Big Lung Trial Research Articles

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also underway to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies.

Management of early-stage non-small-cell lung cancer (NSCLC)

Approximately 1.5 million new cases of lung cancer are diagnosed annually worldwide. Around 85% of these tumours are non-small-cell lung cancer (NSCLC). The optimal treatment for early-stage NSCLC (i.e. clinical stages I and II) is surgery, mostly lobectomy. In patients with functional limitations, an alternative to surgical resection is radiotherapy, and stereotactic irradiation may play a greater role in the future. Despite optimal local management, five-year survival rate of resected NSCLC ranges between 73% for pathological stage Ia and 25% for pathological stage IIIa. In the early 1990s, a large overview of the role of chemotherapy in NSCLC using updated individual data showed a 13% reduction in the risk of death with adjuvant chemotherapy at five years (P = 0.08), suggesting an absolute benefit of 5% [1]. These results constituted the rationale for a new generation of randomised studies with cisplatin-based regimens. The ALPI trial included patients with resected stage I-IIIa NSCLC. They were randomly allocated to receive either three courses of mitomycin (8mg/m2 day 1); vindesine (3mg/m2 days 1 and 8); cisplatin 100mg/m2 day 1 every three weeks or no adjuvant treatment after complete resection [2]. Overall 1209 patients were enrolled into the study; 1088 patients were analysed with a median followup of 63 months. The hazard ratio (HR) was 0.94 for overall survival and 0.89 for disease-free survival. No statistically significant difference was observed even if the difference was borderline significant for stage II disease. The IALT was a large worldwide randomised study whose aim was to determine the impact on overall survival of three to four cycles of a cisplatin-based chemotherapy (CT) after complete surgical resection in patients with stages I−III NSCLC [3]. Thoracic radiotherapy may be given according to the preregistration policy of each centre. There were 932 patients allocated to CT and 935 patients in the control arm. After a median follow-up of 56 months, there was a significant difference in overall survival between the two arms (HR= 0.86 [0.76–0.98], P < 0.03). Disease-free survival was also significantly different (HR= 0.83 [0.74–0.94], P < 0.003). The effect was no longer significant at 90 months (HR= 0.91 [0.81– 1.02], P = 0.10) owing to a higher rate of non-cancerrelated deaths in the chemotherapy arm. ERCC1 was evaluated by immunohistochemistry in 761 tumour specimens of patients in the IALT-Bio programme [4]. ERCC1 expression was positive in 44% and negative in 56%. A benefit of cisplatin-based adjuvant chemotherapy was associated with the negative expression of ERCC1 (test for interaction, P = 0.009). In the post-operative subgroup of the Big Lung Trial, no benefit from adjuvant chemotherapy was observed among 381 patients, but the population was heterogeneous, in particular concerning the quality of the resection and the compliance with chemotherapy [5]. A Japanese randomised study compared adjuvant tegafur-uracil (UFT) for two years with no treatment in patients with completely resected stage I NSCLC [6]. Among 979 eligible patients, there was a significant advantage in favour of UFT (P = 0.036), but the benefit was restricted to the 27% of patients with T2N0 NSCLC. At the 2004 ASCO meeting, the Japanese adjuvant UFT meta-analysis confirmed a significant advantage of the drug compared with controls in 2003 patients (P < 0.001). The NCI-Canada conducted a phase III trial (JBR 10) comparing surgery alone with surgery followed by adjuvant chemotherapy with cisplatin and vinorelbine in 459 eligible patients with stage Ib and II resected NSCLC [7]. They showed a 15% benefit at five years (P = 0.012). The benefit was restricted to stage II patients. In the ANITA 1 trial, which also concerned patients with completely resected NSCLC, chemotherapy consisted of four cycles of cisplatin-vinorelbine [8]. A total of 831 patients were included. Again, there was a survival advantage for adjuvant chemotherapy (HR: 0.80 [0.66–0.96], P = 0.017).

