An open phase II trial of gemcitabine, oxaliplatin and vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients.

The purpose of this multicentric Phase II study was to evaluate the safety and efficacy of a gemcitabine/oxaliplatin/vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients. Patients followed a fortnightly drug schedule, receiving on day 1, vinorelbine 25mg/m(2) (20-min infusion); gemcitabine 700 mg/m(2) (70-min infusion, fixed 10mg/m(2)/min); and on day 2, oxaliplatin 85 mg/m(2) (2-h infusion). Thirty-nine patients with a median age of 58 years received a total of 306 cycles (median 8 cycles); 67% were males. Most had adenocarcinoma (51%), large-cell (23%) and squamous cell carcinoma (21%); 15% had stage IIIB and 85% stage IV. There was one complete response (3%; 95% CI: 0.1-13%), 15 partial responses (PR) (38%; 95% CI: 23-55%), and 13 patients with stable disease (33%; 95% CI: 19-50%) of at least 2 months duration, for an overall non-progression rate of 74%. Median progression-free survival (PFS) was 4.1 months (95% CI: 3.1-8.7) and overall survival was 11.7 months (95% CI: 7.7-19.4). No treatment-related deaths occurred and very few grade 3-4 events were observed. Overall, the regimen was well tolerated and the planned recommended dose intensity was safely delivered to more than 95% of patients. This triple combination therapy study yielded favourable efficacy and toxicity results, which merit further evaluation in prospective randomised trials.

Competing events determining relapse-free survival in limited small-cell lung carcinoma. The French Cancer Centers' Lung Group.

PURPOSE: We report results in terms of relapse-free survival (RFS), obtained in patients with limited small-cell lung carcinoma (SCLC) treated by four consecutive alternating protocols, using a competing risk approach with local recurrences, distant metastases, and death unrelated to cancer as competing events. PATIENTS AND METHODS: Two hundred two patients with limited SCLC were included in four consecutive protocols alternating radiotherapy and chemotherapy (CT). The alternating schedule consisted of six cycles of CT (doxorubicin, etoposide [VP16213], and cyclophosphamide [CAVP16], plus methotrexate in the first protocol; cisplatin replaced methotrexate in the other three protocols) and three courses of thoracic radiotherapy at a total dose of 45, 55, 65, and 61 Gy in the four consecutive protocols, respectively (accelerated hyperfractionation was used in the first course of the fourth protocol). A 1-week rest followed each CT cycle and each course of radiotherapy. Seventy-six percent of patients were in complete remission at the end of the induction treatment. RFS variables were determined according to a model assuming competing risks to define the first cause of failure (local disease, distant metastasis, or intercurrent death). RESULTS: No significant differences were observed between the four treatment groups. Overall results showed a 2-year cumulative incidence rate of failure of 75%. When analyzed, the first cause of failure was local recurrence only, 33%; distant only, 25%; distant and local simultaneously, 9%; and intercurrent death, 8%. CONCLUSIONS: The methodology of competing risks allowed an unequivocal description of first events in limited SCLC. The extent of the local problem has been relatively overshadowed by the use of conventional descriptive methods.

Phase I/II study of escalating doses of vinorelbine in combination with oxaliplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: Oxaliplatin is a platinum compound active in non-small-cell lung cancer (NSCLC) patients, and vinorelbine (VNB) is an active reference agent. This phase I/II study was performed to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the recommended dose (RD) of a VNB/oxaliplatin combination given to previously untreated patients with advanced NSCLC. PATIENTS AND METHODS: Oxaliplatin was given at the fixed dose of 130 mg/m2 (2-hour intravenous [IV] infusion) on day 1. VNB was administered on days 1 and 8 (10-minute IV infusion), with doses starting at 22 mg/m2/d and escalated by 2 mg/m2 increments until MTD. Treatment was repeated every 3 weeks. No special hydration measures or prophylactic granulocyte colony-stimulating factors were used. RESULTS: Twenty-seven patients (20 men, 7 women) received 110 cycles total at six different VNB dose levels. Neutropenia was the DLT. Although no patient experienced DLT at the highest dose level (32 mg/m2/d), multiple treatment delays (54% of cycles) and dose reductions (34% of cycles) were required at this dose level. Others toxicities were mainly limited to grade 1 peripheral neuropathy and grade 1/2 nausea/vomiting. The relative dose-intensity of administered VNB from dose levels 3 to 6 (26 to 32 mg/m2) remained stable, whereas grade 3/4 neutropenia increased. All patients were assessable for activity; there were 10 objective responses, including one complete response (37% response rate). CONCLUSION: The present combination can be safely administered in an outpatient setting. The RD is VNB 26 mg/m2 days 1 and 8 with oxaliplatin 130 mg/m2 day 1 every 3 weeks.

