Randomized multicentric phase II study of carboplatin/gemcitabine and cisplatin/vinorelbine in advanced non-small cell lung cancer GFPC 99-01 study (Groupe français de pneumo-cancérologie).

PURPOSE: To evaluate the efficacy and safety of gemcitabine and carboplatin in the treatment of previously untreated patients with advanced non-small cell lung cancer (NSCLC). METHODS: A randomized phase II study was conducted by the Groupe Français de Pneumo-Cancérologie (GFPC) in 15 centers. The patients were randomized in either arm A (GC): gemcitabine 1250 mg/m2 on days 1 and 8+carboplatin AUC 6 mg/(mLmin) on day 1; or in arm B (VP): vinorelbine 30 mg/m2 weekly+cisplatin 80 mg/m2 on day 1. Treatment cycles were repeated every 3 weeks. RESULTS: A total of 100 patients were randomized with stage IV or stage III NSCLC with malignant pleural effusion: 51 patients in arm A and 49 patients in arm B. A total of 190 cycles were administered in the GC arm and 172 cycles in the VP arm, with a median of four cycles per patient in each arm. The dose intensity was 84.9% for gemcitabine, 99.8% for carboplatin, 97.7% for cisplatin and 67.7% for vinorelbine. The objective response rates were 19.6% (95% CI, 9.8-33.1) for GC and 29.2% (95% CI, 17.0-44.1) for VP in an ITT analysis. The response duration was 169 days in arm A and 226 days in arm B. The TTP was similar with 140 days (GC) and 148 days (VP), respectively. Overall survival rates were 334 days in the GC combination and 304 days in the VP combination. Overall, the treatment was safe and toxicities observed were different in each arm: neutropenia was the most common toxicity in the VP treatment, whereas thrombocytopenia was more frequent in the GC combination. Anemia was similar in both arms. Non-haematologic toxicity was mild. One toxic death in arm A and three toxic deaths in arm B were observed. CONCLUSION: In terms of response rate, the gemcitabine-carboplatin combination was not efficient enough to allow further phase III study. Survival data are in the same range as the standard arm. This chemotherapy is feasible and may represent an alternative to a standard cisplatin-based regimen, allowing treatment in an outpatient setting.

[Use of 153Sm-EDTMP to relieve pain from bone metastasis in lung cancer]. / 153Samarium-EDTMP et contrôle de la douleur liée aux métastases osseuses des cancers bronchiques.

INTRODUCTION: The treatment of bone metastasis from lung cancer is palliative in nature with elimination of pain being the primary goal. Management is based on pharmacologicalmethods (steroids, morphine, and pamidronate) and radiotherapy. However, other treatments have been developed including the systemic radiopharmaceutical 153Sm-EDTMP. CASE REPORTS: We report data from 6 lung cancer patients with bone metastases treated with 153Sm-EDTMP. Demographic and therapeutic data, pain evaluation by visual analogue scale (VAS) and change in opioid analgesia requirements (expressed as intravenous morphine equivalent) as well as survival were studied. Pain associated with bone metastasis (median VAS = 8 [7-9], median morphine dose = 167 mg [100-800 mg]) did not significantly improve (median VAS after 153Sm-EDTMP = 8.5 [5-10], median morphine dose after 153Sm-EDTMP = 185 mg [30-2 200 mg]) in this group of patients. CONCLUSION: Our results combined with current data in the literature concerning the use of this treatment in the treatment of bone pain associated with metastatic lung cancer suggest that at present its use cannot be recommended outside the context of clinical of clinical trials.

Docetaxel and concurrent radiotherapy after two cycles of induction chemotherapy with cisplatin and vinorelbine in patients with locally advanced non-small-cell lung cancer. A phase II trial conducted by the Groupe Francais de Pneumo-Cancerologie (GFPC).

