and December 31st 2018. Patients with lung cancer as the second primary cancer were excluded and a 6-months landmark threshold was applied to exclude patients with synchronous SPC, patients dead without SPC or with a follow-up inferior to 6 months. A propensity score (PS) was calculated on the following baseline covariates: Age at locally advanced or metastatic diagnosis, sex, smoking status, metastatic status, performance status and histological type. The inverse probability of treatment weighting approach was used on the analyses aiming to assess the impact of ICI administered for AMLC, on the risk of occurrence of SPC. RESULTS: Among the 10 796 patients, 148 (1.4%) patients had a diagnosis of SPC in a median interval of 22 (min-max: 7-173) months. All the patients (100%) with locally advanced or metastatic LC received at least one systemic treatment including (chemotherapy regimen (n = 9 851, 91.2%); ICI (n = 4 648, 43.0%); targeted treatment (n = 3 500; 32.4%). 40 (0.9%) SPC were reported in the 4 648 patients with metastatic LC treated with ICI vs 108 (1.7%) out of the 6 148 who did not receive immunotherapy (p < 0.0001). The multivariate analysis identified that treatment with ICI in patients with AMLC is associated with a reduced risk of SPC (HR = 0.40, 95% CI 0.27-0.58). CONCLUSION: Treatment with ICI in AMLC patients was associated with a significantly reduced risk of SPC. Prospective studies are required to confirm these results.

RADIORYTHMIC: Phase III, Opened, Randomized Study of Postoperative Radiotherapy Versus Surveillance in Stage IIb/III of Masaoka Koga Thymoma after Complete Surgical Resection.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that may be aggressive and difficult to treat. Knowledge and level of evidence for treatment strategies are mainly based on retrospective studies or expert opinion. Currently there is no strong evidence that postoperative radiotherapy after complete resection of localized thymoma is associated with survival benefit in patients. RADIORYTHMIC is a phase III, randomized trial aiming at comparing postoperative radiotherapy versus surveillance after complete resection of Masaoka-Koga stage IIb/III thymoma. Systematic central pathologic review will be performed before patient enrollment as per the RYTHMIC network pathway. PATIENTS AND METHODS: Three hundred fourteen patients will be included; randomization 1:1 will attribute either postoperative radiotherapy (50-54 Gy to the mediastinum using intensity-modulated radiation therapy or proton beam therapy) or surveillance. Stratification criteria include histologic grading (thymoma type A, AB, B1 vs B2, B3), stage, and delivery of preoperative chemotherapy. Patient recruitment will be mainly made through the French RYTHMIC network of 15 expert centers participating in a nationwide multidisciplinary tumor board. Follow-up will last 7 years. The primary endpoint is recurrence-free survival. Secondary objectives include overall survival, assessment of acute and late toxicities, and analysis of prognostic and predictive biomarkers. RESULTS: The first patient will be enrolled in January 2021, with results expected in 2028.

[Management of immune-related toxicities associated with immune checkpoints inhibitors: Data from the multidisciplinary meeting « ToxImmun ¼ in Eastern Occitania]. / Gestion des toxicités induites par les inhibiteurs de checkpoint immunologique : données de la réunion de concertation pluridisciplinaire « ToxImmun ¼ en Occitanie Est.

Immune checkpoint inhibitors (ICIs) can cause numerous and complex immune-related adverse events whose management need a multidisciplinary approach. Herein, we investigated 114 requests, mostly concerning patients suffering from lung cancer, that were submitted to the « ToxImmun ¼ multidisciplinary meeting in Eastern Occitania between December the 17th 2018 and January the 20th 2020. The leading reasons for the request concerned the putative causal link between immunotherapy and immune-toxicity and its management, followed by possible retreatment after temporary withdrawn because of adverse event, and finally the possibility to initiate ICIs in patients with pre-existing autoimmunity. Colitis, hepatitis and myocarditis were the most frequent immune-related adverse events (IRAEs), both all grade and grade 3-4. Sicca syndrome (with or without Sjogren criteria) was also frequent (26% of cases) and seems to be associated with severe toxicity and multi-toxicity. The mean time to first IRAE was 3.8 months, a time shortened with the use of anti-PD-L1 agents or ICI combination. A majority of requests came from initial evaluation by the internist confirming the early and main role of this specialty in the management of immunotoxicity. Expansion of this regional multidisciplinary meeting, coordinated by internists and medical oncologists, could improve management of immune-related adverse events for the patients' benefits.

Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.

BACKGROUND: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. PATIENTS AND METHODS: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications. CONCLUSION: Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02304809.

Challenging BRAF/EGFR co-inhibition in NSCLC using sequential liquid biopsies.

OBJECTIVES: There is some controversy surrounding theBRAFV600E mutation in patients with lung adenocarcinomas. Although the BRAFV600E mutation is sensitive to BRAF inhibitors, the efficiency of these inhibitors on patients harboring an EGFRL858R/del19/EGFRT790M/BRAFV600E pattern remains unknown. MATERIALS AND METHODS: Here, we presented the case of a patient with initial response followed by progression on osimertinib. Resistance mutations (EGFRT790M, EGFRC797S, BRAFV600E, MET amp and HER2 amp) were assessed in the tissue or plasma DNA using NGS and digital droplet PCR at progression and during osimertinib treatment. RESULTS: Resistance to osimertinib coincided with the emergence of an additional tumor cell subpopulation carrying the knownBRAFV600E resistance mutation. The patient exhibited two tumor subclones (EGFRdel19/T790M and BRAFV600E) that displayed distinct responses to successive tyrosine kinase inhibitors. CONCLUSION: We report the first successful example of using sequential treatment with dabrafetinib/trametinib and osimertinib. Our finding provided that unique tumor biopsies deliver incomplete genetic information, and highlighted the complementary role of circulating tumor DNA to tissue biopsies and CT-scans to efficiently monitor response to osimertinib.

Effects of cigarette smoking on reproduction.

BACKGROUND Cigarette smoking is associated with lower fecundity rates, adverse reproductive outcomes and a higher risk of IVF failures. Over the last few decades, prevalence of smoking among women of reproductive age has increased. This review focuses on current knowledge of the potential effects of smoke toxicants on all reproductive stages and the consequences of smoke exposure on reproductive functions. METHODS We conducted a systematic review of the scientific literature on the impact of cigarette smoking and smoke constituents on the different stages of reproductive function, including epidemiological, clinical and experimental studies. We attempted to create hypotheses and find explanations for the deleterious effects of cigarette smoke observed in experimental studies. RESULTS Cigarette smoke contains several thousand components (e.g. nicotine, polycyclic aromatic hydrocarbons and cadmium) with diverse effects. Each stage of reproductive function, folliculogenesis, steroidogenesis, embryo transport, endometrial receptivity, endometrial angiogenesis, uterine blood flow and uterine myometrium is a target for cigarette smoke components. The effects of cigarette smoke are dose-dependent and are influenced by the presence of other toxic substances and hormonal status. Individual sensitivity, dose, time and type of exposure also play a role in the impact of smoke constituents on human fertility. CONCLUSIONS All stages of reproductive functions are targets of cigarette smoke toxicants. Further studies are necessary to better understand the deleterious effects of cigarette smoke compounds on the reproductive system in order to improve health care, help to reduce cigarette smoking and provide a better knowledge of the molecular mechanisms involved in reproductive toxicology.

[The contribution of cognitive-behavioural therapies to smoking cessation]. / Apport des thérapies cognitivo-comportementales dans le sevrage tabagique.