Influence of pretreatment clinical characteristics on the response rate to mitomycin/vindesine/cisplatin (MVP) in unresectable non-small cell lung cancer. ATTIT (Association pour le Traitement des Tumeurs Intra-Thoraciques).

The authors report their experience with the MVP (mitomycin/vindesine/cisplatin) regimen of the Memorial Sloan-Kettering Cancer Center (MSKCC) which showed the highest response rate in non-small cell lung cancer (NSCLC). The aim was to respect the original reported schedule to appreciate its activity, because the same drug combination with dose and schedule variations used by other investigators has failed to reproduce the original report results. 82 consecutive previously untreated patients with unresectable and/or metastatic NSCLC received mitomycin (8 mg/m2 days 1, 29, 71), vindesine (3 mg/m2, days 1, 8, 15, 22, 29, 43, 57, 71) and cisplatin (120 mg/m2, days 1, 29, 71), with evaluation on day 71. 24 objective responses were noted (29%) (2 complete response/22 partial response) (95% CI 19%-39%), without differences according to histology. Differences in median survival were noted according to the performance status and type of response. Overall survival rates in responding patients were similar to those noted with the original schedules. Analysis of selection criteria showed that there were more patients with bone (P less than 0.01) or liver metastases (P less than 0.05), less women (P less than 0.001) and less adenocarcinoma (P less than 0.001) than the MSKCC trial. A dose intensity analysis showed only a minimal difference in the average weekly doses of vindesine (10% lower than MSKCC trial: 1.8 mg/m2 vs. 2.25 mg/m2). Disease improvement, a subjective response criterion used in the MSKCC trial, was probably underestimated in the current study. We conclude that the potential benefit of chemotherapy with a three-drug combination in NSCLC is greatest in patients with stage IIIa and IIIb disease or stage IV disease with a good performance status and a low metastatic volume.

Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). ATTIT. Association pour le Traitement des Tumeurs Intra Thoraciques.

The aim of this phase II study was to determine the antitumour activity and safety of trans-1-diaminocyclohexane-platinum (oxaliplatin) in previously untreated advanced non-small cell lung cancer (NSCLC) patients. 33 patients with unresectable and measurable NSCLC were entered into this phase II study between January 1992 and January 1994. Patients had either locoregional disease with performance status 2 (19 patients) or a stage IV disease (14 patients). Oxaliplatin (130 mg/m2) was given on an out-patient basis (2-h infusion, every 21 days) without hydration. Response was assessed after every two courses. One hundred courses were administered, with a mean of three courses per patient (range 1-12). All patients were evaluable for response; 1 had a complete response, and 4 a partial response (overall response rate 15%, 95% confidence interval 5.1-31.9%). The median response duration was 5.9 months. All cycles (n = 100) were evaluable for toxicity assessment. Transient reversible, cold-related finger dysesthesias occurred in 29 patients, but were mild, and disappeared in most cases within a few days. We observed brief episodes of pharyngolaryngeal discomfort (8 patients, 11 episodes) accompanied in 4 cases (3 patients), by transient episodes of inspiratory stridor, leading 2 patients to treatment withdrawal. We conclude that oxaliplatin has activity in poor-prognosis NSCLC and that this treatment is feasible in out-patients; the absence of renal and haematological toxicity makes this drug a good candidate for further evaluation in NSCLC.

Systemic mast cell disease associated with primary mediastinal germ cell tumor.

