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Summary Background The aim of this study was to analyze SCLC patients beyond 30 months, particularly their outcome, their way of life, and factors which could influence relapses, second-primary cancers and death. Patients and methods Between January 1986 and May 1995, 263 SCLC patients who survived longer than 30 months were included from 52 French institutions. The analysis was performed on the 155 cases confirmed by a pathologic review. Results Physical, mental and psychological states were considered as normal at 30 months in respectively 70.3%, 87.7% and 67.7% of patients, not influenced by prophylactic cranial irradiation, number of chemotherapy cycles, CCNU or cisplatin. Therapeutic sequelae were neurological impairment (13%), pulmonary fibrosis (18%) and cardiac disorders (11%) at 30 months. Return to work was possible for 40% of patients in the first two years following diagnosis. Among 43 relapsing patients, 33 benefited from a second-line treatment. Their median survival was 12 months since retreatment, and seven patients have survived again longer than 30 months. Age > 60 at the time of diagnosis was found as an independent factor increasing the risk of relapse beyond 30 months (OR = 2.46, IC 95% (1.16–5.26), P = 0.01). The risk of relapse became less than 10% beyond five years. Twenty patients (13%) developed a second primary cancer in a mean time of 58.6 months. The risk of second primary cancer was increased by a number of chemotherapy cycles > 6 (OR = 3.25, IC 95% (1.08–9.8) P = 0.02) and by an age > 60 (OR = 2.92, IC 95% (1.07–7.97), P = 0.03). Five- and 10-year survival rates were respectively 68% and 44%. In these patients having reached a 30-month survival, three independent factors were predictive of a survival longer than five years: age ≤60 at the time of diagnosis (OR = 2.85, IC 95% (1.23–6.6), P = 0.01), chest radiotherapy (OR = 3.1, IC 95% (1.28–7.69), P – 0.006) and absence of relapse (OR = 4.5, IC 95% (1.75–12.5), P – 0.002). This study suggests that: 1) therapeutic sequelae are rather mild, allowing return to work in 40% of patients; 2) relapsing 30-month survivors can benefit from second-line treatment; 3) SCLC cure can be achieved with a 10-year follow-up.

The purpose of this study was to evaluate and compare the antiemetic effectiveness and tolerability of Navoban® (tropisetron) and Zofran® (ondansetron) following high-dose (≥ 50 mg/m2) cisplatin chemotherapy. In a randomised, multi-centre, double-blind, double-dummy, parallel group study, 117 evalua

Pirarubicin (THP) (Roger Bellon Laboratory, France) is a new anthracycline under clinical development. In order to assess the efficacy and toxicity of the drug in small-cell lung carcinoma (SCLC), we have undertaken this trial in front-line therapy in patients with metastatic disease, PS less than 3 and at least one evaluable lesion. Responses were assessed after two cycles of THP (60 mg/m2 i.v. bolus every 3-4 weeks) and a further cross over to VP16 + CDDP (three cycles) was systematic whatever the response to THP. This crossover was performed after only one cycle in case of obvious progression. From June 1988 to April 1990, 32 patients were enrolled: 6 were ineligible (4 non-SCLC, 2 M0), 26 patients were fully evaluable for THP and 18 patients for VP16-CDDP. The characteristics of the patients were as follows: mean age 57.4 years (38-71); T4: 54%; T3: 27%; T2: 19%; N3: 62%; N2: 35%; No: 4%. The efficacy was as follows 1 complete response and 2 partial responses (confirmed by endoscopy); 12 patients received only one cycle because of obvious progression; the overall response rate is 12% (95% confidence interval 0-24%). The patient who had complete response after pirarubicin remained in CR after VP16-CDDP, whereas the 2 patients who had partial response achieved CR for one and PR for the other; among the 15 who did not respond 1 CR and 7 PR were observed. The only significant toxicity of THP was granulopenia without infection. THP seems to be an effective anthracycline in SCLC, and the study is continuing. A response could be reached in 50% of the nonresponders with standard therapy and 10 of 24 patients (42%) finally responded. Therefore, this schedule for testing new drugs in metastatic SCLC appears ethically acceptable.

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.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.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.

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).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.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.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.

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.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.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.

Paraneoplastic syndromes sometimes lead to the discovery of an intrathoracic tumour, notably small cell lung cancer (SCLC).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.Recognition of PEM allows the diagnosis and early treatment of the underlying cancer, strongly influencing the prognosis, particularly in SCLC.

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.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.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.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.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.

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.

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.A prospective study of the tolerance of the endoscopic examination was made on 100 consecutive patients by self-administered questionnaire.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.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.

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.

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.

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.

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.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.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.