Adjuvant Cisplatin and Vinorelbine for Completely Resected Non-small Cell Lung Cancer: Subgroup Analysis of the Lung Adjuvant Cisplatin Evaluation

To evaluate the impact of adjuvant cisplatin-vinorelbine in completely resected non-small cell lung cancer and identify patients likely to benefit from this regimen in the Lung Adjuvant Cisplatin Evaluation (LACE) database. The overall LACE meta-analysis showed survival benefit with cisplatin-based adjuvant chemotherapy (5-year survival benefit of 5.4%, hazard ratio [HR] 0.89, p = 0.004). Subgroup analysis for the cisplatin-vinorelbine regimen was prespecified in the LACE statistical analysis plan. Patients randomized to cisplatin-vinorelbine or observation were the largest subgroup (41%) and the most homogeneous in terms of drug doses and eligibility. The LACE-vinorelbine cohort included trials evaluating cisplatin-vinorelbine versus observation. Overall survival was the primary end point. Other studies randomizing patients to other chemotherapy or observation (LACE-other) were also evaluated. The LACE-vinorelbine cohort included 1888 patients from four studies (Adjuvant Navelbine International Trialist Association, Big Lung Trial, International Adjuvant Lung Cancer Trial, and National Cancer Institute of Canada Clinical Trials Group JBR.10). Baseline characteristics were similar to the LACE-other but had fewer patients with stage IA (2% versus 11%). Survival improvement at 5 years was 8.9% with cisplatin-vinorelbine versus observation (HR 0.80, 95% confidence interval: 0.70-0.91, p <0.001). Stage was a significant predictor for survival (test for trend, p = 0.02; benefit at 5 years: 14.7% [stage III], 11.6% [stage II], and 1.8% [stage I]). Similar benefits were seen for disease-free survival (HR 0.75 [0.67-0.85, p <0.001], stage III [HR 0.62, 0.50-0.76], stage II [HR 0.69, 0.57-0.83], and stage I [HR 0.95, 0.767-1.19]). The overall result was statistically superior to LACE-other (LACE other HR 0.95, 0.86-1.05, interaction p = 0.04). In subgroup analyses, adjuvant cisplatin-vinorelbine provides a superior survival benefit and can be recommended in completely resected stages II and III non-small cell lung cancer.

Closeness to Death and Quality of Life in Advanced Lung Cancer Patients

Aims It has been recommended that closeness to death is considered when designing and reporting quality-of-life (QoL) studies in patients with advanced cancer. The aim of this work was to assess whether this finding holds when adjusting for previous QoL. Materials and methods The study sample comprised 107 advanced non-small cell lung cancer patients randomised to the Big Lung Trial – QoL Study. Baseline and week 12 QoL data and patient characteristics were considered. Univariate and multivariate analysis of week 12 QoL considered baseline QoL scores, closeness to death, patient characteristics and treatment. Results Univariate analyses showed significantly different week 12 QoL according to closeness to death for nine of 15 QoL domains. Multivariate analyses showed closeness to death to be independently predictive of only three QoL domains, with performance status and baseline QoL being more predominant. Conclusions In the present study, closeness to death was not found to be as important a factor in multivariate analysis as previously found. We recommend that previous QoL and performance status are considered in the design and analysis of QoL studies in which QoL is assessed at multiple time points in patients with advanced cancer, and that closeness to death may also be considered.