The first known case of systemic mast cell disease associated with a germ cell tumor is reported. Six months after the complete remission of a primary mediastinal germ cell tumor treated by chemotherapy and resection, a young man had a series of episodes of hypotension and syncope and, a few months later, a gastric hemorrhage and coagulation disorder. The diagnosis of systemic mast cell disease was made in view of bone marrow and liver biopsies. A transient circulating heparin-like anticoagulant was noted. The occurrence in a short period of these two unusual conditions, given previous knowledge of hematologic disorders associated with germ cell tumors, suggests that the present association is not a coincidence. Systemic mast cell disease should be considered among the hematologic disorders associated with a germ cell tumor.

ASTRO (American Society for Therapeutic Radiology and Oncology) plenary: Effect of chemotherapy on locally advanced non-small cell lung carcinoma: a randomized study of 353 patients. GETCB (Groupe d'Etude et Traitement des Cancers Bronchiques), FNCLCC (Féderation Nationale des Centres de Lutte contre le Cancer) and the CEBI trialists.

Most patients with locally advanced non small cell lung carcinoma are treated with external thoracic radiotherapy. Because of the high incidence of distant metastasis the addition of chemotherapy has been proposed. The present randomized study was conducted from June 1983 to February 1989 and included 353 patients. The trial compared arm A, thoracic megavoltage radiotherapy alone at a total dose of 65 Gy in 26 fractions and 45 days, to arm B that comprised the same radiotherapy preceded and followed by 3 monthly cycles of VCPC (vindesine 1.5 mg/m2 d 1-2, cyclophosphamide 200 mg/m2 d 2-4, cisplatinum 100 mg/m2 d 2 and lomustine 75 mg/m2 d 3). Disease was deemed unresectable but non-metastatic after bronchoscopic, radiologic, CAT, and nuclear scans and physical examinations. Only patients in clinical, radiological, endoscopic, and histological complete remission were considered as locally controlled; these patients were monitored by fiberoptic bronchoscopy and systematic biopsies to the primary site. One hundred seventy-seven patients received thoracic radiotherapy alone and 176 received the combined modality. Twenty-seven percent of arm B patients had an objective response after 2 VCPC cycles. At the time of final assessment, performed 3 months after the end of thoracic radiotherapy in both arms, there were 20% of complete responders in arm A versus 16% in arm B. The two-year survival rate was 14% in arm A versus 21% in arm B (p = 0.08, logrank test). The distant metastasis rate was 67% in arm A versus 45% in arm B (p less than 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively). The striking effect of VCPC chemotherapy on the incidence of distant metastasis did not have a significant impact on overall survival. We conclude that thoracic tumor control remains a significant problem in unresectable non small cell lung cancer.

Alternating radiotherapy and chemotherapy in 173 consecutive patients with limited small cell lung carcinoma. GROP and the French Cancer Center's Lung Group.

One-hundred seventy-three patients with limited small cell lung cancer were included in three consecutive protocols alternating radiotherapy and chemotherapy. The alternating schedule consisted of six courses of chemotherapy (doxorubicin, VP16213, cyclophosphamide, and methotrexate in the first protocol; methotrexate being replaced by cisplatinum in the other two protocols) and three series of thoracic radiotherapy delivering a total dose of 45, 55, and 65 Gy in each consecutive protocol. Radiotherapy was started after the second course of chemotherapy. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. Seventy percent of patients were in complete remission at the end of the induction treatment. The actuarial 5-year local control was 60% and the 5-year overall survival was 18%. Sixty percent of patients developed distant metastases. The death rate unrelated to cancer was 10%. These results show that alternating radiotherapy and chemotherapy schedules are reproducible, and provide a consistent long-term local control and a long-term survival rate exceeding 15% in limited disease.

Alternating radiotherapy and chemotherapy schedules in limited small cell lung cancer: analysis of local chest recurrences.