To assess the toxicity and efficacy of high dose ifosfamide in stage IV NSCLC.In a previous trial, we have determined maximum tolerated dose for 3-days ifosfamide treatment by 3-weeks schedule as 9 g/m2 according to hematologic tolerance. We therefore set up a phase II to study the toxicity and efficacy of this schedule in chemotherapy naive metastatic NSCLC. Ifosfamide (+ mesna 1 g/m2) was administered by a two hour infusion (3 g/m2) for three days every three weeks. Patients received three mesna bolus infusions (1 g/m2) at 4, 8 and 12 hours after the end of ifosfamide infusion. Antitumoral efficacy was performed after 2 cycles and treatment could be pursued for responding patients until disease progression. From september 1995 to January 1997, 31 patients have been included in this study. Median age was 60.7 years +/- 1.33 (41-70) for 27 males and 4 females. Patients (pts) presented metastases in lung for 10 pts, bone for 10 pts, liver for 6 pts, adrenal for 4 pts and multiorgan metastatic localisation for 1 patient. Seven patients were unassessable: 1 lost for follow-up, 1 sudden death, 5 treatment interruptions before evaluation time and 3 toxic deaths (9.6%).neutropenia grade 4 (10 pts and 1 death), cardiotoxicity grade 4 (1 pt) and 2 deaths following neurotoxicity grade 4. We achieve 4 partial responses (13%, 95CI: 3.6-29.8), 10 progressive diseases (32.3%, 95CI: 16.7-51.4) and 10 stabilizations (32.3%, 95CI: 16.7-51.4). Median response duration was 91 days +/- 55 d. Median survival was 9.3 months, e.g. 280 days (8-863). Overall survival at one year is 48%.This modality of high dose ifosfamide is as effective as standard monotherapy schedules in stage IV NSCLC. Unexpected toxicities particularly hematological ones could be due to a short duration of fractionated treatment. Results in term of survival leads us to further evaluate ifosfamide monotherapy treatment on a 5-day schedule basis.

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.

Bronchial cancer associated with a homolateral malignant pleurisy is classed as T4 whether the pleural disease is a direct extension or metastatic. Effusions without neoplastic cells do not enter into the TNM classification. Investigations of pleural disease consist initially of needle biopsies, completed sometimes by a thoracoscopy, which enable a precise staging and also the achievement of a pleurodesis. A review of the literature does not currently establish the value of a pleurectomy in cases of a homolateral effusion in bronchial carcinoma. Surgical excision may be carried out in a case of neoplastic pleurisy where no pleural invasion is found without knowing the benefits in terms of survival. The inverse exists, with local or diffuse pleural invasion without pleurisy, which are difficult to evaluate by imagery techniques. Thus certain authors recommend pleural lavage during surgical operations for bronchial cancer even without pleural disease: positive cytology seems to be a poor prognostic feature and would justify adjuvant treatment. Thoracoscopy should be carried out when the neoplastic nature of a pleurisy has not been established by needle biopsy in order to evaluate the resectability of the tumour in the absence of surgical contra-indication. In the case of a disabling neoplastic pleurisy a pleurodesis carried out at the time of pleuroscopy may avoid the recurrence of the effusion. Talc is most often employed for pleurodesis but Bleomycin or Tetracycline are also used. In the case of failure to re-expand a shrunken lung the failure of the pleurodesis may lead to a pleuroperitoneal shunt. The type of homolateral pleural disease in bronchial cancer with local invasion by contiguity as against pleural metastases should appear in the TNM classification because there are different treatments and also a different prognosis.

BACKGROUND The efficacies of granisetron plus dexamethasone and dexamethasone alone in controlling delayed nausea and vomiting after cisplatin chemotherapy (> or = 69 mg/m2) were compared in a multicentre, double-blind, placebo-controlled comparative study. PATIENTS AND METHODS In all, 654 patients (of whom 619 were evaluable) received prophylactic granisetron plus dexamethasone before chemotherapy on day 0; on day 1 complete responders and non-responders were randomized separately to receive dexamethasone, 8 mg b.d. p.o., with either granisetron, 1 mg b.d. p.o., or matching placebo for six days. RESULTS Over days 1-6 the complete response rates were 54.5% (dexamethasone group) and 52.1% (dexamethasone plus granisetron group). Response rates were higher over days 4-6 (71.8% and 70.7%, respectively) than over days 1-3 (60.4% and 57.9%, respectively). Significantly more patients who responded to antiemetic treatment during day 0 were responders over days 1-6 (63% vs. 17%; P < 0.001). No other treatment-related differences were found. Adverse events tended to be minor, with constipation and headache the most common. Overall, there were no significant differences in the safety profiles of the two regimens, but constipation and abdominal pain were significantly more common in the dexamethasone plus granisetron group. CONCLUSIONS Granisetron plus dexamethasone did not appear to confer additional benefit over use of dexamethasone alone in controlling delayed nausea and vomiting following cisplatin chemotherapy. Control of acute nausea and vomiting, however, appeared to be an important factor influencing delayed nausea and vomiting.

