Landmark clinical trial shows survival benefits for late-stage lung cancer (from ASCO Meeting May, 2000)

More than 1200 patients with previously untreated stage IIIB or stage IV non-small cell lung cancer (NSCLC) were enrolled in a study comparing the effectiveness of 3 platinum-based combination regimens containing third-generation drugs active against NSCLC, compared with a control arm of cisplatin and paclitaxel. The regimens were gemcitabine plus cisplatin, docetaxel plus cisplatin, and paclitaxel and carboplatin. No significant difference in survival was found among the 3 treatment arms when compared to the control arm of the study, which was conducted by the Eastern Cooperative Oncology Group (ECOG). The median time of survival was 7.8 months. The one-year survival rate was 33.5%, and the two-year survival rate was 12%. Only the paclitaxel and carboplatin arm showed statistically fewer life-threatening side effects than the other three regimens.

THE RESULTS OF A large meta-analysis of 52 randomized clinical trials showed conclusively that the administration of chemotherapy offers a significant, but modest, survival advantage for all stages of non–small-cell lung cancer (NSCLC)  In early-stage disease, postoperative cisplatin-based adjuvant chemotherapy is associated with  an absolute survival benefit of 5% at 5 years. For patients with more advanced tumors,  a 10% absolute improvement in survival at 1 year over supportive care alone.   Currently, randomized trials using the most active regimens for advanced NSCLC have shown consistent overall response rates of approximately 30% to 40% and 1-year survival rates of 35% to 40%.This represents a clear advance over the 10% 1-year survival rate that can be expected with supportive care alone.

The role of second-line chemotherapy after initial treatment with a platinum-based regimen remains largely undefined. In a recent review of second-line chemotherapy for NSCLC, Fossella reported disappointing results for the treatment of this patient population. In almost half the studies, no responses were seen, and in most of the others, the overall response rate was less than 15%. Median and 1-year survival rates were seldom reported see study below by Shepherd.

Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy.

Shepherd FA,   J Clin Oncol 2000 May 10;18(10):2095-2103

University of Toronto,
PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life. PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m(2) (49 patients) or 75 mg/m(2) (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P <.001), as was median survival (7.0 v 4.6 months; log-rank test, P =.047). The difference was more significant for docetaxel 75 mg/m(2) patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P =.010; 1-year survival, 37% v 11%; chi(2) test, P =.003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2), three of whom died, and in one patient treated with docetaxel 75 mg/m(2). Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m(2), the benefits of docetaxel therapy outweigh the risks.

Cochrane Database Syst Rev 2000;2:CD002139

Chemotherapy for non-small cell lung cancer.

Non-Small Cell Lung Cancer Collaborative Gr  Meta-analysis Group, MRC Clinical Trials Unit

[ata from 52 trials and 9387 patients were included. The results for modern regimens containing cisplatin favoured chemotherapy in all comparisons and reached conventional levels of significance when used with radical radiotherapy and with supportive care. Trials comparing surgery with surgery plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death, equivalent to an absolute benefit of 5% at 5 years). Trials comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio 0.87 (13% reduction in the risk of death equivalent to an absolute benefit of 4% at 2 years), and trials comparing supportive care with supportive care plus chemotherapy gave a hazard ratio of 0.73 (27% reduction in the risk of death equivalent to a 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size of effect was seen in any subgroup of patients. In all but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison. REVIEWER'S CONCLUSIONS: At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in the treatment of non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.

Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.

Bonomi P, J Clin Oncol 2000 Feb;18(3):623-31

Rush-Presbyterian St. Luke's Medical Center, Chicago, IL,

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.

Eastern Cooperative Oncology Group experience with chemotherapy in advanced non-small cell lung cancer.

Bonomi P   Chest 1998 Jan;113(1 Suppl):13S-16S

Section of Medical Oncology, Rush Medical College,

Eastern Cooperative Oncology Group (ECOG) investigators have tested a variety of single-agent and combination regimens in patients with non-small cell lung cancer (NSCLC) during the last 2 decades. The following observations have been made. (1) The mitomycin/vinblastine/cisplatin regimen produced a trend for higher response rates in two studies and a significantly higher response rate in a third study. Survival, however, tended to be shorter in patients receiving this regimen. (2) Carboplatin produced a 9% overall response rate and a median survival of 31.7 weeks, which was slightly but significantly longer than the median survivals obtained with three combination chemotherapy regimens. (3) Paclitaxel produced an overall response rate of 21% and a 1-year survival rate of 40% in previously untreated NSCLC patients. This observation led to a phase III trial in which paclitaxel (135 mg/m2 and 250 mg/m2) was combined with cisplatin and compared with etoposide/cisplatin. Response rates for each of the paclitaxel/cisplatin regimens (26% for 135 mg/m2 paclitaxel and 31% for 250 mg/m2) were significantly higher than the response rate for etoposide/cisplatin (12%), but response between the two paclitaxel/cisplatin arms was not significantly different. At this point, there is a trend toward longer survival in each of the paclitaxel/cisplatin arms, but the final survival analyses have not been completed. In the next phase III trial, ECOG will evaluate paclitaxel (135 mg/m2) plus cisplatin in comparison to three other regimens--docetaxel/cisplatin, gemcitabine/cisplatin, and carboplatin/paclitaxel.

Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: a meta-analysis and the Cancer and Leukemia Group B randomized trial.

Lilenbaum RC, List M, Desch C   Semin Oncol 1999 Oct;26(5 Suppl 15):52-4

University of Miami School of Medicine and The Mount Sinai Comprehensive Cancer Center, Miami Beach, FL 33140, USA.

Several randomized trials have compared single-agent chemotherapy with combination chemotherapy in advanced non-small cell lung cancer. In general, response rates were higher with combination regimens, but their impact on survival is unclear. We conducted a meta-analysis of 25 trials involving a total of 5,156 patients with advanced non-small cell lung cancer randomized to a single-agent arm versus a combination arm. The results showed that combination chemotherapy produced a nearly twofold increase in response rate and a modestly improved 1-year survival rate compared with single-agent chemotherapy. However, toxicity was significantly increased, with a 3.6-fold increase in treatment-related mortality. In a subset analysis of trials using either a platinum analog or vinorelbine as single agents and as a component of the combination regimen, the difference was no longer statistically significant, suggesting that more active single agents provide similar survival with less toxicity than combination regimens. Based on these results, the Cancer and Leukemia Group B initiated a large randomized trial comparing paclitaxel with paclitaxel + carboplatin in stage IIIB-IV non-small cell lung cancer patients. The trial will be able to detect a 30% difference in survival. An extensive quality of life analysis and a resource utilization comparison will allow estimation of the incremental cost per quality of life-year gained. This trial will be the first in the United States to prospectively collect and analyze such data in a multidisciplinary approach.

Chemotherapy for advanced non-small cell lung cancer: past, present, and future.

Ramanathan RK, Belani CP  Semin Oncol 1997 Aug;24(4):440-54

Department of Medicine, University of Pittsburgh,

Until recently, chemotherapeutic intervention in advanced and metastatic non-small cell lung cancer (NSCLC) has been viewed with a certain degree of nihilism. Although meta-analysis of randomized clinical studies from the 1970s and 1980s comparing cisplatin-based chemotherapy to best supportive care in metastatic NSCLC showed improvement in survival, it was modest at best. A number of novel agents have been developed with significant activity against NSCLC in the past 5 to 6 years and are being incorporated into the therapy of this disease. These agents include paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. Clearly there has been improvement in response rates, and in some cases the responses have been durable with an increase in the number of 1- and 2-year survivors. The next generation of studies has evaluated combinations of these novel agents with either cisplatin or carboplatin for patients with NSCLC and the results have been provocative, with 1-year survival rates as high as 54%. A randomized phase III study of the Eastern Cooperative Oncology Group has shown the superiority of paclitaxel-cisplatin regimens over etoposide-cisplatin for patients with advanced and metastatic NSCLC. The vinorelbine-cisplatin regimen has also proven to have significant, albeit modest benefit in survival when compared with cisplatin alone. These combination regimens have now become the reference regimens in ongoing randomized studies. There is continued interest in developing new agents, or selective approaches that effect novel targets with the hope of showing improved therapeutic activity. Some of these approaches include gene therapy, monoclonal antibodies, and introduction of antisense oligodeoxynucleotides. With better understanding of the molecular and cellular biology of lung cancer, the hope for the future is to combine the mechanistic approaches with new drug development to define an effective, optimal, and definitive regimen for NSCLC.

Adjuvant chemotherapy in non-small cell lung cancer.

Le Chevalier T   Semin Oncol 1998 Aug;25(4 Suppl 9):62-5

Department of Medicine, Institut Gustave-Roussy, Villejuif, France.

Surgery is the main curative treatment of patients with non-small cell lung cancer (NSCLC), but half of all patients will experience local or distant failure after complete resection. An individual data-based meta-analysis has suggested a 13% reduction in the risk of death and an absolute benefit of 5% at 5 years with adjuvant cisplatin-containing chemotherapy in patients with resected NSCLC. These data led several national and international groups to initiate a new generation of adjuvant trials in resected NSCLC, and more than 2,500 patients have already been included in these randomized studies. Chemotherapy can also be proposed preoperatively. Two randomized studies, which included 60 patients each, strongly suggested a benefit from neoadjuvant chemotherapy in patients with stage III NSCLC. A large French randomized study that included 375 patients with early stage NSCLC who did or did not receive preoperative chemotherapy has recently been completed. This study should help clarify the role of neoadjuvant chemotherapy in operable NSCLC.