An analysis of the chest recurrences was conducted in 72 consecutive patients with limited small cell lung cancer treated in two successive phase II trials alternating six induction chemotherapy courses and three series of thoracic radiotherapy, followed by maintenance chemotherapy. The total radiation dose was 45 Gy (3 series of 15 Gy) in the first trial, and 55 (20, 20 and 15 Gy) in the second. The effect of the irradiated volume was investigated by comparing the local relapse rates in the group of patients treated by radiation fields encompassing the initial tumor volume to another group in which the initial target volume was not fully covered by radiation fields. The definition of these two groups was performed retrospectively by examination of radiological, fiberoptic bronchoscopy initial findings, technical radiation charts and check films. The local recurrence rate were 33 and 36% in each group (no significant difference). This finding could suggest that tumor shrinkage after chemotherapy might allow the use of "reduced" radiation volumes. However, the limited number of patients does not permit a definite conclusion. The effect of radiation dose was investigated by comparing the local control rates in the two consecutive trials which delivered 45 and 55 Gy, respectively. No difference in long-term local control was found: the addition of 10 Gy in the second trial only seemed to delay the appearance of local recurrences by 6 months. Twenty percent of patients died from a local relapse without evidence of distant metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic mastocytosis following mediastinal germ cell tumor: an association confirmed.

A 24-year-old man had a mediastinal embryonal carcinoma containing yolk sac foci. Combination chemotherapy with cisplatin, bleomycin, etoposide, and vinblastine was given, and the residual mass was then resected. Histology showed only necrotic cells. No other treatment was given. Two years later the patient presented with episodes of flushing and syncopes related to a systemicmastocytosis. Bone marrow examination showed a diffuse infiltration with large, atypical mast cells often with multilobulated nuclei. The patient suffered several episodes of cardiovascular collapse and died during one of these episodes, 8 months after the diagnosis of systemic mastocytosis and 40 months after the diagnosis of mediastinal tumor. Autopsy findings included the absence of mediastinal tumor and a diffuse liver and spleen mast cell infiltration. This was the second case with the similar clinicopathologic picture of two rare diseases being associated. This fact supports the hypothesis of a distinct entity, part of the mediastinal germ cell tumor/hematologic malignancy syndrome. The hypothesis of a cytokine secretion induced by mediastinal germ cell tumor supporting mast cell proliferation may be considered.

Interactions between cigarette smoking and the natural history of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is characterized by an inflammation of the walls of the respiratory airspaces that proceed to fibrotic alveolar derangement. Smoking habits are associated with changes in the number and the activation state of immune and inflammatory alveolar cells. Cigarette smoke could interact with the course of this disease. To evaluate the effects of smoking on IPF, 11 smokers and 16 nonsmokers were compared. Clinical presentation, PFTs, BAL cell populations, short-term glucocorticoid responsiveness and survival were evaluated. Similar PFT results were observed in both groups. Lymphocyte cells were higher in nonsmokers than in smokers. Glucocorticoid responsiveness was mainly observed in nonsmokers. Nonsmoking status was not associated with survival advantage. We conclude that the subset of IPF characterized by an aggressive onset, a BAL fluid high lymphocyte count and a substantial PFT improvement after therapy began, occurs predominantly in the absence of cigarette smoking habits.

Alternating radiotherapy and chemotherapy in limited small cell lung cancer: the IGR protocols. French FNCLCC Lung Cancer Study Group.

Two-hundred two patients with limited small cell lung cancer were tested by four consecutive alternating radiotherapy and chemotherapy protocols. The alternating schedule consisted of six cycles of chemotherapy (doxorubicin, etoposide, and cyclophosphamide, plus methotrexate in the first protocol; cisplatin replaced methotrexate in the other three protocols) and three courses of thoracic radiotherapy at a total dose of 45, 55, 65 and 61 Gy in the four consecutive protocols, respectively. A 1-week rest followed each chemotherapy cycle and each course of radiotherapy. Seventy-six percent of patients were in complete remission at the end of the induction treatment. Overall results showed a 2-year cumulative incidence rate of failure of 75%. The first cause of failure was local recurrence only, 33%; distant only, 25%; distant and local simultaneously, 9%; and intercurrent death, 8%. Overall survival rate at 5 years was 16%. No significant differences were observed between the four treatment groups. Alternating radio-chemotherapy approaches are feasible and currently included in Phase III trials.