The aim of this study was to analyze SCLC patients beyond 30 months, particularly their outcome, their way of life, and factors which could influence relapses, second-primary cancers and death.Between January 1986 and May 1995, 263 SCLC patients who survived longer than 30 months were included from 52 French institutions. The analysis was performed on the 155 cases confirmed by a pathologic review.Physical, mental and psychological states were considered as normal at 30 months in respectively 70.3%, 87.7% and 67.7% of patients, not influenced by prophylactic cranial irradiation, number of chemotherapy cycles, CCNU or cisplatin. Therapeutic sequelae were neurological impairment (13%), pulmonary fibrosis (18%) and cardiac disorders (11%) at 30 months. Return to work was possible for 40% of patients in the first two years following diagnosis. Among 43 relapsing patients, 33 benefited from a second-line treatment. Their median survival was 12 months since retreatment, and seven patients have survived again longer than 30 months. Age60 at the time of diagnosis was found as an independent factor increasing the risk of relapse beyond 30 months (OR = 2.46, IC 95% (1.16-5.26), P = 0.01). The risk of relapse became less than 10% beyond five years. Twenty patients (13%) developed a second primary cancer in a mean time of 58.6 months. The risk of second primary cancer was increased by a number of chemotherapy cycles6 (OR = 3.25, IC 95% (1.08-9.8) P = 0.02) and by an age60 (OR = 2.92, IC 95% (1.07-7.97), P = 0.03). Five- and 10-year survival rates were respectively 68% and 44%. In these patients having reached a 30-month survival, three independent factors were predictive of a survival longer than five years: ageor = 60 at the time of diagnosis (OR = 2.85, IC 95% (1.23-6.6), P = 0.01), chest radiotherapy (OR = 3.1, IC 95% (1.28-7.69), P = 0.006) and absence of relapse (OR = 4.5, IC 95% (1.75-12.5), P = 0.002). This study suggests that: 1) therapeutic sequelae are rather mild, allowing return to work in 40% of patients; 2) relapsing 30-month survivors can benefit from second-line treatment; 3) SCLC cure can be achieved with a 10-year follow-up.

A Phase I trial of carboplatin therapy was performed on patients with locally advanced non-small cell lung cancer who had been previously treated with cisplatin, mitomycin and a vinca aklaloïd. This was administered as a daily bolus infusion or as a continuous infusion for 6 weeks with concurrent daily thoracic radiation. All patients had to be objective responders or to show no change after chemotherapy. The carboplatin was started at 10 mg/m2 per day, and increased to 15 mg/m2 per day and 20 mg/m2 per day, if treatment was feasible in successive cohorts of at least six patients. The radiation therapy consisted of 62-66 Gray on the tumor and the ipsilateral mediastinal nodes, 50 Gray on the mediastinum and 40-45 Gray on the supraclavicular lymph nodes. Twenty-nine patients took part in this study. Thrombocytopenia was the principal dose-limiting toxicity, with 15 mg/m2 per day of bolus or continuous infusion. Other toxicities included a fall in haemoglobin level, a fall in white-blood cell count, nausea and vomiting. The median survival time was 12 months, but the response rate cannot be determined among patients selected on the basis of response to chemotherapy. The recommended Phase II dose for patients previously treated with cisplatin containing chemotherapy, is 10 mg/m2 per day of either a bolus or continuous infusion.

Human papillomaviruses (HPV) have been implicated in the pathogenesis of human squamous cell carcinoma, specially of cervical carcinomas. In previous studies concerning primary lung cancer, DNA of HPV subtypes was detected by in situ hybridization or polymerase chain reaction (PCR), up to 30% of the cases, namely in squamous cell carcinomas. A series of 31 frozen biopsies of lung carcinomas (surgical biopsies or through fiber optic bronchoscopy) were examined for the presence of HPV DNA by nested PCR. Primers for the two steps were type-specific primers (6/11-16 and 18; kit Amplicis-HPV) for the transforming region of HPV. HPV-DNA was found in five tumors: in two of 18 cases of squamous cell carcinoma (11%), in one of four cases of adenocarcinoma, in one of six cases of small cell carcinomas and in the unic case of neuro-endocrin carcinoma. No case of the two large cell undifferentiated carcinomas was positive. There were three cases of HPV 6/11, one case of HPV 16, and one sample positive for HPV 6/11 and HPV 18. No morphologic changes consistent with HPV lesions were observed. The frequency of 11% among the squamous cell carcinomas is near those found by previous studies (9 to 20% for HPV 6-11-16-18). For the first time, HPVs have been detected in neuro-endocrin tumors, and this have to be confirmed by studies of many more cases. So HPV might play a role as promoter in carcinogenesis of any types of lung carcinoma, although at a low frequency.