CONTEXT: The most satisfactory treatment for patients with locally advanced non-small-cell lung cancer (NSCLC) is combination chemotherapy-radiotherapy (CT-RT). The optimal treatment modalities remain to be determined. OBJECTIVE: We conducted a multicenter phase II trial of the docetaxel-radiotherapy combination after induction chemotherapy with cisplatin-vinorelbine. The main endpoint was the objective response rate. PATIENTS AND METHODS: Patient with inoperable stage locally advanced NSCLC received induction chemotherapy consisting of two cycles of cisplatin 100 mg/m2 on D1 and vinorelbine 25 mg/m2 on D1, D8, D15 and D22. Patients with responses or stable disease then received concurrent RT-CT consisting of 25 mg/m2/week docetaxel and single-fraction radiotherapy (66 grays (Gy) in 33 fractions) over 6.5 weeks. RESULTS: Fifty-six patients were enrolled from 1 July 2000 to 31 December 2001. Sixteen patients left the trial after induction chemotherapy, eight for progression, five for toxicity, and two for intercurrent events. One patient underwent surgery after induction chemotherapy. In total, 40 of the 56 patients received RT-CT. Twelve (30%) of these 40 patients experienced grade III or IV pulmonary or esophageal toxicity. In the intention-to-treat analysis, the objective response rate was 46.4% (95% CI 33.0-60.2). The median time to progression was 6.2 months [1.1-26.0]. The median survival time was 13 months [0.3-44.9 months]. Nine patients progressed during RT-CT, six with brain metastases. CONCLUSION: Weekly docetaxel with concurrent radiotherapy, following chemotherapy is acceptable. The tumor response rate is moderate. Further trials are required to determine the risk-benefit relationship of this treatment schedule, and the possible benefit of adding other cytotoxic drugs.

CYFRA 21-1 level predicts survival in non-small-cell lung cancer patients receiving gefitinib as third-line therapy.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) as gefitinib emerged as an accepted treatment in second- or third-line setting in NSCLC. However, clinical surrogate markers of EGFR-TKI activity in NSCLC patients remain to be identified and we studied the prognostic value of CYFRA 21-1 in this setting. Serum samples from 53 patients with NSCLC receiving gefitinib after failure of at least a platinum-containing regimen were prospectively collected from January 2002 to December 2003. Multivariate analysis demonstrated an independent negative impact on survival for a level of CYFRA 21-1 higher than 3.5 ng ml(-1) (HR=2.45, 95% CI 1.13-5.29; P=0.02). In conclusion, CYFRA 21-1 is a tool available to predict the survival of NSCLC patients receiving gefitinib as third-line therapy in an independent manner. In case of a CYFRA 21-1 level higher than 3.5 ng ml(-1), treatment with gefitinib needs further evaluation giving its relative poor effect on survival.

[Disordered higher functions in a smoker]. / Troubles des fonctions supérieures chez un fumeur.

INTRODUCTION: Paraneoplastic syndromes sometimes lead to the discovery of an intrathoracic tumour, notably small cell lung cancer (SCLC). MATERIALS AND METHODS: We report the case of a patient presenting with a paraneoplastic syndrome characterised by disordered higher functions and convulsions, representing a paraneoplastic encephalo-myelitis (PEM). This PEM led to the diagnosis of SCLC. The diagnostic features and progress of the PEM are discussed. CONCLUSION: Recognition of PEM allows the diagnosis and early treatment of the underlying cancer, strongly influencing the prognosis, particularly in SCLC.

[Difficulties associated with Lambert-Eaton syndrome]. / Difficultés autour d'un syndrome de Lambert-Eaton.

INTRODUCTION: The diagnosis and treatment of the neurological paraneoplastic syndromes associated with lung cancer can pose a challenge both to general physicians and neurologists as well as pulmonologists. CASE REPORT: A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma. A lobectomy was performed for a pT2N0M0 lesion. A significant improvement of neurological symptoms was seen. The myasthenic syndrome reappeared 21 months later. A local and general relapse was diagnosed. The patient died 10 months later despite chemotherapy. CONCLUSION: LEMS occurs because of an immunological reaction against voltage-dependent calcium channels. LEMS is generally associated with small cell lung cancer occurring in three percent of cases. However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition.

[Tolerance of fiberoptic bronchoscopy by self-administered questionnaire: in the words of the patients]. / Evaluation de la tolérance de la fibroscopie bronchique par auto-questionnaire: la parole aux patients...

INTRODUCTION: Fibreoptic bronchoscopy is currently undertaken by the majority of respiratory physicians, but under varying conditions. Though complications are rare the tolerance of this examination is sometimes poor, particularly when it is performed under local anaesthesia. The undesirable effects may reduce the value of the examination as well as causing discomfort for the patient. METHODS: A prospective study of the tolerance of the endoscopic examination was made on 100 consecutive patients by self-administered questionnaire. RESULTS: There were no major and 7 minor complications (7%). 45% of the patients were anxious but the experience of the operator tended to reassure them (p=0.07). 30% of the patients reported some pain, which tended to be exacerbated by anxiety (44% vs 18%, p=0.008) and the supine position (57% vs 43%, p=0.047). 37% of patients reported nausea, and 50% dyspnoea, without any significant predictive factor. 79% would agree to a repeat examination under the same conditions and 92% said that they had received information appropriate to the examination undergone. CONCLUSION: The tolerance of fibreoptic bronchoscopy under local anaesthesia is poor and perhaps overestimated by respiratory physicians. Patient information is essential. A national enquiry could lead to the standardisation of techniques.