Recurrent chromosome aberrations in human lung squamous cell carcinomas.

Cytogenetic study of seven cases of previously untreated lung squamous cell carcinomas (SQC) is reported. Chromosome numbers vary from 38 to 538, with a majority of hypotriploid karyotypes with complex rearrangements. The numbers of recurrent imbalances were evaluated in considering the average number of chromosomes or chromosome segments in each analyzed metaphase and for each case. In decreasing order of frequency, deficiencies for 3p, 5q, 8p, Y, 5p, 10p, 13, and, to a lesser degree, for 8q, 9, 10q, 11pter, 14, 15, and 21 were observed; the excesses principally involve 1q, 3q, and 7q. In three tumors, homogeneously staining regions were observed at various chromosome sites. Most chromosome rearrangements occurred after breakage in constitutive heterochromatin, and no recurrent breakpoints were found in euchromatin except 11p15. The major consequences of these anomalies may be chromosomal imbalances, leading to hemizygosity and perhaps related to gene dosage, rather than to alterations of genes.

Cytogenetic study of five cases of lung adenosquamous carcinomas.

The cytogenetic study of five cases of untreated adenosquamous carcinoma of the lung allows us to propose a number of characteristic anomalies. All tumor cells were hyperdiploid, with a mean chromosome number ranging from 59 to 83, and had many clonal chromosome rearrangements. The chromosomes the most frequently affected by these rearrangements were, by decreasing order, 1, 3, and 15; 7 and 8; and 17. No recurrent breakpoints were observed in euchromatic regions, most breaks (45/66) involving juxtacentromeric heterochromatin or immediately adjacent regions. Although chromosome 3 was frequently rearranged, no recurrent deletions of its short arm were observed.

[Respiratory sequellae after alternated chemotherapy and radiotherapy for small cell anaplastic cancer]. / Sequelles respiratoires après chimiothérapie et radiothérapie alternées pour cancer anaplasique à petites cellules.

The authors analyze the respiratory sequelae in 19 patients with limited small cell lung carcinoma who survived for more than 30 months following an alternating chemo-radiotherapeutic combined regimen. The clinical tolerance measured with respiratory functional test is acceptable. In two patients an effort dyspnea is increased by evolutive, chronic obstructive bronchopneumopathy. Radiologic sequellae are constant and correlated with the volume of irradiation and cumulative etoposide doses. The role of a combined chemo-radiotherapeutic in pulmonary toxicity is discussed.

[Chemo-radiotherapy combination in small cell bronchial carcinomas. Limitations and results in 109 patients treated with an alternating protocol]. / Association chimio-radiothérapique dans les carcinomes bronchiques à petites cellules. Limites et résultats chez 109 malades traites avec un schéma d'alternance.

One hundred and nine patients with limited small cell lung carcinoma were entered in a phase II study alternating six cycles of combination chemotherapy and three courses of mediastinal radiotherapy. Chemotherapy consisted of doxorubicin 40 mg/m2 day 1, etoposide 75 mg/m2 days 1, 2, 3, cyclophosphamide 300 mg/m2 days 3, 4, 5, 6, and methotrexate 400 mg/m2 day 2 (+folinic acid rescue) or cisplatin 100 mg/m2 day 2. The total mediastinal radiation dose was 45 or 55 Gy. A 6 to 8 cycle maintenance chemotherapy followed this induction protocol. The complete remission rate at the end of the induction therapy was 79%. The local recurrence rate was 25% and the distant metastases rate was 52%. Median survival is 17.2 +/- 1.2 months and survival rate at 3 years is 26%. Lethal toxicity occurred in 3% of patients during induction therapy, and long term survivors are being evaluated. Our results justify further investigations with this alternating schedule.

[Combination of chemotherapy (vindesine, lomustine, cisplatin, cyclophosphamide) and thoracic radiotherapy in nonresectable non-small cell bronchial carcinoma: final results of a phase II clinical trial]. / Association chimiothérapie (vindésine, lomustine, cisplatine, cyclophosphamide)--radiothérapie thoracique dans les carcinomes bronchiques non à petites cellules inopérables: résultats définitifs d'un essai phase II.

