Vicente Alberola

Randomized Phase III Study of Gemcitabine-Cisplatin Versus Etoposide-Cisplatin in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

PURPOSE We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.

Cisplatin Plus Gemcitabine Versus a Cisplatin-Based Triplet Versus Nonplatinum Sequential Doublets in Advanced Non–Small-Cell Lung Cancer: A Spanish Lung Cancer Group Phase III Randomized Trial

PURPOSE To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV-VI). RESULTS Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV-VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV-VI, 27%; CG v GV-VI, P =.003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV-VI, 27%; P <.05); neutropenic fever (CG, 4%; CGV, 19%; GV-VI, 5%; P <.0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV-VI, 3%; P =.0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV-VI, 6%; P <.0001). CONCLUSION On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.

Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non–Small-Cell Lung Cancer

PURPOSE To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non-small-cell lung cancer. PATIENTS AND METHODS In this phase III trial, 624 patients with stage IA (tumor size > 2 cm), IB, II, or T3N1 were randomly assigned to surgery alone (212 patients), three cycles of preoperative paclitaxel-carboplatin followed by surgery (201 patients), or surgery followed by three cycles of adjuvant paclitaxel-carboplatin (211 patients). The primary end point was disease-free survival. RESULTS In the preoperative arm, 97% of patients started the planned chemotherapy, and radiologic response rate was 53.3%. In the adjuvant arm, 66.2% started the planned chemotherapy. Ninety-four percent of patients underwent surgery; surgical procedures and postoperative mortality were similar across the three arms. Patients in the preoperative arm had a nonsignificant trend toward longer disease-free survival than those assigned to surgery alone (5-year disease-free survival 38.3% v 34.1%; hazard ratio [HR] for progression or death, 0.92; P = .176). Five-year disease-free survival rates were 36.6% in the adjuvant arm versus 34.1% in the surgery arm (HR 0.96; P = .74). CONCLUSION In early-stage patients, no statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment.

14-3-3σ Methylation in Pretreatment Serum Circulating DNA of Cisplatin-Plus-Gemcitabine-Treated Advanced Non–Small-Cell Lung Cancer Patients Predicts Survival: The Spanish Lung Cancer Group

PURPOSE Survival in patients with advanced non-small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2-M checkpoint control gene, could be a predictor of longer survival. PATIENTS AND METHODS A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. RESULTS 14-3-3sigma methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3sigma methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001). CONCLUSION Methylation of 14-3-3sigma is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

Phase II Trial of Paclitaxel Plus Gemcitabine in Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

PURPOSE Given the cisplatin-related myelotoxicity and nonhematologic toxicities, we were prompted to undertake a study of the noncisplatin combination of paclitaxel plus gemcitabine to evaluate the efficacy, tolerance, and survival of this combination in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients received gemcitabine 2,000 mg/m(2) and paclitaxel 150 mg/m(2) on days 1 and 15 of a 28-day cycle, for a maximum of eight cycles. RESULTS Between December 1997 and June 1998, 89 untreated NSCLC patients were enrolled; 30 (34%) had stage IIIB disease (23 with malignant pleural effusion and seven without), and 59 (66%) had stage IV disease. Eighty-six percent of patients had a performance status of 0 or 1. The median number of cycles administered was four (range, one to eight cycles). The mean dose-intensity for both paclitaxel and gemcitabine was nearly 100%. Hematologic and nonhematologic toxicities were mild. Thirty-eight patients received second-line chemotherapy after completion of the study. The overall intent-to-treat response rate was 32.2%, with a higher response rate for stage IIIB patients (43.3%) than for stage IV patients (26.3%). Overall median survival was 9.9 months, and 1-year survival was 38.8% (14.2 months for stage IIIB and 7.7 months for stage IV; P =.007). Median survival was 10.2 months for patients with a performance status of 0 or 1 and 4.8 months for patients with a performance status of 2 (P =.007). CONCLUSION A biweekly paclitaxel/gemcitabine regimen was well tolerated, with an acceptable response rate and a reasonable median survival time, especially in patients with good performance status. It merits further exploration in future studies.

Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine

UNLABELLED New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients. MATERIAL AND METHODS Eligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0-1. Patients received intravenous doses of vinorelbine 25 mg/m² on day 1 and 8 and cisplatin 75 mg/m² on day 1, every 21 days, for a maximum of eight cycles. RESULTS 94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0-12.9). Overall median time to progression was 5.89 months (95% CI 5.2-6.6). Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p=0.036), MDR13435CC (HR CT vs. CC, 2.01; p=0.017; HR TT vs. CC, 1.54; p=0.22), and decreasing age (HR of age, 0.97; p=0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p=0.001). There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity. CONCLUSION In our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age.

Economic evaluation in a randomized phase III clinical trial comparing gemcitabine/cisplatin and etoposide/cisplatin in non-small cell lung cancer☆

INTRODUCTION Information on the relative cost-effectiveness of treatments for cancer is being increasingly sought as pressure on health care resources increases. The objective of this study was to assess the cost-effectiveness of gemcitabine/cisplatin (GC) versus cisplatin/etoposide (CE) in patients with advanced non-small cell lung cancer (NSCLC), using resource utilization data collected in conjunction with the first randomized clinical trial comparing both combinations. METHODS Efficacy and medical care resource utilization data were collected prospectively in an open-label, multicenter, randomized, comparative, phase III trial conducted in Spain which compared gemcitabine/cisplatin and cisplatin/etoposide in 135 chemonaive patients with Stage IIIB or IV NSCLC. There were no differences between both regimens when survival was used as primary end-point, so a cost-minimization analysis was used to compare them. In addition, cost-effectiveness analyses were conducted when percentage of responses and time to progression were used as secondary end-points. RESULTS There were no differences between both regimens when survival was selected as the efficacy end-point. Despite the higher chemotherapy cost of GC when compared to CE, there were no differences in total direct costs (584523 pts for GC and 589630 pts for CE; P=NS) between both regimens. Potential savings with GC were mainly associated with a decrease in hospitalization rate. There were differences in favor of GC when response rate (40.6% for GC and 21.9% for CE; P<0.05) and time to disease progression (8.7 months for GC and 7.2 months for CE; P<0. 05) were used as clinical end-points. GC presented a favorable cost-effectiveness profile when compared to CE. CONCLUSIONS This prospective economic evaluation conducted alongside a clinical trial offers valuable preliminary information on the potential efficiency of the combination gemcitabine-cisplatin in NSCLC. Future assessments based on larger clinical trials focused on survival and naturalistic economic studies conducted in real clinical practice settings are necessary to confirm these findings.

Genetic testing for chemotherapy in non-small cell lung cancer.

Cisplatin or carboplatin is commonly used with gemcitabine, docetaxel, paclitaxel, or vinorelbine as chemotherapy doublets in the treatment of advanced non-small-cell lung cancer (NSCLC). Several randomized trials have failed to identify major differences in survival between any of these doublets. This lack of evidence for improvement in survival with any chemotherapy regimen has created a tabula rasa where no more large randomized trials should be conducted without including a genetic analysis. Patients see survival as their major concern, and other considerations, such as cost and quality of life, are relegated to lower positions. Genetic alterations related to the transcription-coupled repair pathway of the nucleotide excision repair system (TC-NER) have revealed the subset of patients who are resistant to cisplatin. TC-NER involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. For a long time, ERCC1 mRNA levels have been known to correlate with DNA repair capacity in various tissues. Levels of DNA cisplatin adducts in peripheral blood and buccal mucosa cells predict chemotherapy response, and high ERCC1 mRNA levels have been related to chemoresistance in ovarian cancer and in malignant lymphocytes from chronic lymphocytic leukemia. Moreover, in some instances, mRNA expression has been correlated with polymorphisms. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated NSCLC patients. An ongoing customized ERCC1-based chemotherapy trial has been designed based on this knowledge. Patients are randomized to the control arm of cisplatin/docetaxel or to the experimental arm, where docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. To date, 86 patients have been included.

Targeted therapy in combination with gemcitabine in non-small cell lung cancer

Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.

Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum.

BACKGROUND Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment. METHODS Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint. RESULTS Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types. CONCLUSIONS Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.