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Purpose and Methods: We investigated whether a high-dose chemotherapy regimen of cyclophosphamide 1,800 mg/m2, 4'-epidoxorubicin 60 mg/m2, etoposide 330 mg/m2, and cisplatin 120 mg/m2 given monthly for four cycles with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) support (5 micrograms/kg daily for 10 days) could improve the survival of patients with extensive-stage small-cell lung cancer (SCLC) compared with a standard-dose regimen (cyclophosphamide 1,200 mg/m2, 4'-epidoxorubicin 40 mg/m2, etoposide 225 mg/m2, and cisplatin 100 mg/m2) given monthly for six cycles. Planned cumulative doses of the drugs were the same in both treatment arms except for cisplatin (which was 80% in the higher-dose plus rhGM-CSF group)., Results: At the time of the preplanned interim analysis, 125 patients, 60 in the standard-dose group and 65 in the higher-dose plus rhGM-CSF group, had entered the study; 116 were eligible, 55 in the standard-dose group and 61 in the higher-dose group. All patients were included in the analyses. The cumulative doses of each drug actually delivered were significantly higher in the standard-dose group. No difference in response rates was observed between the two groups. There were significantly greater hematologic toxicities, documented infections, and transfusions of RBCs and platelets in the higher-dose plus rhGM-CSF group. Patients in this group proved to have a shorter survival duration and a shorter time to relapse than patients in the standard-dose group (median overall survival: standard-dose, 10.8 months; higher-dose, 8.9 months; log-rank test with adjustment for prognostic variables, P = .0005; respective probabilities of relapse at 1 year, 77 +/- 0.6 and 96 +/- 2.2; log-rank test, P = .013)., Conclusion: A 50% increase in dose-intensity for this four-drug regimen could not be achieved with GM-CSF due to excessive toxicity in patients with extensive-stage SCLC.

Twenty patients with locally advanced or metastatic non-small cell lung cancer entered a study of recombinant human methionyl G-CSF (r-metHuG-CSF) as an adjunct to ifosfamide, cisplatin and etoposide (IPE) regimen. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection) and etoposide 100 mg/m2 given on days 1-4 of a 21-day cycle. r-metHuG-CSF, 5 micrograms/kg, was administered subcutaneously from day 5 to day 14. Eighteen out of 20 patients completed the three courses (57 evaluable cycles). Grade 3-4 neutropenia affected 50, 42 and 22% of the patients during cycles 1, 2 and 3, respectively, whereas thrombocytopenia was observed in 25% of the patients throughout the chemotherapy protocol. Haematological toxic events requiring transfusions and/or antibiotics were responsible for 11 unplanned hospitalizations. Among these only three were exclusively devoted to febrile neutropenia care, the remaining eight being mainly required for blood transfusions. There were no deaths during the study duration. Dose reductions were needed in 65% of the patients and chemotherapy was delayed by thrombocytopenia in five patients. The total relative dose intensity was 84%. Eleven (55%) patients responded (one complete and 10 partial responses). Median survival was 9.5 months. We concluded that IPE combination chemotherapy can be administered safely with the support of r-metHuG-CSF inasmuch as neutropenia appears as mild to moderate and manageable. Optimal delivery of chemotherapy is still limited by other toxicities, mainly thrombocytopenia, but the successful relative dose intensity observed herein deserves further studies designed to analyze a dose intensity-survival relationship in non-small cell lung cancer.

In a previous study we found that tumor responses as assessed by CT scan and fiberoptic bronchoscopy are sometimes discordant. We hypothesize that the response-survival relationship might vary according to the method of tumor response assessment. In a multivariate analysis of survival using the landmark method, we evaluated the prognostic significance of tumor response assessed by CT scan or fiberoptic bronchoscopy together with bronchial tumor location and histology of bronchial biopsies at restaging. A total of 133 lung cancer patients (50 small cell lung cancers and 83 non-small cell lung cancers) were entered in controlled chemotherapy trials and prospectively evaluated for chest tumor response by CT scan and fiberoptic bronchoscopy (FOB). Only 106 patients were fully evaluable for response by both methods. For these patients, a statistical concordance was observed between the two tests (kappa = 0.271; p < 0.001). There was a significant correlation between response and survival whatever the test used. However, only CT scan evaluation resulted in a classification showing that the more unfavorable the response stage was, the worse the survival became with no intersection between survival curves. Cox's hazard model demonstrated that CT-evaluated progression, proximal bronchial location at second FOB (intermediate, main bronchus or trachea) and positive histologic status at restaging were all prognostic determinants of poor survival. In conclusion, CT-evaluated response led to the best response-survival relationship as this method classified patients into four groups with different outcomes. Fiberoptic bronchoscopy should be avoided in patients who were found to have no endobronchial lesion during the pretreatment staging. For patients with pretreatment assessable endobronchial lesions, the decision of a second FOB depends on the results of CT restaging: FOB is probably unnecessary in patients for whom progression is disclosed by CT scan. In patients for whom CT scan discloses tumor response or stabilization, bronchial tumor location and histology of bronchial biopsies at second FOB are independent prognostic factors.

This study was designed to analyze the possible immunomodulation induced in vivo by haematopoietic growth factors following anti-cancer chemotherapy. Haematologic and cytokine kinetics (IL-1, IL-6, TNF alpha and soluble interleukin-2 receptor (sIL-2R)) were studied in patients with SCLC receiving high dose regimens of chemotherapy and recombinant human GM-CSF (group A), or standard doses of chemotherapy without rhGM-CSF (group B). Six patients were prospectively enrolled and randomized in each group. The kinetics of haematopoiesis following chemotherapy did not significantly differ between the two groups. In group A, the plasma sIL-2R level increased regularly during rhGM-CSF treatment reaching a 2.5-fold elevation at day 12 whereas it remained stable in group B. Conversely, IL-1 alpha decreased to an undetectable level in group A whereas it increased slightly from day 14 to day 18 in group B. As sIL-2R could compete with lymphocyte surface receptors and as IL-I is an important cytokine involved in acute phase response, our results might be regarded as reflecting a transient decrease in the cell-mediated immune response in small cell lung cancer patients receiving high dose chemotherapy combined with rhGM-CSF.