The study was designed to evaluate the value of vinorelbine in a cisplatin-mitomycin-vinca alkaloid regimen for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). A group of 227 patients with inoperable NSCLC in stage III (58%) or stage IV (42%) were included in this randomized multicenter trial comparing a reference regimen (VDS group, n = 113) cisplatin (120 mg/m2 on day 1, day 29 and day 71), mitomycin (8 mg/m2 on day 1, day 29 and day 71) and vindesine (3 mg/m2/week for 5 weeks and then every 2 weeks up to the 15th week) to a cisplatin-mitomycin-vinorelbine combination (VNB group, n = 114), with cisplatin and mitomycin at the same doses, and vinorelbine 25 mg/m2/week for 16 weeks. The objective response rate (evaluated at 17th week) was 17% in the VDS group and 25% in the VNB group (P = 0.15). Median survival was 33.4 weeks and 34.5 weeks in the VDS and VNB arms, respectively. Overall survival duration was not significantly different between the two arms (logrank test, P = 0.20) despite a trend to an increased survival in the VNB group. This essentially benefited the patients with stage III disease with a clear-cut lengthening of median (45.9 vs. 33.4 weeks) and 1 year survival (44.6% vs. 26.2%, P0.05) in favor of the VNB group. Nevertheless, there was no significant difference in overall survival (logrank, P = 0.13). Survival duration of the patients with stage IV disease was comparable in the two arms (logrank test, P = 0.90). Grade 3 or 4 neutropenia was found in 61% and 87% of the VDS and VNB groups, respectively (P0.01). Grade 2-4 peripheral neuropathy was observed in 23% of the patients in the VDS group and in 6% of the patients in the VNB group (P0.01). Replacement of vindesine by vinorelbine in a cisplatin-mitomycin-vinca alkaloid chemotherapeutic regimen did not lead to a significant improvement in objective response rate or in duration of survival. There was a reduction in neurotoxicity at the expense of an increased hematologic toxicity. However, for patients with stage III disease there was an increase in 1 year survival with the vinorelbine combination.

To evaluate the pronostic value of an elevated seric carcinoembryonic antigen (CEA10 ng/ml) at diagnosis, in patients with lung cancer, a pair study was done: couples of patients with same staging and histologic type were established, one patient with high CEA level compared to one patient with normal CEA level (5.5 ng/ml). Other markers were measured: neuron specific enolase (NSE), squamous cell carcinoma (SCC) or Cyfra 21-1. Survival was the end point of comparison. For 89 couples created, patients with low CEA level had a better survival rate at one year ( p = 0.02), this prognosis advantage was confirmed by a comparison of survival curves with Mantel-Cox and Breslow test (p = 0.01), but not by the signs test. These differences were also observed for the 71 couples of squamous cell carcinomas and adenocarcinomas, and the apparied signs test was still not significant. The poor prognosis persisted for patients with high CEA level, when one another marker's level (NSE or SCC or Cyfra 21-1) was increased, in comparison with patients with any marker increased. On 29 couples of all histological subtypes or on the 25 couples of non small cell lung cancer, the signs test and the comparison of survival curves were significant, but not the 1 year survival rate. This study shows that a CEA level greater than 10 ng/ml at diagnosis is a poor pronostic factor in patients with lung carcinoma, independent of the stage of disease and of the histologic type.

Collaborative phase I and II studies of the combination of gemcitabine and cisplatin in patients with advanced non-small cell lung cancer are ongoing at five centres in the UK and France. In the initial completed phase I study, 16 patients (15 evaluable) have been entered using a fixed dose of gemcitabine 1000 mg/m2 given as a 30 min intravenous infusion weekly for 3 weeks. On the third week the gemcitabine was immediately followed by cisplatin with pre- and post-hydration. This regimen required only 1 night of hospitalization every 4 weeks. The study design was for sequential groups of patients to receive 3 dose levels of cisplatin (60 mg/m2, 75 mg/m2 and 100 mg/m2) but these doses would be modified and the number of patients at any dose level could be increased if significant toxicity was observed. Three patients were to be entered at the first two dose levels and 10 patients were to confirm the maximum tolerated dose (if reached) or expand the database on toxicity at the final predetermined dose level. The major haematological toxicities were neutropenia (grade 4 in 3 patients) and thrombocytopenia (grade 3 or 4 in 5 patients) but both were of short duration and uncomplicated. Grade 3 nausea and vomiting occurred in 12 patients but was no worse than would be expected from cisplatin alone. Alopecia was not a problem (no hair loss in 10 patients and grade 1 or 2 in 6 patients) and no significant renal or neurotoxicity was seen. A phase II study using cisplatin 100 mg/m2 in combination with gemcitabine 1000 mg/m2 has been opened and to date 19 patients are evaluable for response. Eight (42%) have achieved partial remissions. The study is ongoing and will recruit 50 evaluable patients.