Assessment of Quality of Life in the Supportive Care Setting of the Big Lung Trial in Non–Small-Cell Lung Cancer

The Big Lung Trial (BLT) was a large, pragmatic trial to evaluate the addition of chemotherapy to primary treatment (ie, surgery, radical radiotherapy, or supportive care) in non-small-cell lung cancer (NSCLC). In the supportive care group, there was a small but significant survival benefit in patients treated with chemotherapy compared with supportive care alone (no chemotherapy). A substudy was undertaken to evaluate the quality of life (QoL) implications of the treatment options. QoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires C30 (QLQ-C30) and LC17, and daily diary cards. EORTC QLQ-C30 and LC17 were collected at 0, 6 to 8, 12, 18, and 24 weeks. Diary cards were completed during the first 12 weeks of the study. The primary end point was global QoL at 12 weeks. A total of 273 patients were randomly assigned: 138 to no chemotherapy and 135 to chemotherapy. There was no evidence of a large detrimental effect on QoL of chemotherapy. No statistically significant differences in global QoL or physical/emotional functioning, fatigue and dyspnea, and pain were detected at 12 weeks. Higher rates of palliative radiotherapy in the no chemotherapy arm may have lessened differences in QoL. Global QoL, role functioning, fatigue, appetite loss, and constipation were prognostic indicators of survival at 12 weeks. There were no important adverse effects of chemotherapy on QoL.

Role of adjuvant chemotherapy in the treatment of non-small-cell lung cancer

The role of adjuvant chemotherapy in the treatment of non-small-cell lung cancer (NSCLC) is described. The intrinsic resistance of NSCLC tumors to chemotherapy necessitates the use of complete surgical resection of the malignant growth as the primary modality of treatment; however, only about one third of patients are appropriate candidates for surgical resection. While several cytotoxic combinations have been used to treat metastatic NSCLC, no single regimen is considered the standard of care. Given the poor prognosis of patients with NSCLC, adjuvant chemotherapy has been investigated as a treatment option but has not demonstrated a consistent survival benefit. Several recent studies have sought to clarify the role of adjuvant chemotherapy in the treatment of NSCLC: the Big Lung Trial, the International Adjuvant Lung Cancer Trial (IALT), the Adjuvant Lung Project Italy trial, and a study of the combination of uracil and tegafur, which is not yet available in the United States. The IALT, the largest trial among the four and sufficiently powered to detect a survival benefit, revealed a modest increase in survival. Complicating the issue is the financial cost of adjuvant therapy, especially in light of the small survival benefit gained. The use of adjuvant chemotherapy in patients with NSCLC can lead to a modest increase in survival. Platinum-based regimens are the most studied and should be considered the regimens of choice. However, further studies are needed to determine the optimal regimen and patient population that would derive the most benefit from this treatment.

The ALPI Trial: The Italian/European Experience with Adjuvant Chemotherapy in Resectable Non–Small Lung Cancer

Postoperative treatments for lung cancer have been evaluated for more than two decades, but in the majority of the studies no significant and clinically meaningful effect on survival has been shown. In 1995, a meta-analysis of eight cisplatin-based adjuvant chemotherapy trials in 1,394 patients with non-small cell lung cancer showed a 13% reduction in the risk of death (P = 0.08). The nonstatistically significant benefit reported in the meta-analysis prompted the planning of several randomized studies of platinum-based chemotherapy. Three studies addressed the issue of adjuvant chemotherapy in all the resected stages of non-small cell lung cancer (I-IIIA): the Italian/European study Adjuvant Lung Cancer Project Italy, the International Adjuvant Lung Cancer study, and the British Big Lung Trial. In contrast to the International Adjuvant Lung Cancer, the Adjuvant Lung Cancer Project Italy and the underpowered British Big Lung Trial failed to prospectively confirm a significant role of adjuvant chemotherapy in completely resected non-small cell lung cancer. In this article, we will discuss the findings of the Adjuvant Lung Cancer Project Italy study in the context of the International Adjuvant Lung Cancer and British Big Lung Trial.