Neoadjuvant chemotherapy was tested in non-small cell lung cancer in an attempt to increase the resectability of the tumor and to treat the microscopic metastatic disease known to be responsible for the majority of failures in surgically treated patients. This review deals with published trials. Most of them are feasibility studies in Stage III NSCLC. Obviously, the heterogeneity of eligibility criteria from one study to another prevents general conclusions on the usefulness of neoadjuvant chemotherapy. However, it is possible to conclude that neoadjuvant chemotherapy has an antitumor activity; the majority of the studies report a 60% objective response rate including a significant number of complete responses and a 50% complete resection rate. Neoadjuvant chemotherapy does not increase morbidity after surgery except when it is combined with preoperative radiation therapy. At the time of writing, one Phase III randomized study comparing neoadjuvant chemotherapy followed by surgery with surgery alone has been published. This study concludes that the combined modality treatment improves the survival of patients with locally advanced non-small cell lung cancer. Taken as a whole, the literature deserves further studies to determine the place of neoadjuvant chemotherapy in lung cancer.

Indirect immunoperoxidase was used to determine the reactivity of C219 (P-glycoCHEK C219, Centocor Diagnostics, Malvern, PA), a monoclonal antibody (Mab) with high affinity for an internal epitope of the P-glycoprotein encoded by the multidrug resistance (MDR1) gene, in 40 surgically resected primary lung tumours. C219 reactivity was qualitatively classified in seven small cell lung cancers (SCLC), 29 non small cell lung cancers (NSCLC), and four carcinoid tumours. Ploidy was analysed by means of static cytometry using a computer-assisted image processor following Feulgen staining of cytologic prints of 32/40 lung tumours. Indirect immunoperoxidase reactivities of Mabs S-L 11.14 and MOC-1 were also studied to characterize the expression of cluster 1 lung cancer antigens and hence to determine among the NSCLC those which expressed the neural cell adhesion molecule (NCAM). Eighteen (45%) lung tumours strongly expressed P-glycoprotein as an immunostaining of many islets of malignant cells or almost all malignant cells. In addition, 8/40 tumours (20%) showed a weak reactivity (few immunostained cells) and 14/40 (35%) no reactivity. There was no difference of reactivity when NSCLC were compared with SCLC. The expression of P-glycoprotein in NSCLC did not vary significantly when the stage of disease was considered. Among the 29 NSCLC, 10 (36%) expressed S-L 11.14 and MOC-1. The NCAM positive NSCLC did not show any difference of P-glycoprotein expression in comparison with NCAM negative ones. Finally, C219 immunoperoxidase reactivity did not significantly differ according to the ploidy status. In conclusion, the internal epitope of the P-glycoprotein encoded by the MDR1 gene is frequently expressed by lung tumours of any histological type. This expression is not higher in Stage III and IV lung cancers in comparison with Stage I and II ones, or in NSCLC in comparison with SCLC either. Thus, the C219 related epitope seems to have a weak implication in the lower chemosensitivity of both advanced stages and NSCLC.

Cytokeratins are intermediate filaments of the cytoskeleton that are expressed by bronchial epithelium and its neoplastic counterpart, lung cancer. A new immunoradiometric assay referred to as CYFRA 21-1 makes it possible to titrate in the serum a cytokeratin 19 fragment. This study deals with the sensitivity, specificity and applicability of this serum marker in squamous cell carcinoma. Sera from non malignant pulmonary diseases were taken as controls. In comparison with carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC T-A4) and neuron specific enolase (NSE), CYFRA 21-1 was the most accurate marker. The area under the CYFRA 21-1 ROC curve was significantly greater than those of CEA, SCC T-A4 and NSE. Using a 3.6 ng/ml threshold, as determined by the ROC curve, CYFRA 21-1 was significantly correlated with tumor mass.

Tumor response is one of the most important criteria in the analysis of chemotherapy. A chest computed tomographic (CT) scan and fiberoptic bronchoscopy (FOB) might give different results, as they analyze different aspects of the effects of chemotherapy on lung cancer. The response of the chest tumor in 103 patients with stage III or IV lung cancer (35 with small-cell lung cancer [SCLC] and 68 with non-small-cell lung cancer [NSCLC]) who prospectively entered chemotherapy trials was studied in order to determine the concordance between the chest CT scan and FOB. The chest CT scan allowed an assessment of tumor response in almost all patients, whereas FOB was not able to evaluate this response in 15 of the 103. The frequency of an evaluable endobronchial lesion did not depend on histology (SCLC, 97 percent; NSCLC, 93 percent; chi 2 = 0.85; not significant [NS]) or tumor T classification (T1-2, 83 percent; T3, 94 percent; T4, 97 percent; chi 2 = 1.49; NS). Tumor location in the bronchial airway did not differ when SCLC and NSCLC were compared. Thus, it is not possible to predict a subgroup of patients in whom FOB may be optional. In the group of 88 patients who were evaluable for response using both FOB and CT scan, a statistical concordance of the response classification was observed. The response was overevaluated by CT scan in 22 patients for whom data obtained by FOB appeared to be critical in the evaluation of tumor response. The concordance of response data obtained when the 2 methods were used was lower in NSCLC in comparison with SCLC. Thus, the use of FOB in the analysis of tumor response might be important, especially for NSCLC, inasmuch as FOB modulates the CT-evaluated response.