Long-duration, weekly treatment with gemcitabine plus vinorelbine for non-small cell lung cancer: a multicenter phase II study.

In this phase II study, gemcitabine and vinorelbine were combined at suboptimal doses for weekly administration in advanced non-small cell lung cancer (NSCLC). The primary objectives were to determine objective response rate (ORR) and time to progression (TTP). Secondary endpoints were safety and overall survival. Chemonaive patients with histologically or cytologically confirmed stage IIIB or IV NSCLC received vinorelbine (25 mg/m2) immediately followed by gemcitabine (800 mg/m2) once each week (on day 1) for 6 months without rest. From May 1998 to May 1999, 40 patients were enrolled (85% males; 70% stage IV) with a median age of 65.5. A total of 478 doses were administered, with a median of 9 per patient (range 2-72). The ORR was 27.5% (95% CI, 15.1-44.1%). The median TTP was 3.5 months (95% CI, 2.9-4.4 months). At a median follow-up of 6.5 months, the median survival was 11.6 months, and survival rates at 1 and 2 year(s) were 47.5% and 15.8%, respectively. The most common grade 3/4 hematologic toxicity was neutropenia, in 70% of patients, with febrile neutropenia in 28%. The most common grade 3/4 non-hematologic toxicity was transaminase elevation, in 22.5% of patients, which was transient and reversible. The other most prominent toxicities were, unexpectedly, pulmonary and cardiac toxicities. Based on these results, weekly, long-term administration of gemcitabine-vinorelbine appears to be an active regimen in NSCLC that warrants further investigation.

[Mesothelioma: advances in chemotherapy]. / Mésothéliome pleural: actualités en chimiothérapie.

Chemotherapy is often the only treatment possible for locally advanced or metastatic mesothelioma. This paper recalls which drugs might have therapeutic benefits in this condition and reviews recent studies of chemotherapy or targeted therapy. If the patient cannot be enrolled in a therapeutic trial the first line therapy in the absence of contraindications is a combination of cisplatin and pemetrexed, the latter having received a licence for this indication in September 2004. Among the alternatives reviewed are taxanes, liposomal anthracyclines, topoisomerase inhibitors, cisplatin derivatives, vinca alkaloids, and antimetabolites. Although the first three have show little or no benefit the vinca alkaloids (vinorelbine, vinflunine) and particularly the antimetabolites (gemcitabine, raltitrexed, pemetrexed) are very promising. Recent studies have looked most frequently at combinations of an anti-metabolite and a platinum salt, with data available from nearly 200 patients treated with gemcitabine. These studies have had fairly homogeneous results showing a one year survival of about 50%. Some preliminary data from studies of second line chemotherapy is also available. Finally studies of targeted therapies such as anti-EGFR, anti VEGF and anti PDGF are underway but have not as yet demonstrated major therapeutic benefit.

[Pain management in bone metastasis of pulmonary origin: new interventional and metabolic techniques]. / Nouvelles techniques interventionnelles et métaboliques dans la prise en charge des métastases osseuses.

Invasion of bone by a metastatic lesion is the most common cause of pain in cancer patients. Pain management in these patients is an important and difficult task. The pain is not always properly controlled by high doses of specific medication, radiation therapy or chemotherapy. When these therapies do not provide adequate pain relief, percutaneous vertebroplasty, cementoplasty, radiofrequency ablation and internal radiotherapy appear to be elegant and efficient complementary alternative pain control methods.

[Results of the ARPE trapezometacarpal prosthesis: a retrospective study of 37 cases]. / Résultats de la prothèse trapézomátacarpienne ARPE: à propos de 37 implantations.

We report the outcome of the ARPE trapezometacarpal prosthesis in the treatment of primary osteoarthritis of the thumb. The prosthesis based on a ball and socket system and is uncemented. This study presents the results of 37 consecutive implantations in 29 patients; 28 women, one man, eight bilateral (21 right, 16 left). The mean age at operation was 67 years at a mean of 36 months follow-up (maximum 7 years). Four patients were excluded (1 died, 3 lost to follow up). Preoperative radiological grading according to Comtet was 1 or 2. Patients all had low functional demand. Most of the patients were satisfied and pain free. Mobility was increased, including dorsal extension of the first metacarpal. Radiographic analysis and measurement of the scaphometacarpal index demonstrated a postoperative increased length of the thumb column, with a slight decrease at follow up. This phenomenon is due to sinkage of the prothesis into the cancellous bone. Mechanical complications occurred in four patients within the first four years. Removal of the prosthesis, trapeziectomy and tendon strip plasty were performed in three cases with good final results. This prothesis is a good surgical treatment of primary, isolated TM osteoarthritis in patients with minimal osteoporosis and low functional demands.