Human papillomaviruses (HPV) have been implicated in the pathogenesis of human squamous cell carcinoma, especially of cervical carcinomas. In two previous studies concerning squamous cell carcinomas of the lung, DNA of HPV subtypes 6/11/16/18 (and 31/33/35 for one study) was detected by in situ hybridization in 7% to 30% of the cases. A series of 31 frozen biopsies of lung carcinomas were examined for the presence of HPVDNA by nested polymerase chain reaction (PCR). Type-specific primers (6/11, 16 and 18; Amplicis HPV(R)) located in the E6 or E7 transforming region of HPV were used. HPV DNA was found in 2 of 18 cases (11%) of squamous cell carcinoma, in 1 of 4 cases of adenocarcinoma and in 2 of 7 cases of neuro-endocrine cancers. The two large cell undifferentiated carcinomas were HPV negative. There were three cases of HPV 6/11, one case of HPV 16, and one sample positive for HPV 6/11 and HPV 18. No any consistent morphologic change with HPV lesions could be observed whereas squamous metaplasia could be seen only in squamous cell carcinomas. The frequency of 11% among the squamous cell carcinomas is comparable to those previously reported in studies utilizing in situ hybridization. To our knowledge HPV DNA had never been detected previously in adenocarcinomas or neuro-endocrine tumors. This finding should be confirmed by the investigation of larger series, but suggests that HPV could play a role in carcinogenesis of different types of lung carcinoma, although at low frequency.

The purpose of this study was to evaluate and compare the antiemetic effectiveness and tolerability of Navoban (tropisetron) and Zofran (ondansetron) following high-dose (or = 50 mg/m2) cisplatin chemotherapy. In a randomised, multi-centre, double-blind, double-dummy, parallel group study, 117 evaluable chemotherapy-naive patients who received Navoban were compared with 114 who received Zofran. Patient diary cards were used to assess both acute (Day 1) and delayed (Days 2-6) nausea and vomiting. Total control of acute vomiting was achieved in 54% of Navoban and 65% of Zofran patients (p = 0.052), and total control of acute nausea in 66% and 62% respectively (p = 0.655). Total control of delayed vomiting was achieved in 44% of Navoban patients and 46% of Zofran patients (p = 0.765), and of delayed nausea in 56% and 47% respectively (p = 0.207). Both reactions combined were totally prevented during the entire 6-day trial period in 22% of Navoban and 24% of Zofran patients (NS), while a further 42% of patients in both groups remained largely free from both nausea and emesis. The few adverse reactions (e.g. headache, constipation, diarrhoea) were mainly mild and typical of the 5-HT3-receptor antagonists. In conclusion, there were no significant differences in efficacy and tolerability between Navoban 5 mg once daily and the highest recommended dose of Zofran (32 mg on Day 1, followed by 8 mg three times a day).

Between February 1992 and May 1993, 22 patients older than 75 years, with non small cell lung cancer, were treated with carboplatin and oral etoposide. There were 18 men and four women with a median age of 79 years. Fourteen patients had an epidermoid carcinoma: four had an adenocarcinoma and four had an undifferentiated carcinoma. Carboplatin was administered intravenously on day 1 at a dose of 300 mg/m2; oral etoposide was administered at a dose of 600 mg/m2 (two capsules daily) for 9, 10, 11, or 12 days according to body surface. Courses were repeated every 28 days for a total of three courses.15 patients (68%) had received previous chemotherapy. Myelosuppression was the main problem with one grade IV and five grade III hematologic toxicities. We observed one mild neurologic toxicity.19 patients were evaluable for response. We observed one complete response (5%), five disease stabilizations (26%) and 13 disease progressions. Median survival was 5 months. These results led to discontinue this study.