INTRODUCTION: Behavioural therapies have been developed on the basis of Pavlov's and Skinner's learning theories. They have recently benefited from advances in the understanding of information handling and the organisation of perceptions of experience. It is for these two reasons that these treatments are called cognitive behaviour therapies (CBT). They have now achieved an important role in the treatment of addictions including tobacco smoking. Currently CBT's are seen as promising because they rely on cognitive restructuring combined with learning of new behaviour while following a process appropriate to the changing dynamic of the smoker. BACKGROUND: They have recently been recognised as of grade A effectiveness by the French Institute of Medical Research and may be recommended to all smokers whose primary intention is to stop. The establishment of a collaborative rapport and a therapeutic attitude are essential. They may be used during the three stages of cessation: preparation, stopping, and the prevention of relapse. A personalised functional analysis provides the patient with a management program using behavioural and, above all, cognitive techniques. The ideal is to combine a pharmacological and an optimised cognitive-behavioural approach. VIEWPOINT: The management of smoking patients has advanced with the understanding of a very complex problem, often associated with anxiety-depressive co-morbidities and other addictions. Tobacco specialists, psychiatrists, cognitive-behavioural therapists and addiction therapists must work together in the future, particularly in respect of research protocols. CONCLUSIONS: Cognitive-behavioural therapy is a useful technique in the personalisation and optimisation of management of the patient, particularly in the prevention of relapse. However, the evaluation of CBT is difficult methodologically and there are few studies evaluating CBT alone. On the other hand, CBT is effective, particularly where there are anxiety or depressive co-morbidities or other addictions that are found more and more frequently during consultations for tobacco smoking.

[Smoking cessation in patients with lung cancer]. / Indications et méthodes d'aide au sevrage tabagique chez un patient fumeur atteint de cancer bronchique.

Smoking cessation is an important part of the management of patients with lung cancer. Continued smoking has been found to diminish treatment efficacy, to exacerbate side effects and to have a detrimental effect on survival. Smoking increases postoperative pulmonary complications and tolerance and efficacy of medical treatment (chemotherapy, targeted therapy, radiotherapy) are diminished. Moreover, the quality of life of current smokers is lower and the risk of a second primary malignancy is increased. Hospitalization is a good opportunity to propose smoking cessation. Clinical practice guidelines recommend the use of combined behavioral and pharmacological therapies. The efficacy of smoking cessation programs for cancer patients has been demonstrated. There is a clear dose-response relationship between number of contacts, intensity level of person-to-person contact and total amount of contact time. Multidisciplinary approaches increase abstinence rates. First line phamacotherapies (nicotine replacement therapy and sustained-release antidepressant bupropion) have been found to be safe and effective. Varenicline is a new drug for smoking cessation but it remains to be evaluated in oncology patients.

[Treatment of epithelial thymic tumours: towards a multidisciplinary management]. / Traitement des tumeurs épithéliales thymiques.

INTRODUCTION: Thymic epithelial tumours (TET) are rare. Their optimal management is still not well defined on account of their rarity and the consequent difficulty of clinical research into the subject. This review presents the current clinical and therapeutic data, emphasising the need for a multidisciplinary management of advanced stage TET. CURRENT SITUATION: Three situations may be defined: localised tumours requiring radical surgery following a careful search for associated paraneoplastic syndromes; tumours with capsular invasion requiring surgery and adjuvent radiotherapy; advanced stage TET where only multimodal treatment is capable of improving the prognosis by increasing the percentage of complete resections while optimising local control with adjuvent radiotherapy. VIEWPOINT: An evaluation of the multimodal strategies for the treatment of advanced stage TET requires the establishment of multidisciplinary collaborative trials. The contribution of new therapies, somatostatin analogues and targeted therapies needs to be defined. CONCLUSIONS: The management of advanced stage TET should rest upon a multidisciplinary dialogue between a team of specialists, ideally in the framework of collaborative trials.

[Small cell lung cancer (CPC). Small cell bronchial carcinoma: therapeutic management]. / Les cancers à petites cellules (CPC). Prise en charge thérapeutique.

Small cell bronchial carcinoma holds a prominent position among malignant tumours on account of its high incidence and the problems of its treatment. The diagnostic approach is dictated by the concern not to overlook any metastatic sites. Small cell bronchial carcinoma is often metastatic at the time of diagnosis and should be considered an actual or potential systemic disease. Chemotherapy is therefore the basis of treatment. It should consist of at least a two drug regime combining cisplatin and etoposide. In extensive disease, that is when all the disease cannot be contained within one irradiation field, chemotherapy alone is recommended. In limited disease combined simultaneous radiotherapy and chemotherapy is recommended. Prophylactic cranial irradiation is indicated in patients in complete remission after chemotherapy. The therapeutic armamentarium has recently been enlarged by the development of new antineoplastic drugs and the development of non-toxic targeted agents including those influencing angiogenesis. The understanding of the specific mechanisms of drug resistance and the study of the tumour phenotypes and genotypes will allow, in the future, the development of treatments adapted for each patient.

Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin.

BACKGROUND: This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine-docetaxel (GD) combination versus cisplatin-vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m(2) days 1 and 8 plus docetaxel 85 mg/m(2) day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m(2) day 1 plus vinorelbine 30 mg/m(2), days 1, 8, 15 and 22, every 4 weeks for six cycles). RESULTS: A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83-1.32], and for overall survival, it was 0.90 (95% CI 0.70-1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively. CONCLUSIONS: There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.

[Do combinations without cisplatin represent an alternative to conventional chemotherapy in non-small cell lung cancers?]. / Les associations sans platine: une alternative aux chimiothérapies conventionnelles des cancers bronchiques non à petites cellules?

Chemotherapy of advanced non-small cell lung cancers is based on cisplatin, which prolongs survival. However, the high toxicity of double-type combinations including cisplatin warrants the search for alternatives. New anti-cancer cytotoxic agents exhibit improved efficacy-toxicity ratio. Bitherapy, without cisplatin and with new molecules, provides hope of improvement in survival without deterioration in quality of life. Several randomised trials, already published or presented with mature results, suggest that certain bitherapies with new cytostatic agents are an alternative to the classical cisplatin-based bitherapies. The recent modifications in the guidelines of the American Association of Clinical Oncology take into account these recent results by admitting that "chemotherapy without cisplatin can be used as an alternative to the first-line platin-based chemotherapies". This brief review of the literature underlines the methodological questions raised by the publication of randomised studies essentially assessing gemcitabine-vinorelbine or gemcitabine-taxane combinations, by confronting them with either mono-chemotherapies or reference chemotherapy based on cisplatin. The assessment criteria selected in such studies are discussed.

[Smoking habits, attitudes and knowledges of medical students of Medicine, Pharmacy and Odonto-Stomatology's Faculty of Dakar, Senegal]. / Habitudes de fumer, attitudes et connaissances des étudiants en médecine de la Faculté de Médecine, de Pharmacie et d'Odonto-Stomatologie de Dakar, Sénégal.

INTRODUCTION: Smoking is a public health problem that does not spare the medical profession. We set out to determine the prevalence of smoking in medical students in Dakar and to assess their attitudes and knowledge in the face of this problem. METHODS: A cross sectional study was conducted by means of an auto-questionnaire among 1547 medical students between 3 and 31 May 2001. There were 1061 males (68.6%) and 486 females (31.4%). RESULTS: The overall prevalence of regular or occasional smoking was 34.6%, with 42.8% in the first cycle, 38% in the second and 19% in the third. It was significantly higher among males at 76.4%. The average age of starting smoking ranged from 10 to 22 years and average duration from 5 to 26 years. The influence of fashion was the most frequent initiating factor at 37.4% and 96.6% smoked commercial cigarettes. Nicotine dependence, assessed by the Fagerstrom score, was average in 59.3%, strong in 14% and very strong in 4.7%. 58.8% smoked in public places and 78.2% thought they could give up smoking within the next 5 years. 8.4% were unaware of the effects of tobacco on health and 20.5% of the relationship between tobacco and the diseases quoted. 37.7% of future doctors would not systematically avoid smoking in the presence of patients but 79% wished to ban advertising and 70.4% to ban the use of tobacco in hospitals. 94.4% of students wanted health care workers to be educated about the effects of smoking. CONCLUSIONS: Tobacco smoking among medical students has increased between 1989 (28.7%) and 2001 (35.6%). This observation should stimulate the establishment of a course on the pathology of tobacco smoking and the integration of education and prevention within the medical curriculum, increase the awareness of smokers and above all help them stop.

Dose-finding, pharmacokinetic and phase II study of docetaxel in combination with gemcitabine in patients with inoperable non-small cell lung cancer.