Seventy-five patients with locally advanced non small cell lung carcinoma were entered in a phase II study combining chemotherapy (vindesine, lomustine, cisplatin and cyclophosphamide) and radical thoracic radiotherapy delivering a total dose of 60-65 Gy. Patients were regularly assessed by radiological and fiberoptic bronchoscopy examinations in order to evaluate local control. An objective response was observed in 22 patients (29%) after initial chemotherapy (2 complete remissions and 20 partial responses). The complete response rate after the combined schedule was 30%. Toxicity of this combination was acceptable. Median survival was 13.5 months. Actuarial risk of developing distant metastases at 3 years was 60%. However, the main cause of failure was local with 80% of uncontrolled or recurrent thoracic tumor in the first 2 years of follow-up. The present study shows that local control remains a major problem in the management of patients with inoperable non metastatic non small cell lung cancer.

Limited small cell lung cancer: possible prognostic impact of initial chemotherapy doses.

While the effect of chemotherapy dose on tumor response in small cell lung cancer has been fairly well established, the effect on survival has been retrospectively analyzed only in some series. This particular point was studied in a series of 52 consecutive patients with limited small cell lung cancer treated by an alternating radiotherapy-chemotherapy schedule. The induction treatment consisted of 6 chemotherapy cycles (the planned doses were: doxorubicin 40 mg/m2 day 1, VP16213 75 mg/m2 days 1-3, cyclophosphamide 300 mg/m2 days 3-6, and cisplatinum 100 mg/m2 day 2) alternated after the first 2 cycles with 3 courses of thoracic radiotherapy delivering a total dose of 55 Gy. Eighty-one percent of patients went into complete remission and the 3-year relapse-free survival was 24%. A multivariate analysis of prognostic factors took into account age, sex, T stage, performance status, delayed hematological toxicity to the first course of chemotherapy, actual dose/m2 of each drug during the first course and mean dose/course delivered during the induction treatment after the first cycle of chemotherapy. It was possible to identify 3 independent factors influencing overall survival and relapse-free survival: actual initial dose of cisplatinum, actual initial dose of cyclophosphamide and the T stage. The effect of the initial dose of cisplatinum and cyclophosphamide proved to be linear on relapse-free survival. The results of this analysis show a possible effect of initial doses of chemotherapy in the management of limited small cell lung cancer in terms of both distant metastasis and overall survival rates.

[Non-ventilatory functions of the cells of the respiratory system]. / Les fonctions non ventilatoires des cellules de l'appareil respiratoire.

The physiology of the respiratory system was limited until recently to study of the structures subjected to simple physical laws and involved in gas exchanges only. Today, the airways and lung itself are conceived as complex living structures adapted to defence against exogenous, microbiological, organic and inorganic substances which reach the respiratory epithelium, contained in the 10 to 12 m3 of air entering and leaving the lungs daily. In addition, the considerable surface area represented by the endothelium of the pulmonary circulation is a site of synthesis and elimination, the implications of which are increasingly important in the area of the metabolism of endogenous substances: prostaglandins, vasomotor substances and the bioconversion of drugs and toxic agents. This is an increasingly large area of research and investigation, the clinical applications of which appear to be more and more frequent and important.

[Chronic obstructive bronchopneumopathies. What should be measured? When and how?]. / Bronchopneumopathies chroniques obstructives. Que faut-il mesurer? Quand et comment?

Tobacco smoking, which is the main cause of chronic obstructive lung disease, produces two different disorders, each following an independent course: hypersecretion of mucus and impairment of ventilation. The most significant as regards prognosis is the latter. Its early detection requires fine respiratory function tests, notably flow-volume loops. At the chronic lung obstruction stage, conventional spirometry provides information on the degree of obstruction, and other additional tests can be used to investigate for possible emphysema. The potential repercussions of the disease on gas exchanges must be assessed by measuring arterial blood gases. Such measurements are usually performed on subjects awake and at rest, but they can be supplemented by exercise tests or examinations during sleep. A critical analysis of the values obtained is useful to decide whether oxygen therapy is needed and to follow up this treatment in patients with chronic respiratory failure.