An individual dose adaptation for cisplatin (CDDP), etoposide and gallium chloride (GaCl3) was proposed to improve the efficacy of this combination chemotherapy and avoid its toxicity. A clinical study was performed in 28 non small cell lung cancer patients, to verify this hypothesis. CDDP and etoposide were administered as continuous infusions every 3 weeks and GaCl3 orally during and between the CDDP-etoposide sequential infusions. CDDP doses were adjusted to achieve, during each 5 day infusion, an area under the total plasma platinum concentrations versus time curve (AUC Pt 0-120) ranging between 80,000 and 100,000 micrograms/l.h. Etoposide dosages were 120 mg/24 h during days 1-3 of the CDDP infusion. GaCl3 dosages were adjusted to obtain plasma gallium (Ga) concentrations ranging between 200 and 400 micrograms/l. The proposed methods of adaptation were successful from a pharmacokinetic point of view as AUC Pt 0-120 were respectively 81351 +/- 4788, 88268 +/- 8451 and 88331 +/- 8778 micrograms/l.h during the first 3 courses, and plasma Ga concentrations, determined during the 2nd and 3rd CDDP courses, 16 hours after the beginning of the CDDP infusion, were respectively 264 +/- 127 and 313 +/- 186 micrograms/l. However, these results were not pharmacodynamically successful and the therapeutic window was not confirmed. Past clinical trials with GaCl3 will be reviewed, as well as the factors which modify the pharmacokinetics or the pharmacodynamic effects of CDDP and GaCl3. From this review, an optimal dosage of 400 mg GaCl3 could be proposed to potentiate a combination chemotherapy with a platinum compound. The target AUC of the platinum compound should be the AUC avoiding its cumulative toxicity.

This subject interests the practitioner as it will enable him to predict, at the time of diagnosis, what are the chances for the treatment being successful, how long will the survival be, etc.? Unquestionable factors are the extent of the tumour expressed as stage, the number of metastasis sites and the histological nature of the cancer. Possible factors are: 1) In non-small cell carcinomas: Stage 1: P 53 mutation, satellite nodules found at surgery, tumour size less than 2 cm in diameter. Operated cancers: absence of invaded lymph nodes, small size of the tumour, mutation on P 185 Neu, codon 12 mutation of the cancer ras, mutation of P 53. Effectiveness of chemotherapy: positive NSE labeling. 2) Small cell carcinomas: extent of the lesions, number of metastasis sites and performance index. When these prognostic factors are known, they must be taken into account for the attempted treatments. On the other hand, factors of poor prognosis may influence the therapeutic approach.

The efficacy of the association of cisplatinum-mitomycine and vindesine on inoperable non-small cell bronchial cancer has been assessed in a prospective study. Cisplatinum 120 mg/m2 and mitomycine 8 mg/m2 on day 1, day 28 and day 70, and vindesine 3 mg/m2 once per week for the first cycle, once every 15 days for the second and third cycles. 98 patients were included in the study between February 1989 and June 1990: there were 89 men and 9 women with a mean age of 60. There were 57 epidermoid cancers, 22 adenocarcinomas, 1 neuroendocrine carcinoma and 18 large cell cancers. There was an objective response (RO) in 25% (of whom 5% had a complete response) without any significant difference between the 56 cancers at stage III (32% RO) and 42 cancers in stage IV (17% RO). The median survival of the responders was 14 months again 5 months for the non-responders. The initial loss of weight seemed to be a prognostic factor because the number of objective responders was significantly greater in the patients with only a small weight loss: 37% of RO if the weight loss was less than 5%, against 11% for a weight loss of greater than 5%. The myelotoxicity of this association was important because 85% of those patients presented with a leucopenia at least grade II OMS. Peripheral neuropathies occurred in 27% of cases: 4 cases of cardiotoxicity were reported.

We report six cases in which patients presented with acute dyspnoea following injections of either vindesine or vinorelbin. These patients were receiving chemotherapy in association with cisplatin, mitomycin, and vindesine or vinorelbin, for inoperable bronchial cancer. Three of the patients had evidence of airflow obstruction before these incidents. The clinical picture suggested bronchospasm and appeared in the two hours following an injection of the vinca alkaloid and a significant time away from the administration of the mitomycin. Additional respiratory support was necessary in one patient, the bronchial spasm stopped spontaneously in three cases, and following bronchodilator in two. The respiratory toxicity of vinca alkaloids (vindesine, vinblastin) was observed in 4% of the cases, uniquely when they were associated with mitomycin. Vinorelbin seems to possess the same respiratory toxicity. The bronchospasm, sometimes very severe, seems to occur in the two hours following the injection in the case of the cytotoxics and some time after the administration of mitomycin. The recurrence of the bronchospasm is a constant feature when the vinca alkaloid is readministered. This side effect is different to the pulmonary fibrosis due to mitomycin. Clinical follow up and spirometry is thus necessary in those patients receiving chemotherapy in which vinca alkaloids and mitomycin are associated and the regime should be followed after each administration of a vinca derivative. After the first episode of dyspnoea, it is probably wise to stop the administration of these anti-mitotics to prevent any further respiratory side-effects which could be more severe.