Preoperative chemotherapy for non-small cell lung cancer.

Surgery has been considered the standard of care in patients with early-stage non-small cell lung cancer (NSCLC), as well as in some cases of stage III, for a long time. Poor survival after complete resection has led to the search for new therapeutic strategies such as combining anticancer treatments. However, at the present time, attempts to combine chemotherapy and radiotherapy after surgery have failed to show any significant impact on survival among patients with completely resected NSCLC.

An ongoing randomized study of neoadjuvant chemotherapy in resectable non-small cell lung cancer.

The purpose of this trial is to assess the possible benefit of neoadjuvant chemotherapy before surgery in patients with operable non-small cell lung cancer. Patients with operable stages I (except T 1N0), II, or IIIA disease are eligible for this ongoing trial. Patients are randomized into two arms. Surgery is performed first in group I; patients found to have T3 tumors or N2 lymph nodes are given postoperative radiotherapy. Group 2 patients start with two cycles of chemotherapy; following surgery, two more cycles are administered in responder patients and, as in group I, patients with T3 tumors or N2 lymph nodes are given radiotherapy. Chemotherapy is the MIP protocol: mitomycin 6 mg/m2 day I, ifosfamide 1.5 g/m2 days 1 to 3, cisplatin 30 mg/m2 days I to 3, and mesna 1,200 mg/m2 days 1 to 3. One hundred fifty patients were enrolled between June 1991 and September 1993. By the time this report was prepared, 117 patients had completed all assigned treatment, 63 in group I and 54 in group 2. There were two ineligible patients, one in each group. Forty-nine patients underwent thoracotomy in the chemotherapy-surgery group and 62 in the surgery-only group. There was only one progression after two cycles of chemotherapy. Rates of exploratory and incomplete surgery were 17% in group I and 12% in group 2. The trial is ongoing.

Phase I study of vinorelbine and carboplatin in advanced non-small cell lung cancer.

Thirty-one patients with previously untreated advanced non-small cell lung cancer were included in a Phase I study to determine the optimal dose of Carboplatin (CBDCA) which preserves the best Navelbine (NVB) dose-intensity. NVB was administered at a 30-mg/m2 fixed-dose on days 1-8/q 3 weeks, whereas CBDCA doses were planned to be escalated from 275 to 400 mg/m2 on day 1/q 3 weeks for six successive groups of patients. The toxicity limiting dose of CBDCA in the combination was 350 mg/m2 on day 1/q 3 weeks because of repetitive Grade IV neutropenia, and the optimal dose of CBDCA was 325 mg/m2 on day 1/q3 weeks, offering a 86.4% NVB and a 92.6% CBDCA relative dose-intensity for the first 9 weeks. Responses were observed at each step. This study demonstrates the feasibility and the efficacy of the NVB-CBDCA combination. It suggests that dose-intensity calculation can be helpful to determine the recommended dose for Phase II studies of new drug combinations.

Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma.

Brain metastases are a frequent feature of the course of non-small cell lung carcinoma (NSCLC). The potential usefulness of prophylactic cranial irradiation (PCI) has led to the search for target groups likely to derive benefit. This multivariate analysis looked for factors predictive of brain metastases in a group of stages I-III NSCLC patients under care of the thoracic oncology unit of Besançon University Hospital from 1977 to 2001. All the patients had the same follow-up. They were divided into two groups: BM+ when they had a brain metastasis as the first site of progression, whether solitary or not, and BM(-) otherwise. Variables analysed were age, gender, performance status (0-1 versus 2-3), weight-loss stage T-status, N-status, pathological type, type of treatment, administration of chemotherapy, use of cisplatin and response to treatment. Three hundred and five patients were eligible and there were 77 patients (25.25%) in the BM+ group. Median time to onset of brain metastases was 12 months (1-163 months) and median survival from the diagnosis of brain metastases was 6 months (1-65 months). Factors predictive of brain progression were age < or =62 years (RR: 2.5, 95% CI: 1.33-4.76 and P = 0.004), T4 tumour status (RR: 3.75, 95% CI: 1.72-8.21 and P = 0.0009), N2-3 (RR: 2.61, 95% CI: 1.32-5.15 and P = 0.0057), and adenocarcinoma (RR: 3.39, 95% CI: 1.78-6.46 and P = 0.0002). No aspect of treatment plays a role in the frequency of this type of metastasis. These factors predictive of brain progression could serve as a basis for the selection of patients with the aim of sitting of studies on prophylactic cranial irradiation in NSCLC.

