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.

Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort.

PURPOSE: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. PATIENTS AND METHODS: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. RESULTS: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. CONCLUSION: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

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.

[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.

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.

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.

[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.

[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.

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.

[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.

[Appropriate medication prescribing in older people]. / Bon usage des médicaments chez le sujet âgé.

Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists.

Neoadjuvant etoposide, ifosfamide, and cisplatin followed by concomitant thoracic radiotherapy and continuous cisplatin infusion in stage IIIb non-small cell lung cancer.

OBJECTIVE: To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. RESULTS: Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. CONCLUSION: Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.

Cyfra 21-1, neuron specific enolase and prognosis of non-small cell lung cancer: prospective study in 621 patients.

BACKGROUND: CYFRA 21-1, a serum cytokeratin 19 fragment, and neuron specific enolase (NSE), the gamma-subunit of enolase, are putative markers of lung cancer. Their clinical applicability as prognostic factors in non-small cell lung cancer (NSCLC) would need an appraisal by simultaneous evaluation of other known survival determinants in a large population followed over a long period. AIM: To determine the prognostic value of different clinical and routine biological variables at presentation with particular attention paid to the above-mentioned markers. METHODS: 621 histologically proven and previously untreated NSCLC patients have been prospectively studied (seven were lost to follow-up). Median follow-up was 4 years and 2 months. At presentation, 16 clinical and biological variables were recorded. Serum NSE and CYFRA 21-1 were assayed blind without any clinical information given. RESULTS: The serum CYFRA 21-1 distribution differed significantly according to histology, disease stage and performance status, with the highest levels observed in squamous cell carcinomas, metastatic stage, positive mediastinal nodal status and poor performance status. However, the respective "receiver operating characteristic" curves showed that the CYFRA 21-1 serum level did not accurately predict tumour stage. Serum NSE distribution correlated neither with tumour stage nor with performance index and its sensitivity in the whole NSCLC was low. In the Cox proportional hazard model, the following variables were independent determinants of a poor outcome: performance status 2 or 3, hazard ratio (HR): 2.25; Nodal status N(2-3), HR: 1.84; Metastatic disease, HR: 1.73; NSE>12.5 ng/ml, HR: 1.52; CYFRA 21-1>3.6 ng/ml, HR: 1.41 and Tumour status T(3-4), HR: 1.31. When the survival analysis was restricted to the 274 patients affected by a metastatic stage, we observed that performance status, nodal status, NSE and CYFRA 21-1 remained prognostic determinants with similar hazard ratios. CONCLUSION: The prognostic information given by a high serum CYFRA 21-1 level is independent from other well-known variables such as performance status and disease stage and is perennial throughout extended follow-up period. A high NSE level also prognosticates a poor outcome probably by reflecting tumour heterogeneity and underestimated neuroendocrine differentiation.

Concomitant brain radiotherapy and vinorelbine-ifosfamide-cisplatin chemotherapy in brain metastases of non-small cell lung cancer.

AIM: To determine whether or not brain radiotherapy and concomitant three-drug chemotherapy is feasible and yields anti-tumour activity in patients with non-small cell lung cancer and brain metastases at time of presentation. PATIENTS AND METHODS: Twenty-three previously untreated patients suffering from non-small cell lung cancer and brain metastasis were prospectively included in this feasibility study. Most of the patients had neurological symptoms and an Eastern Collaborative Oncology Group (ECOG) performance index over 2. Treatment consisted of three courses of whole brain radiotherapy (18 Gy in 10 fractions) and vinorelbine, 30 mg/m2 on days 1 and 8, ifosfamide, 1.5 g/m2 daily from day 1 through day 3 with uromitexan uroprotection, and cisplatin, 100 mg/m2 on day 2. A cycle restarted every 28 days. RESULTS: Eighteen patients completed the three-cycle programme. All patients were affected by a grade 4 neutropenia and 14 of them experienced a febrile episode. Other toxicities were mild to moderate and manageable. Received-dose intensities of vinorelbine, ifosfamide and cisplatin were 80, 90 and 90%, respectively. Overall response rate was 30%. Specific evaluation of brain response demonstrated complete response for seven patients, and partial response in six (objective brain response rate, 56%). All responders benefited by a remission of symptoms and improvement of performance index. Median survival from start of protocol was 7.6 months. CONCLUSION: Although the high rate of toxicity requiring re-admission, concomitant brain radiotherapy plus vinorelbine, ifosfamide and cisplatin chemotherapy is feasible in patients suffering from brain metastasis, and demonstrates an anti-tumour activity for this particular subset of stage IV non-small cell lung cancer. The development of such an aggressive approach needs further comparative evaluation.

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.

Phase I-II study of high dose epirubicin plus cisplatin in unresectable non-small-cell lung cancer: searching for the maximal tolerated dose.