[Acute pulmonary toxicity due to gemcitabine: a role for asbestos exposure?]. / Toxicité pulmonaire aiguë de la gemcitabine: un rôle pour l'exposition à l'amiante?

INTRODUCTION: Gemcitabine is an important drug in the treatment of non-small cell lung cancer. Myelosuppression is the most common toxic effect but its use sometimes leads to severe pulmonary toxicity by means of diffuse alveolar damage or sub-acute interstitial pneumonitis. METHODS: A retrospective study was made of all the patients treated in our department with this drug, alone or in combination. Episodes of acute dyspnoea during the course of chemotherapy were identified, and data were collected concerning the past history, the illness and the treatment in patients who had developed a respiratory failure attributable to gemcitabine. RESULTS: 312 patients had been treated with gemcitabine over a 5 year period and 18 had developed episodes of acute dyspnoea, of which 6 (1.9%) were attributed to the drug itself. Of these patients 4 had notifiable industrial disease (no. 30bis) secondary to asbestos exposure (odds ratio=85, 95% confidence interval 13-546) and 5 were active smokers. The possible role of intracellular ATP pool depletion secondary to asbestos exposure or smoking as a predisposing factor in the development of gemcitabine pulmonary toxicity is discussed. CONCLUSION: Smoking and asbestos exposure should be taken into account in future studies of gemcitabine pulmonary toxicity.

Phase I trial of gemcitabine and carboplatin in metastatic non-small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie Study.

BACKGROUND: The purpose of this study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the 21 days carboplatin plus gemcitabine regimen in previously untreated patients with stage IV non small-cell lung cancer (NSCLC). METHODS: At least three patients were entered at each dose level. The starting dose was carboplatin AUC 4 mg/ml per min (Area Under the Curve; Calvert formula) on day 1 and gemcitabine 750 mg/m(2) on days 1 and 8. Carboplatin was increased to AUC 5 (level 3, 4) then to AUC 6 (level 5-7). Gemcitabine was increased to 875 (level 2, 3), 1000 (level 4, 5), 1250 (level 6) and finally 1500 mg/m(2) (level 7). Twenty-nine patients were entered into this phase I study. RESULTS: At dose level 6, a DLT (grade 4 thrombocytopenia) was observed in one out of six patients. At dose level 7, no DLT was observed during the first course, so the MTD was not reached. During the second course, two out of four patients presented grade 4 thrombocytopenia. None of the five patients receiving two courses at level 6 presented a DLT, so this level was retained for further phase II studies. Of the 25 patients assessable for response, five achieved partial responses with a response rate of 20% (95% CI, 7 to 41%). The median survival time was 7 months and the 1-year survival rate was 24% (95% CI, 9 to 45%). CONCLUSION: The combination of carboplatin given on day 1 and gemcitabine given on days 1 and 8 every 3 weeks seems to be an acceptable regimen. The DLT consists exclusively of severe thrombocytopenia. Despite the MTD was not reached with carboplatin AUC 6 mg/ml per min and gemcitabine 1500 mg/m(2), the recommended dose for further phase II studies is carboplatin AUC 6 mg/ml per min and gemcitabine 1250 mg/m(2).

Bilateral bronchioloalveolar lung carcinoma: is there a place for palliative pneumonectomy?

OBJECTIVE: Bronchioloalveolar lung carcinoma (BAC) is characterized by bronchial and lymphatic dissemination explaining multifocal and bilateral spreading. Bilateral BAC is usually considered as a contraindication to surgery. Regarding poor efficacy of symptomatic and oncological treatments, we hypothesized that surgery might play a role to palliate hypoxemia associated with serious intrapulmonary shunting, as well as continuous bronchorrhea. METHODS: We retrospectively studied here four consecutive patients, who underwent palliative pneumonectomy. RESULTS: The shunt was confirmed again at the time of the surgery by a pulmonary artery occlusion demonstrating immediate improvement in arterial oxygen saturation from 89% at baseline to 98% after occlusion. Lung resections consisted of a left pneumonectomy in three cases and a right pneumonectomy in one. PaO(2) levels under 5l/min oxygen therapy improved dramatically when comparing preoperative data (mean 50.5 mmHg) to post-operative results (mean 150 mmHg). One patient died postoperatively. Three patients, who experienced an uneventful immediate post-operative course, received chemotherapy after surgery. Improvement of quality of life is testified by the absence of both symptoms and any need for oxygen therapy for few months. Disabling symptoms reappeared at 1, 8 and 10 months. Survival of these patients was 3, 12 and 18 months. CONCLUSIONS: These results support the interest of consideration of a surgical resection for highly selected patients presenting with bilateral BAC and severe intrapulmonary shunting.