A randomised comparison of radical radiotherapy with or without chemotherapy for patients with non-small cell lung cancer: Results from the Big Lung Trial

BackgroundA meta-analysis of trials comparing primary treatment with or without chemotherapy for patients with non-small cell lung cancer published in 1995 suggested a survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings studied, but it included many small trials, and trials with differing eligibility criteria and chemotherapy regimens. MethodsThe Big Lung Trial was a large pragmatic trial designed to confirm the survival benefits seen in the meta-analysis, and this paper reports the findings in the radical radiotherapy setting. The trial closed before the required sample size was achieved due to slow accrual, with a total of 288 patients randomised to receive radical radiotherapy alone (146 patients) or sequential radical radiotherapy and cisplatin-based chemotherapy (142 patients). ResultsThere was no evidence that patients allocated sequential chemotherapy and radical radiotherapy had a better survival than those allocated radical radiotherapy alone, HR 1.07 (95% CI 0.84–1.38, P=0.57), median survival 13.0 months for the sequential group and 13.2 for the radical radiotherapy alone group. In addition, exploratory analyses could not identify any subgroup that might benefit more or less from chemotherapy. ConclusionsDespite not suggesting a survival benefit for the sequential addition of chemotherapy to radical radiotherapy, possibly because of the relatively small sample size and consequently wide confidence intervals, the results can still be regarded as consistent with the meta-analysis, and other similarly designed recently published large trials. Combining all these results suggests there may be a small median survival benefit with chemotherapy of between 2 and 8 weeks.

Highlights from the Tenth World Conference on Lung Cancer.

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus. Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity. Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.

O-11 Estimating the financial cost of supportive care plus cisplatin-based chemotherapy compared with supportive care alone in the treatment of patients with advanced non-small cell lung cancer (NSCLC) using data from the big lung trial (BLT)

O-11 Estimating the financial cost of supportive care plus cisplatin-based chemotherapy compared with supportive care alone in the treatment of patients with advanced non-small cell lung cancer (NSCLC) using data from the big lung trial (BLT)

O-212 The Big Lung Trial (BLT): Determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the radical radiotherapy setting

O-212 The Big Lung Trial (BLT): Determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the radical radiotherapy setting

O-179 The Big Lung Trial (BLT): Determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the surgical setting

O-179 The Big Lung Trial (BLT): Determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the surgical setting

O-60 The big lung trial quality of life study: Determining the effect of cisplatin-based chemotherapy for supportive care patients with non-small cell lung cancer (NSCLC)

O-60 The big lung trial quality of life study: Determining the effect of cisplatin-based chemotherapy for supportive care patients with non-small cell lung cancer (NSCLC)

Neoadjuvant chemotherapy in non small cell lung cancer—the UK experience

I would like to present a surgeon’s view of neoadjuvant chemotherapy and our experience in the United Kingdom. The problem for lung cancer surgeons is that no matter how successful and satisfying the operation, more than 50% of the patients will develop recurrent tumour [1]. It is therefore only a foolish surgeon who thinks that surgery alone is adequate treatment. Surgeons should be prepared to work closely with oncologists and facilitate multimodality treatment. Preoperative chemotherapy may improve postoperative survival rates by treating micrometastases at the start of treatment or by controlling the growth of residual tumour stimulated by the release of growth factors released by surgery and the subsequent healing process. In my practice in the UK we enter patients into the EORTC-08941 trial for neoadjuvant treatment in histologically proven stage IIIa NSCLC and use the Big Lung Trial to enter patients for neoadjuvant or adjuvant chemotherapy for stage I or II or resected stage IIIa disease. We are considering the Medical Research Council (MRC) LU 22 trial for neoadjuvant chemotherapy for ‘otherwise resectable’ non-small cell lung cancer (NSCLC).

The Big Lung Trial (BLT): A major randomised trial to determine the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC)

The Big Lung Trial (BLT): A major randomised trial to determine the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC)

66 Reasons for the poor recruitment of patients with lung cancer into randomised clinical trials (RCT): The experience of 2 centres in the big lung trial (BLT)

66 Reasons for the poor recruitment of patients with lung cancer into randomised clinical trials (RCT): The experience of 2 centres in the big lung trial (BLT)