BACKGROUND: The good efficacy-toxicity ratio of both docetaxel and gemcitabine in non-small cell lung cancer (NSCLC) stimulates the investigation of the combination of these drugs as a first line chemotherapy. This two-step study firstly aimed at determining the maximum tolerated and recommended doses of docetaxel given every 3 weeks in combination with a fixed dose of gemcitabine; the phase I study paid particular attention to pharmacokinetics. Afterwards, the safety and efficacy of the recommended dose was carefully assessed in the phase II-step. METHODS: The following range of docetaxel dosages were tested in the phase I study; 60, 75, 85, and 100 mg m(-2) given on day 8 in combination with gemcitabine 1000 mg m(-2) delivered on days 1 and 8 of a 3-week cycle. Haematopoietic growth factors were not allowed. The treatment was delivered on an outpatient basis. Main eligibility criteria consisted of stage III b or IV histologically proven NSCLC, Eastern Co-operative Oncology Group (ECOG) performance status PS < or =2, age < or =70 years, measurable disease, adequate blood counts, chemistry, and no symptomatic brain metastasis. RESULTS: Four centres enrolled 49 patients (eight having been pre-treated); 16 in phase I and 33 in phase II. The maximal tolerated dose was almost reached at the last dose level (i.e. docetaxel, 100 mg m(-2)). Consequently, we considered the 85 mg m(-2) level as the recommended dose. There was a positive relationship of the docetaxel dose to the area under the curve of this drug. Toxicity was assessable in all patients. Among the 200 cycles delivered, 192 were assessable for this feature. Main toxicity was grade 3-4 neutropenia affecting 23 patients (47% of the population; 23% of the cycles). Six febrile episodes were recorded leading to two treatment-related deaths. Another patient died from congestive cardiac failure. In addition, six patients experienced interstitial pneumonitis, (one half considered as severe), two of them having received the recommended dose. All patients recovered from this toxicity after corticosteroids. Fourteen patients out of the whole population (29%; 95% CI [17-43], including ten patients receiving the recommended dose), achieved an objective response. Median follow-up was 14 months (range, 0.3-29.4). Median survival was 11.2 months (95% CI [8.3-13.2]), and the 1-year survival rate was 45%. CONCLUSION: Gemcitabine, 1000 mg m(-2) days 1 and 8 in combination with docetaxel, 85 mg m(-2), day 8, given every 3 weeks could be considered as an active regimen with manageable toxicities in locally advanced or metastatic NSCLC. This study deserves further comparisons with classical platinum-based regimens.

Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data.

In lung cancer, DNA content abnormalities have been described as a heterogeneous spectrum of impaired tumour cell DNA histogram patterns. They are merged into the common term of aneuploidy and probably reflect a high genotypic instability. In non-small-cell lung cancer, the negative effect of aneuploidy has been a subject of controversy inasmuch as studies aimed at determining the survival-DNA content relationship have reported conflicting results. We made a meta-analysis of published studies aimed at determining the prognostic effect of aneuploidy in surgically resected non-small-cell lung cancer. 35 trials have been identified in the literature. A comprehensive collection of data has been constructed taking into account the following parameters: quality of specimen, DNA content assessment method, aneuploidy definition, histology and stage grouping, quality of surgical resection and demographic characteristics of the analysed population. Among the 4033 assessable patients, 2626 suffered from non-small-cell lung cancer with aneuploid DNA content (overall frequency of aneuploidy: 0.65; 95% CI: (0.64-0.67)). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death for patients affected by a nearly diploid (non-aneuploid) non-small-cell lung cancer. Survivals following surgical resection, from 1 to 5 years, were chosen as the end-points of our meta-analysis. Patients suffering from a nearly diploid tumour benefited from a significant reduction in risk of death at 1, 2, 3 and 4 years with respective OR: 0.51, 0.51, 0.45 and 0.67 (P< 10(-4)for each end-point). 5 years after resection, the reduction of death was of lesser magnitude: OR: 0.87 (P = 0.08). The test for overall statistical heterogeneity was conventionally significant (P< 0.01) for all 5 end-points, however. None of the recorded characteristics of the studies could explain this phenomenon precluding a subset analysis. Therefore, the DerSimonian and Laird method was applied inasmuch as this method allows a correction for heterogeneity. This method demonstrated an increase in survival at 1, 2, 3, 4 and 5 years for patients with diploid tumours with respective size effects of 0.11, 0.15, 0.20, 0.20 and 0.21 (value taking into account the correction for heterogeneity;P< 10(-4)for each end-point). Patients who benefit from a surgical resection for non-small-cell lung cancer with aneuploid DNA content prove to have a higher risk of death. This negative prognostic factor decreases the probability of survival by 11% at one year, a negative effect deteriorating up to 21% at 5 years following surgery.