[Multiple pulmonary leiomyomatous nodules: benign metastasing leiomyoma?]. / Nodules léiomyomateux multiples du poumon: léiomyome métastatique bénin?

Pulmonary smooth muscle lesions are rare explaining their imperfect understanding. Two cases of multiple pulmonary leiomyomatous lesions in patients who previously underwent surgery for benign uterine leiomyoma are reported. Literature was reviewed to know if the controversial question of benign metastasising leiomyomas could be resolved. Therapeutic possibilities of this pathology are also discussed.

Phase II trial of paclitaxel and carboplatin in metastatic small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie study.

PURPOSE: To evaluate the efficacy and safety of paclitaxel and carboplatin in the treatment of previously untreated patients with metastatic small-cell lung cancer (SCLC). PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with an Eastern Cooperative Oncology Group (ECOG) score < or = 2 and life expectancy > or = 12 weeks. Paclitaxel (200 mg/m(2)) was infused over 3 hours, before carboplatin (area under the curve [AUC] 6; Calvert formula) infused over 1 hour, once every 3 weeks for six cycles maximum. Prednisolone, dexchlorpheniramine, and ranitidine were standard premedication. Response to treatment was assessed every two cycles, and nonresponding patients were withdrawn from the trial to receive standard chemotherapy. RESULTS: Of the 50 patients entering the study, 48 and 46 patients were assessable for toxicity and response, respectively. The overall response rate was 65%, with complete responses in three patients. Five patients had stable disease (11%) and 11 patients experienced progressive disease (24%). Median survival was 38 weeks, and median duration of response was 20 weeks. One-year survival was 22.5%. For a total of 232 cycles, grade 3 and 4 toxicity was 33% for neutropenia, 3.5% for thrombocytopenia, and 4% for anemia. Four patients had neutropenic fever (one toxic death). Nonhematologic toxicity was mainly grade 1 and 2 paresthesia (21% of patients); grade 3 myalgia/arthralgia was observed in 6.5% of patients. CONCLUSION: First-line chemotherapy with paclitaxel and carboplatin in metastatic SCLC achieved a response rate and survival similar to standard regimens. With 1-day administration and a tolerable toxicity profile, this combination merits further investigation.

[Hospitalization facilities required for quality care of lung cancer patients]. / Les modes d'hospitalisation nécessaires pour une prise en charge de qualité en oncologie thoracique.

The purpose of this study was to determine whether good-quality care for patients with lung cancer can be delivered without a full hospitalization unit. Our study included all consecutive untreated lung cancer patients admitted over a two-year period. The following criteria were analyzed retrospectively: residence, age, sex, histology, staging, treatments, administrative data during the first 6 months of treatment, place of death, and duration of last stay before death in the unit. Two hundred six patients were recorded. Twenty-eight percent of the patients had stage IIIB disease and 61% stage IV disease. The first treatment included: surgery (12%), chemotherapy (80%). During the first six months, the median number of hospitalizations was 8 and the median number of full hospitalization days was 17 compared with 6 days for one-day stays. The median duration of the first stay was 5 days whereas the duration of the last one was 3 days. During the first year, 71% of the patients dies: 36% in our unit (47% of them were inpatients for more than 6 days during their last stay). Diagnosis, initial treatment, management of treatment complications and supportive care are not compatible with weekly hospitalization. Full hospitalization is mandatory for good-quality care in a referral cancer unit.

[Hospital information systems ineffectiveness in costing ambulatory chemotherapy in pulmonary oncology]. / Insuffisance de la valorisation PMSI de la chimiothérapie ambulatoire en oncologie pulmonaire.

The real cost of medical consumption was compared with the proportion of medication consumption of (the) GHM n(o) 681 (homogeneous group of patients, chemotherapy for cancer in day care) in the French case mix system (PMSI). For those patients in our thoracic oncology unit (Sainte-Marguerite Hospital, Marseille, France), the real medication cost was calculated from prices paid by the hospital, then compared to the expected expenditures for the medication consumption of the GHM 681, i.e. 678 French francs (24.1% of the 225 ISA points (synthetic activity index)). Over a period of 2 months in 1998, 87 patients (mean age 63 +/- 11) had 194 chemotherapy sessions in day care, with multi-drug therapy in 38 cases. Vinorelbine or gemcitabine represented 81% of the single drug chemotherapy. In 84% of the single drug and 76% of the multi-drug chemotherapy, the real cost of medication consumption was above the allocated budget. The mean cost for single drug chemotherapy was 1722 FF and 2920 FF for multi-drug chemotherapy. The budget allocated by the PMSI shows a deficit in the most cases. To avoid a restriction in the use of some drugs, it appears that the French system of budget evaluation needs to be improved.