Phase I study of paclitaxel (Taxol) plus vinorelbine (Navelbine) in patients with untreated stage IIIb and IV non-small cell lung cancer.

A dose escalation study of paclitaxel in combination with vinorelbine was conducted in 21 patients with previously untreated stage IIIb or IV non-small cell lung cancer (NSCLC). All three patients treated with the initial dose of paclitaxel 135 mg/m(2) administered as a 1-h intravenous infusion and vinorelbine 25 mg/m(2) experienced dose-limiting toxicity (febrile neutropenia). After modification of the dosing schedule, the MTD of paclitaxel was found to be 115 mg/m(2) when combined with vinorelbine 20 mg/m(2) on day 1, followed by vinorelbine 20 mg/m(2) on day 5. Partial responses were achieved in 24% of patients, with a median duration of response of 126 days (range from 84 to 484 days) and a 1-year survival rate of 42%. In conclusion, haematologic toxicity (febrile neutropenia/neutropenia) severely restricts the dosing schedule of combined paclitaxel and vinorelbine, and possibly limits anti-tumour efficacy.

Phase II study of alternating doses of vinorelbine in combination with cisplatin for non-small cell lung cancer (NSCLC): a disappointing experience.

UNLABELLED: In both Phase III trials of vinorelbine-cisplatin (VP) versus single-agent vinorelbine, the received vinorelbine dose intensities were 18.8 and 21.1 mg/m2 per week in the VP arms. Vinorelbine was administered at the weekly dose of 30 mg/m2. A new structure of the vinorelbine-cisplatin regimen delivering alternating doses of vinorelbine (35 mg/m2 on weeks 1, 3, 5 and 17.5 mg/m2 on weeks 2 and 4) was reported to increase the vinorelbine dose intensity in patients with non-small cell lung cancer (NSCLC). To further analyze the ability of such an alternating vinorelbine schedule to enhance vinorelbine delivery, a Phase II study of VP was conducted in NSCLC patients using the previously published alternating doses of vinorelbine for 6 cycles. Cisplatin was administered on weeks 1, 5 and every 6 weeks thereafter, at a dose of 75 mg/m2 in the first 14 patients and at a dose of 100 mg/m2 in the 18 remaining patients. The intended vinorelbine dose intensity was 26.25 mg/m2 per week. The median delivered dose intensities of vinorelbine calculated during the first 8-week period were: all patients, 17.9 mg/m2 per week; patients treated with cisplatin 75 mg/m2, 18.1 mg/m2 per week; patients receiving cisplatin 100 mg/m2, 17.9 mg/m2 per week; naive patients 18.2 mg/m2 per week and previously treated patients. 13.2 mg/m2 per week. Reductions and delays in the vinorelbine treatment mostly occurred on weeks 3 and 7, which are times of high-dose treatments (35 mg/m2) according to the protocol. The partial response rate was 34% (95% C.I. = 26-42%). Median survival was 21 weeks. The main toxicities were febrile neutropenia (nine patients, including two septic deaths) and constipation Grades 3 and 4 (five patients). CONCLUSION: The use of alternating doses of vinorelbine within the VP regimen did not lead to higher vinorelbine delivered dose intensities than those reported with a standard weekly 30 mg/m2 administration.

Concurrent cisplatin/etoposide chemotherapy plus twice daily thoracic radiotherapy in limited stage small cell lung cancer: a phase II study.

Thirty-one previously untreated patients with limited stage small-cell lung cancer (LSCLC) were included in a prospective study, to investigate the feasability and the efficacy of a combined modality treatment using concurrent hyperfractionated chest irradiation and cisplatin (P) plus etoposide (E) chemotherapy. All patients received intravenously P=75 mg/m(2) at day 1, plus E=120 mg/m(2) days 1-3, at 3-week intervals for six cycles. Irradiated patients received 45 Gy in two daily fractions, 5 days a week, from week 4 to week 6. During week 5, prophylactic cranial irradiation was initiated, in one daily fraction of 2.5 Gy for a total dose of 25 Gy. Twenty-nine patients were evaluable for response. Twenty-two (76%) achieved a complete response, five (17%) had a partial response. Five patients are currently alive. The overall response rate was 93% (CI 95% (83.7-100)). The median survival time was 14 months and the 2-year survival rate was 25%. Main toxicities were grade 3-4 esophagitis in half of the patients and myelosuppression. The results are not as optimistic as other studies using a similar regimen.

Small cell lung cancer: patients surviving longer than thirty months. Groupe d'oncologie de langue française.