The usual form of chemotherapy of metastatic small cell lung cancer gives a 50% objective response with a mean survival of 7-8 months. We have tested a new antimitotic drug using pirarubicin alone in 26 patients. After the second treatment we noticed a response level of 12% with moderate toxicity. Then, we undertook classical chemotherapy using cisplatin-V16. After 3 doses the response level was 50% with a median survival of 32 weeks. In our study the use of a single drug pirarubicin in metastatic small cell cancer did not appear to worsen the chance of survival in patients if polychemotherapy was carried out immediately in cases which failed on the single drug. Our monotherapy did not appear to induce resistance to affective polychemotherapy. This method applied carefully to patients with metastatic disease with a strict follow up may be utilised in the assessment of the efficacy of the newer antimitotic drugs.

The authors report a case of pseudo-tumoral thoracic actinomycosis with lysis of a rib in a young man who was a heavy smoker and drinker. This observation is an opportunity to review the usual difficulties of diagnosis in patients with this rare disease occurring most often in a patient who is debilitated with important disease in the teeth and gingival margins. The standard treatment is penicillin G, which leads to a cure within one month.

Between November 1983 and November 1988, 60 patients with cerebral metastases arising from primary lung cancer were treated with chemotherapy. Thirty patients received a 5-day course of cisplatin (total dose: 200 mg/sq.m). The remaining 30 patients received VP 16 in doses of 250 mg/sq.m. administered 12-hourly by intravenous infusion over one hour (total dose: 1,500 mg/sq.m.). Twenty-seven percent of the patients who received cisplatin showed objective responses as assessed by computerized tomography; 10% had serious toxic reactions. Thirty percent of the patients who received VP 16 showed objective responses, but 43% had severe bone marrow aplasia resulting in a 33% death rate due to infection. The median survival of responders was 8 months in both treatment groups. The objective response rates as assessed by histology were 33% in patients with oat-cell carcinoma and 27% in patients with other histological types. VP 16 must be abandoned, being too toxic in high doses. High-dose cisplatin can be used in the treatment of cerebral metastases of lung cancer, side by side with radiotherapy.

CDDP is one of the most active single drugs in non small cell lung carcinoma. High doses of 200 mg/m2 are well tolerated when fractionated doses are used over a period of 5 d. Twenty-four consecutive patients (male, age range 38-70 y) with brain metastasis of lung carcinoma were included in this study. The total dose of CDDP - 200 mg/m2 - was divided into 5 equal daily fractions, infused over 6 h. Parenteral hydratation commenced the night before therapy. Efficiency was assessed by means of CT scan 15-30 d after the last course of chemotherapy. Complete response was achieved if no lesion was found on the CT scan; partial deafness 2 cases, renal toxicity 1 case, severe myelotoxicity 2 cases. Efficiency: failure was observed in 17 cases, objective responses in 7 cases (2 cases without injection contrast in the tumor, 3 partial regressions, 2 complete regressions). Thirty per cent of patients in this study exhibited an objective response with low toxicity. CDDP seems to be very useful in cerebral metastasis of lung carcinoma.

The influence of daily changes in sulfur dioxide (SO/sub 2/) levels on the induction of respiratory symptoms was studied during the 1983-1984 winter in 450 children, aged 9 to 11 yr, living in the Gardanne coal-basin, France. In this area, SO/sub 2/ originates mainly from a coal-fueled power plant. The mean SO/sub 2/ level during the winter was 22 micrograms/m3 in low-pollution areas and 93 micrograms/m3 in polluted areas, with daily SO/sub 2/ levels up to 356 micrograms/m3. Children completed a daily diary about respiratory symptoms. In the polluted communities only we demonstrated a significant association between daily SO/sub 2/ levels (after controlling for temperature and respirable particle variations) and prevalence of upper and lower respiratory symptoms. However, in each polluted town, and for each respiratory symptom, there was no evidence for either a latency period or a delay in the effects of pollutants. Mean daily temperature was also closely correlated with upper and lower respiratory symptoms in most of the polluted and some low-pollution communities. In a second step, the prevalence of respiratory symptoms in each town was compared, during two 2-wk periods, with air pollution levels; higher prevalences were found during the pollution period. In conclusion, moderate dailymore » changes in SO/sub 2/ levels induce a significant but transient increase in the prevalence of respiratory symptoms in children.« less

Symptomatic brain metastases are found in about 40% of patients with small cell lung cancer.Cranial irradiation is the first line treatment for this form of metastatic disease. Frequently brain metastases recur after this treatment or develop after prophylactic cranial irradiation. For these patients no effective antitumour therapy is available. In this study the efficacy of high dose etoposide 1.5 gm-2 was evaluated. In 10 (43%) out of 23 evaluable patients a response was seen. Toxicity was severe with five aplasia-related deaths. For palliative purposes this regimen is too toxic in heavily pretreated patients.