Lenograstim as support for ACE chemotherapy of small-cell lung cancer: a phase III, multicenter, randomized study.

This phase III study was conducted to evaluate the usefulness of lenograstim as support for ACE (doxorubicin, cyclophosphamide, and etoposide) chemotherapy in previously untreated patients with small-cell lung cancer. Patients were randomized to receive up to six 3-week cycles of either ACE alone (n = 139) or ACE with lenograstim support (150 microg/m2/day subcutaneously, days 4-13, n = 141). Compared with the chemotherapy-alone group, the lenograstim support group was more likely to achieve neutrophil recovery (absolute neutrophil count, > or =1.5 x 10(9) cells/l) by day 14 (95.8-100% vs. 14.3-24.1% across the cycles) and less likely to experience at least one infectious episode (36.7 vs. 54.0%; p = 0.004), chemotherapy delay (51.8 vs. 56.2%; NS), or dose reduction (17.3 vs. 27.7%; p = 0.037). Objective response and event-free and overall survival rates were similar. Lenograstim was well tolerated. Lenograstim may allow the interval between cycles of ACE to be reduced to 2 weeks; such dose intensification may lead to more favorable objective response and survival rates.

Humoral immunity against glutamic acid decarboxylase and tyrosine phosphatase IA-2 in Lambert-Eaton myasthenic syndrome.

Some beta-cell-specific autoantigens also are present in the central nervous system. Furthermore, stiff man syndrome, an autoimmune neurological disease, is frequently associated with diabetes and shares with this one an anti-GAD and IA-2 humoral immunoreactivity. We wondered whether these autoantibodies could be found in other neurological diseases with a present or supposed autoimmune origin. So, anti-GAD65 (GAD65A) and anti-IA-2 (IA-2A) autoantibodies were assayed in various neurological diseases. There was a higher prevalence of such antibodies in Lambert-Eaton myasthenic syndrome (LEMS) (GAD65A, 35%; IA-2A, 21%; double positivity, 18%) compared to amyotrophic lateral sclerosis (18%, 12%, and 12%, respectively) and multiple sclerosis (10%, 3%, and 3%, respectively). In LEMS, the humoral reaction was more frequent and/or appeared earlier in the paraneoplastic forms. The detection of such autoantibodies in patients with small-cell lung carcinoma (SCLC) without LEMS suggests that these autoantigens, GAD65 and IA-2, could be produced by SCLC tissue.

[Panhypopituitarism secondary to pituitary metastases]. / Panhypopituitarisme secondaire à une métastase hypophysaire.

BACKGROUND: Hypophyseal metastatic localizations are uncommon and rarely the first expression of a primary cancer. We report an exceptional case revealed by panhypopituitarism and diabetes insipidis. CASE REPORT: Brain MRI visualized an intra- and suprasellar tumoral formation found to be a cribiform adenocarcinoma. The primary tumor could not be identified. Despite radiotherapy, surgery and chemotherapy combining carboplatin and etoposide, the tumor progressed with the development of cervical and mediastinal nodes. The patient died one year after onset of the clinical signs. DISCUSSION: Diagnosis of hypophyseal metastasis is mainly based on indirect evidence: rapid course, invasion of neighboring structures. Optimal management of these rare tumors remains to be determined.

[Long-term survival of a patient with melanoma with late recurrence of pulmonary metastasis treated by repeat surgery]. / Longue survie d'un cas de mélanome malin avec métastases pulmonaires tardives, récidivantes, traitées par chirurgie itérative.

We report the case of a young woman initially treated with surgery, radiotherapy, chemotherapy and BCG therapy for stage II malignant melanoma involving the limbs. Considering that the risk of metastasis is usually maximal between 2 and 5 years after initial treatment, metastatic dissemination of this melanoma was rather unusual. Metastases were observed locally, regionally, and in the lungs 8, 10 and 12 years respectively after the primary diagnosis. Repeat surgery was performed to resect pulmonary nodules. Such surgery is possible in less than 10% of the cases of metastatic melanoma. Our patient has survived without relapse for 21 years after the initial diagnosis and 8 years after the last tumor excision. Recurrent pulmonary metastasis without extrapulmonary dissemination would suggest the tumor cell population was composed of a particular metastatic phenotype.