The purpose of this study was to search for the maximal tolerated dose of cisplatin in the cisplatin plus high-dose epirubicin combination for patients with non-small-cell lung cancer. The following range of cisplatin dosages were tested in a phase I study: 75, 90, 105, and 120 mg/m2 in combination with epirubicin 120 mg/m2 every 3 weeks. Eligibility consisted of previously untreated stage IIIb or IV non-small-cell lung cancers, Eastern Cooperative Oncology Group Performance Status less than or equal to 2, age less than or equal to 70 years, measurable disease, adequate blood counts, chemistry, cardiac function, and no brain metastasis. The maximal tolerated dose was defined as the dose level of cisplatin for which two of three patients or three of six patients developed one or more limiting toxicities during the first course of therapy. Afterward, the maximal tolerated dose of cisplatin was adopted in a subsequent phase II study. Three centers enrolled 42 patients: 18 in phase I and 24 in phase II. The maximal tolerated dose was almost reached at the last dose level (i.e., 120 mg/m2). Taking into account the total duration of the treatment, the real dose intensity for patients treated at the fourth dose level (120 mg/m2) did not differ from that of the third dose level (105 mg/m2). The latter dosage was therefore considered as the maximal tolerated one. In the subsequent phase II study, the median number of cycles received per patient was three (range: one to eight). Fifty percent required a dose reduction of either epirubicin, cisplatin, or both. The main toxicity was neutropenia, resulting in 10 episodes of febrile grade IV neutropenia requiring readmission. Other toxicities were mild to moderate. There was no toxic-related death. On intent-to-treat analysis, 10 patients (33%) achieved an objective response. Among them were three complete responders. Median survival was 8 months. We observed neither detraction nor improvement of quality of life as assessed using the European Organization for Research and Treatment of Cancer QLQ-C30-LC13. Given every 3 weeks in combination with epirubicin 120 mg/m2, the maximal tolerated cisplatin dose is 105 mg/m2. This combination yields activity in non-small-cell lung cancer.

[New cytotoxics in the treatment of bronchial cancers]. / Nouveaux cytotoxiques dans le traitement des cancers bronchiques.

This review presents a synthesis of published studies on the activity of the newer cytotoxic drugs in the treatment of bronchial cancer. It also touches on the early indications of recent results which until now have only been the subject of oral presentations. The taxanes form a new class of anti-cancer drug. Myelosuppression is their limiting factor. These are very active cytotoxic drugs but their toxological profile makes them difficult to use in polychemotherapy. The anti-tumour activity of docetaxel (Taxotere) has been shown. For non-small cell cancer (CNPC) the objective response (OR) is of the order of 26% in new patients and 21% in those who have been pre-treated with a combination of drugs based on Cisplatine. For paclitaxel (Taxol) the OR is around 25% in new patients. In association with a course of cisplatine the efficacy would be dose dependent. For small cell cancer (CPC) it enables a level of OR around 38% as monochemotherapy. Inhibitors of topoisomerase I (topotecan, irinotecan) form another new class of therapy. Myelosuppression again limits their toxicity. Diarrhoea is an additional toxicity of irinotecan (Campto). The inhibitors of topoisomerase I seem particularly active as monochemotherapy in the treatment of smal cell cancer. Haematological toxicity makes them difficult in association. The activity of topotecan (Hycantin) in the treatment of non-small cell carcinoma remains to be studied. For this indication irinotecan would enable an OR of 33% in new patients. The new anti-metabolite, gemcitabine (Gemzar) is characterised by a different mode of action from other cytotoxics used in the treatment of bronchial cancer. For non-small cell carcinoma it is active as monotherapy and in association with cisplatine. Its activity is more modest in the treatment of CPC but few studies are available for this indication. Its toxic profile makes it promising to be used in association. The new spindle drug vinorelbine (Navelbine) is active as monotherapy or associated with cisplatine in the treatment of non-small cell carcinoma. The limiting toxicity is haematological. Its neurotoxicity is moderate compared to agents in the same therapeutic class. These different cytotoxic drugs arouse a ligitimate interest but the optimal therapeutic schemas for their use remain poorly understood (with the exception of vinorelbine). Their place in the therapeutic arsenal remains to be defined whilst waiting for the results of Phase III studies, their routine use cannot be recommended.

[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.

[Neuron-specific enolase (NSE) in the surveillance of small cell cancers. An evaluation of the prognostic information using Markov's model]. / L'énolase neurone-spécifique (NSE) et la surveillance des cancers bronchiques à petites cellules. Une évaluation de l'information pronostique par le modèle de Markov.

RATIONALE: An elevated serum NSE concentration is generally a bad prognostic sign when a diagnosis of small cell lung cancer is made. However, the marker may vary from time to time crossing the discriminant threshold (12.5 ng/ml) in one direction or the other. These variations are presumed to reflect the progress of the disease but it has not been shown that the risk of death from the disease is changed by alterations in the serum concentration of NSE. To resolve this question we have used Markov's mathematical model (homogeneous over time and in three states). METHOD: A prospective study has included 52 patients suffering from small cell cancer and treated with chemotherapy based on cisplatin. The NSE was measured following each treatment and three monthly in subsequent follow up. Markov's model was studying the intensities of transition and the risks of death between the two following transient states: living with an NSE concentration of < or = to 12.5 ng/ml, living with an NSE concentration of > 12.5 ng/ml, and an absorbing state: death. RESULTS: When a level of > 12.5 ng/ml was noted the mean time of maintaining in this state was short (123 days). During this time when a transfer was effected in 44 per cent of cases there is turn towards the opposite state (living with a concentration < 12.5 ng/ml) showing the real reversibility between the two transient states. When a patient had an elevated concentration of serum NSE the risk of death was 2.23 times greater than in the opposite state (living with a low NSE; P < 0.01). CONCLUSION: The observation of an elevated NSE concentration at any time in the follow up of patients suffering from small cell cancer was strongly associated with an elevated risk of death but a return from this state towards a state of less risk (living with a low NSE level) remains possible. This works suggests that the NSE levels may be useful in the follow up of small cell lung cancer.