The prognosis of lung cancer is still very poor. However, during the last few years a favorable trend has been observed, consisting in the stabilization and even the decrease of incidence rate in Western countries. Besides, the sex-ratio shows a divergent trend, increasing in France and decreasing in the United States where lung cancer nowadays is the first cause of cancer deaths in women. The major risk factor, tobacco smoke, is now well established, qualitatively as well as quantitatively. Other air contaminants, occupational factors and air pollutants, have a lesser responsibility. The intervention of nutritional or genetic factors could explain why smokers are not equally susceptible to tobacco smoke. Screening for lung cancer is, and will be, reconsidered in the light of the results of prospective studies initiated 10 years ago under the auspices of the American Cancer Society.

Broncho-alveolar macrophages were obtained by bronchial washing from 20 pairs of matched smokers and non-smokers. The following parameters were studied: phagocytosing ability of macrophages on silica in cell culture in the presence or absence of cotinin, a biocompound of nicotin; migration inhibitory factor (MIF), and power and level of alpha 1-antitrypsin in sera of patients. The results are reported as a function of absolute number of macrophages obtained, their viability, the amount of cigarettes smoked, and the action of cotinin. MIF was stronger in the smokers. There was no difference between the groups as far as power and level of alpha 1-antitrypsin are concerned. Cotinin provokes important lesions in the macrophages. The phagocytic power was not significantly different in smokers and non smokers, but the results were better in non-smokers.

This study involved 20 patients, 13 female and 7 male, with a mean age of 49 years, suffering from localized (6 cases) scleroderma or generalized without Raynaud's syndrome (6 cas), with Raynaud's syndrome (6 cas) or acrosclerosis (2 cases). Respiratory function tests included study of volumes, flow rates, CO transfer (TLCO) and blood gases. There were 38% normal chest X-rays, 58% ventilatory disturbances (predominance of restrictive syndrome and decrease in (TLCO) was found in only 25% of cases. The authors emphasize the extent of pulmonary vascular lesions in these patients.

Every high smokers are not able to make a lung carcinoma, on the over hand nonsmokers can be able to develop a bronchial carcinoma. It is possible that genetic factors can be involved in the occurrence of this carcinoma. Dermatoglyphic studies are one of the technics to appreciate this problem. The study was done upon 37 bronchial carcinoma and 51 lung diseases (European origin, only man, same age). There are some big differences upon: --The Cummins index: the right index as well as the left are higher in bronchial carcinoma than in controls, but it is significative only for the right one (p less than 0,05) (28,89 +/- 3,7 to 26,88 +/- 4,55). --The frequency of the ten fingerprints: the differences between lung carcinoma and controls are highly significative (p less than 0,01) for the whorls (22,7 to 34,9) and slightly significative (p less than 0,05) for the ulna loops (65,4 to 57,4), the other fingerprints (arch, radial loops) are quite the same in the two groups. The studies upon the other figures (TFRC and the position of the axial tri-radius) do not show any differences. It seems to us that the dermatoglyphic studies of men with bronchial carcinoma differ from controls (hospitalized for lung diseases). These population have the same dermatoglyphic structure than a control population from blood donors of Marseilles. The dermatoglyphic studies can be an aid to identify high risk people.

Simultaneous dosage of carcino-embryonic antigen and beta 2-microglobulin was studied in serum and pleural liquid. Among the 20 patients with non-neoplasic infections, the carcino-embryonic antigen was not increased in the serum and only once at a border-line level in the pleura. The level of beta 2-microglobulin seems to be related to the number of lymphocytes in the pleural liquid (increase in 45% of the cases compared to 20% in the serum). Among the 31 cancer patients, carcino-embryonic antigen is increased in the serum of 36% of the cases and in the pleura of 48%. In 5 observations, the pleural levels were considerably increased compared with serum levels, suggesting the existence of a pleural metastasis. The beta 2-microglobulin is elevated in only 26% of the cases in the pleural liquid and in 13% in the serum. At the present state of knowledge, it therefore seems unnecessary to continue investigations concerning the beta 2-microglobulin. On the contrary, the pleural dosage of carcinoembryonic antigen could contribute to the diagnosis.