Brain metastases at the time of presentation of non-small cell lung cancer: a multi-centric AERIO analysis of prognostic factors.

A multi-centre retrospective study involving 4 French university institutions has been conducted in order to identify routine pre-therapeutic prognostic factors of survival in patients with previously untreated non-small cell lung cancer and brain metastases at the time of presentation. A total of 231 patients were recorded regarding their clinical, radiological and biological characteristics at presentation. The accrual period was January 1991 to December 1998. Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The median survival of the whole population was 28 weeks. Univariate analysis (log-rank), showed that patients affected by one of the following characteristics proved to have a shorter survival in comparison with the opposite status of each variable: male gender, age over 63 years, poor performance status, neurological symptoms, serum neuron-specific enolase (NSE) level higher than 12.5 ng ml(-1), high serum alkaline phosphatase level, high serum LDH level and serum sodium level below 132 mmol l(-1). In the Cox's model, the following variables were independent determinants of a poor outcome: male gender: hazard ratio (95% confidence interval): 2.29 (1.26-4.16), poor performance status: 1.73 (1.15-2.62), age: 1.02 (1.003-1.043), a high serum NSE level: 1.72 (1.11-2.68), neurological symptoms: 1.63 (1.05-2.54), and a low serum sodium level: 2.99 (1.17-7.62). Apart from 4 prognostic factors shared in common with other stage IV NSCLC patients, whatever the metastatic site (namely sex, age, gender, performance status and serum sodium level) this study discloses 2 determinants specifically resulting from brain metastasis: i.e. the presence of neurological symptoms and a high serum NSE level. The latter factor could be in relationship with the extent of normal brain tissue damage caused by the tumour as has been demonstrated after strokes. Additionally, the observation of a high NSE level as a prognostic determinant in NSCLC might reflect tumour heterogeneity and understimated neuroendocrine differentiation.

Etoposide plus cisplatin with or without the combination of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study.

BACKGROUND: The combination of etoposide plus cisplatin (EP) is considered to be standard therapy for small-cell lung cancer (SCLC). To determine whether drug intensification improves survival of patients with extensive SCLC, we compared this treatment with a four-drug regimen containing EP plus cyclophosphamide and 4'-epidoxorubicin (PCDE). METHODS: In a phase III clinical trial organized by the French Federation of Cancer Institutes, patients were randomly assigned to receive either EP (n = 109; etoposide at a dose of 100 mg/m(2) on days 1-3 plus cisplatin at 100 mg/m(2) on day 2) or PCDE (n = 117; etoposide and cisplatin given as in EP plus cyclophosphamide at 400 mg/m(2) on days 1-3 and 4'-epidoxorubicin at 40 mg/m(2) on day 1) every 4 weeks. Both groups received a total of six cycles. Survival differences were analyzed by Wilcoxon and log-rank tests. Associations of treatment group and putative prognostic variables with survival were tested in the Cox proportional hazards model. Quality of life was assessed from the responses to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (C30, health status and lung cancer module 13). All statistical tests were two-sided. RESULTS: Patients in the PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm (21% plus 55% versus 13% plus 48%, respectively; P =.02 for difference in combined objective responses). Patients in the PCDE arm survived longer than those in the EP arm (1-year survival rate: 40% and 29%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank P =.0067). In the Cox model, the relative risk of death for patients in the PCDE arm compared with those in the EP arm was 0.70 (95% confidence interval = 0.51 to 0.95); the disease also progressed more slowly in patients in the PCDE arm. Hematologic toxicity was higher in the PCDE arm (22% with documented infections compared with 8% in the EP arm; P =.0038), and the toxicity-related death rate was 9% in the PCDE arm versus 5.5% in the EP arm (P =.22). The global health status showed similar improvement in both arms during treatment. CONCLUSION: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.