The long-term survivors of SCLC are described in 3 different types of study: analysis of prognostic factors of phase II and III chemotherapy trials (3,4,5,6,7,17,18), epidemiological studies (8) and medical registries of LTS (9,10). A small number of patients with small cell lung cancer achieve long-term survival. Most of these patients have a disease limited to the chest at the time of diagnosis. The major concerns of these LTSs are: the relapse of the SCLC, the occurrence of a second primary tumour and the occurrence of a disease related to tobacco consumption. About 20% of the LTSs die of non-cancer related causes and this exceeds the age adjusted mortality. There is a high risk of relapse in the first 4 years after the diagnosis; this risk decreases later, but relapses may be seen until 7 years. Nearly 8% of LTSs developed a SPTs are alive at 8 years; this indicates that cure is possible in SCLC, however, these patients account for less than 3% of the overall population.

Long-term cure of a non-small-cell lung cancer treated by monochemotherapy.

Cure after 8 years of a non-small-cell lung cancer (NSCLC), inoperable because of locoregional spread, is reported. The authors believe this case represents the longest survival after monochemotherapy reported to date and provides the opportunity to review studies of prognostic factors concerning long-term survival in NSCLC.

A phase II study of Navelbine (vinorelbine) in the treatment of non-small-cell lung cancer.

Navelbine (vinorelbine, NVB) is the first semisynthetic 5'-nor-vinca-alkaloid selected for clinical trial. NVB has been shown to have a good level of activity against different experimental solid tumors in animals, with low neurotoxicity. In the phase II study, 78 patients with an inoperable non-small-cell lung cancer (NSCLC) were treated with NVB at a weekly dose of 30 mg/m2. No patient had previously received chemotherapy. Twenty-three of the 78 eligible patients showed a partial response (29.4% with a 95% confidence limits: 19.5-39.5). Eight patients were not evaluable and the percentage of partial response were 32.8% in the evaluable patients group. The median response duration was 34 weeks, and the median survival time for the overall population reached 33 weeks. Grade 3-4 leukopenia was seen in 12.5% of cycles. No thrombocytopenia occurred. At the dosage schedule used, NVB seems a very promising agent in the treatment of NSCLC.

[Standards, options and recommendations for the management of locally advanced non small cell lung carcinoma]. / Standards, otions et recommandationspour la prise en charge thérapeutique des patients atteints d'un cancer bronchopulmonaire primitif non à petites cellules localement avancé.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the management of locally advanced non small cell lung carcinoma. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations are: 1) The management of the locally advanced non small cell lung carcinoma has two main goals: firstly to obtain local control of the disease (or to at least delay local progression in order to improve the survival or relapse free survival), and secondly to prevent the development of metastases. 2) There is a consensus that locally advanced non small cell lung carcinoma should be irradiated. External beam radiotherapy should be of optimal quality and delivered at a minimal dose of 60 Gy by standard fractionation. For patients with a poor life expectancy, this can be delivered as a split-course or hypofractionated scheme. 3) Treatment for patients with a performance status of 0-1 should consist of short duration induction chemotherapy (with a least two drugs one of which must be cisplatin), combined sequentially with conventional radiotherapy. 4) Surgery is contraindicated in extensive N3 disease. Combined radio-chemotherapy (adjuvant or neoadjuvant) is not indicated outside clinical trials. Surgery is justified in stage N2 disease as good local control can be achieved. T4-N0 disease should be treated surgically with curative intent.

[Standards, Options and Recommendations for the management of stage I or II primary bronchial cancers treated exclusively with radiotherapy]. / Standards, Options et Recommandations pour la prise en charge des patients atteints d'un cancer bronchique primitif de stade I ou II traités par irradiation exclusive.

CONTEXT: The 'Standards, Options and Recommendations' (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French cancer centres and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the management of stage I and II non small cell lung carcinoma treated by radiotherapy alone. METHODS: Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French cancer centres. RESULTS: The main recommendations for the management of stage I and II non small cell lung carcinoma treated by radiotherapy alone are: 1) The curative external irradiation with a continual course is an alternative to surgery only in the case of medically inoperable tumors or because the patient refuses surgery; 2) The external irradiation of the primary tumor only without the mediastinum could be proposed in peripheral stage IA. In proximal stage IA and IB, external irradiation should be carried out only as part of prospective randomised controlled trials comparing a localised irradiation of the primary tumor with a large irradiation of the mediastinum and the primary tumor. The treated volume must include the macroscopic tumoral volume with or without the microscopic tumoral volume and with a security margin from 1.5 to 2 cm; 3) There is a benefit to delivering a total dose in the primary tumor higher than 60 Gy in so far as the proposed irradiation, taking into account the respiratory function, does not increase the likelihood of severe adverse events due to radiation; and 4) The change in fractionation, the radiochemotherapy combination, the endobronchial brachytherapy with high dose rate alone or with external irradiation could be proposed only as part of prospective controlled trials for tumors classified as stage IB or II.

[Disseminated infection due to an unusual strain of Nocardia farcinica]. / Infection disséminée due à un germe inhabituel, Nocardia farcinica.

Nocardia farcinica, isolated by Nocard in 1888, has recently been redefined as a separate species to asteroides and has been recognised as human pathogen since 1975. Following airborne contamination, lung infection is most usual with frequent dissemination especially to central nervous system. Usually drug resistance makes treatment difficult. The authors describe the first case of Nocardia farcinica disseminated infection in France with lung primarily affection, empyema and encephalitis.

[Second line chemotherapy in patients with refractory and resistant non small cell lung cancer]. / Chimiothérapie de deuxième ligne chez les patients réfractaires et résistants atteints de cancers du poumon non à petites cellules.

Effectiveness of chemotherapy has been demonstrated in stage IV non small cell lung cancer as well as in stage IIIb disease when combined with radiotherapy. A significant improvement of both survival and quality of life was shown and is thought to be associated with higher efficiency. Therefore, treatment of relapses is now a question of practical interest. Ninety-seven non small cell lung cancer patients who were delivered a second line chemotherapy following primary chemotherapy alone were reviewed. Sixty-five patients were administered a 2 drug cisplatin-based regimen (with etoposide, bleomycin or vinorelbine). Twenty eight patients received no cisplatin but the cyclophosphamide, epirubicin combination or any 2-drug regimen assembled from the following agents: etoposide, mitomycin, ifosfamide. The last 4 patients were given single-agent vinorelbine. Fifteen objective responses (15.2%) (95% CI: 9-24%) were observed. The median response duration was 27 weeks. Response rates were 18.4% (95% CI 9-28%) and 9.3% (95% CI: 0-19%) in cisplatin-based combinations and in other regimens, respectively. No difference in response rates was observed between primary responsive and non responsive patients but response rates were influenced by the choice of the first line combination chemotherapy.

[Restoration of elbow extension in the tetraplegic by transplantation of the posterior deltoid. Study of 21 cases]. / Réanimation de l'extension du coude chez le tétraplégique par transplantation du deltoïde postérieur. Etude de 21 cas.

The authors have transferred the posterior part of the deltoid muscle to the triceps in 21 tetraplegics. A modification of Moberg's technique has been employed utilising a strip of fascia lata reinforced by Dacron sutures to allow rehabilitation after only 3 weeks. Despite limited active extension of the elbow and diminished power, results were considered to be satisfactory by the patients. They benefited from a greater range of movement of the hand, an improved possibility of bearing weight, improvement in the use of wheelchairs and better ability to express their bladder.

[Maintenance chemotherapy in small cell lung cancer: reasons for not using it]. / La chimiothérapie d'entretien dans les cancers bronchiques à petites cellules: des raisons pour ne pas la faire.

There is no consensus as the optimal duration for treatment in patients with small-cell lung cancer. In routine practice, 6 cycles of chemotherapy are usually delivered, but the rate of recurrence after achieving objective response has incited interest in several trials aimed at evaluating the effect of prolonged "maintenance" chemotherapy. Such prolonged regimens may use the same drugs as used in the induction protocol or call upon new drugs. No conclusion can be drawn from the 14 randomized studies conducted to date because of differences in the randomized populations as well as the nature of the treatments tested. Among 9 trials using a maintenance regimen with the same drugs as the induction protocol, there has been no significant difference in long-term survival. One study even found a lower 2-year survival with maintenance therapy. Among 5 trials where the maintenance protocol used drugs different from the induction protocol, survival rate favored maintenance chemotherapy in only 1. Most authors have observed a significant deterioration in quality of life in patients given maintenance chemotherapy, in addition to a number of deaths due to drug toxicity. Patient recruitment had to be interrupted in one study. The percentage of patients who received the entire maintenance protocol was also very low in many trials (20%). There may exit a theoretical advantage to giving maintenance chemotherapy, but does it counterbalance the risk of late complications? An increased risk of a second cancer has been demonstrated in patients given more than 6 cycles in the National Registry of long-term survival. Given the current state of our knowledge, it would not appear reasonable to propose maintenance chemotherapy for patients with small-cell lung cancer outside controlled clinical trial protocols.