International Adjuvant Lung Trial Research Articles

Cisplatin benefit is predicted by immunohistochemical analysis of DNA repair proteins in squamous cell carcinoma but not adenocarcinoma: theranostic modeling by NSCLC constituent histological subclasses

Most non-small-cell lung cancer (NSCLC) patients receive cisplatin-based chemotherapy though clinical response is restricted to a subset of patients. DNA repair protein levels are possible surrogates for cisplatin-induced DNA adduct (and subsequent cell death) repair efficiency and thus molecular determinants of therapeutic efficacy. The International Adjuvant Lung Trial (IALT)-Bio study previously suggested ERCC1 and MSH2 as predictive of cisplatin-based therapeutic benefit. DNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry on a large subset of patients (N = 769) from the IALT trial. Tissue Microarray slides were digitally scanned and signal quantified by user-defined macros. Statistical analyses (univariate and multivariate) of 5-year disease-free survival (DFS) and 5-year overall survival used binary cut-offs (H score low/high expression). In patients with squamous cell carcinoma (SCC), ATM, p53, PARP1, ERCC1, and MSH2 displayed significant (borderline) predictive values, mainly on DFS with chemotherapy efficacy limited to low marker levels. Adenocarcinoma (ADC) results were not significant. BRCA1 and XPF were not significant for predictive modeling in either SCC or ADCs. Here predictive utility of DNA repair enzymes co-segregates with SCC histology, focusing their predictive value to this histological subclass of NSCLC. Distinct mechanisms of chemotherapeutic response or resistance might exist among histological subclasses of solid tumors.

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.

ERCC1 and RRM1 in the International Adjuvant Lung Trial by Automated Quantitative in Situ Analysis

The excision repair cross completing group 1 gene product (ERCC1) and the regulatory subunit of ribonucleotide reductase (RRM1) have been reported as being prognostic of outcome and predictive of therapeutic efficacy in patients with non-small cell lung cancer. Routinely processed surgical specimens from 784 patients from the International Adjuvant Lung Trial were arrayed as tissue microarrays. In situ protein levels were scored with an automated, quantitative analysis system, dichotomized into high and low marker categories, and analyzed for associations with patients' characteristics, survival, and benefit from adjuvant chemotherapy. Scores for both markers were significantly associated with contributing center (P < 0.001) and skewed, with the bulk of scores being low. High scores were more frequent in women for ERCC1 and RRM1 and in older patients and those with adenocarcinoma for RRM1. Low ERCC1 scores indicated significant benefit from adjuvant chemotherapy [hazard ratio (HR) = 0.73 for chemotherapy versus control, P = 0.02]. Although all other survival associations were not statistically significant, low RRM1 scores trended to indicate benefit from adjuvant chemotherapy (HR = 0.84, P = 0.25), and ERCC1 scores were marginally prognostic of survival (HR = 0.77 for high versus low scores, P = 0.10). We conclude that contributing center and specimen quality substantially affect the levels of both markers. Future trials should incorporate the collection and processing of tumor specimens prospectively on standardized protocols to better reveal the impact of biomarkers on clinically relevant outcomes.

Poly(ADP-Ribose) Polymerase Inhibitors

This session not only described several poly(ADP-ribose) polymerase (PARP) inhibitors but also included talks on the science of nuclear excision repair, an oxidized glutathione, and a heat shock protein (HSP) 90 inhibitor. SUMMARY OF PRESENTATIONS Science of Nuclear Excision Repair Dr. George Simon opened the session by presenting the science of nuclear excision repair. He reviewed preclinical data, including evidence that apoptosis increases in cell lines exposed to cisplatin when excision repair cross-complementation group 1 (ERCC1) siRNA is added. He also reviewed clinical data from the International Adjuvant Lung Trial, in which improved survival with adjuvant cisplatin-based chemotherapy was restricted to tumors with low ERCC1. 1 He then focused on trials that designed to tailor therapy to repair genes. The Spanish Customized Adjuvant Treatment trial randomly assigns postresection patients with positive N1 or N2 nodes to docetaxel cisplatin or an experimental arm. Based on data correlating higher breast cancer 1 (BRCA1) mRNA levels with cisplatin resistance and docetaxel sensitivity, 2 the experimental arm assigns treatment by quartile expression for BRCA1 (lowest: gemcitabine cisplatin; 2‐3: docetaxel cisplatin; and highest: docetaxel). The TAilored post-Surgical Therapy in Early-stage NSCLC (TASTE) trial randomizes postsurgical patients to cisplatin pemetrexed or an experimental arm. In the experimental arm, mutations in the epidermal growth factor receptor (EGFR) lead to treatment with erlotinib, whereas treatment for EGFR wild-type patients are assigned based on ERCC1 status (cisplatin pemetrexed versus observation). He then discussed the MADe IT Trail, in which patients with metastatic disease were assigned treatment regimen based on ERCC1 and ribonucleotide reductase M1 (RRM1) levels (Figure 1). Outcomes in this trial exceeded selected historical controls, and the difference was more apparent for

Abstract IA3-1: Variables for individualizing systemic therapy in patients with lung cancer

Abstract Selecting the best therapy for a specific patient with non-small cell lung cancer (NSCLC) has always been the goal for physicians when advising patients and their families. Unequivocal tried-and-true parameters are disease stage, general health status, and the social environment. Other variables, such as age, gender, and histopathology are taken into consideration, but their role in therapeutic decision-making is not firmly established. More recently, tumoral molecular markers, either alone or in combination (referred to as molecular signatures), have emerged as variables for clinical decision making. When evaluating the utility of such markers, it is important to distinguish between the prognostic and predictive utility of a marker. A marker associated with patients’ survival independent of therapy is of prognostic value, while a marker associated with patients’ benefit from a specific therapy is of predictive value. This distinction is best illustrated by ERCC1 (excision repair cross-complementing group 1). In tumor specimens collected from participants in the International Adjuvant Lung Trial, ERCC1 was shown to be both prognostic and predictive. In patients randomized to the trial's control group; i.e., those that did not receive adjuvant chemotherapy, high levels of ERCC1 were associated with longer survival (the prognostic value). In contrast, when taking adjuvant chemotherapy into account, high levels of ERCC1 were associated with lack of benefit from adjuvant chemotherapy (the predictive value); i.e., only patients with low tumoral levels of ERCC1 derived benefit from adjuvant chemotherapy. In practice, predictive markers are of greatest value since they can guide clinical decision making, while a purely prognostic marker is of little or no value to clinical decision making. Many other molecular parameters have since emerged that can be used for decision making. These include EGF receptor mutations, eml4/alk rearrangements, Kras mutations, RRM1 expression levels, TS expression levels, and oncogenic pathway signatures. All of these variables have emerged from laboratory investigations and correlative clinical investigations. Prospective validation studies are required to solidify current knowledge, and many are in progress. Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-1.

MutS Homologue 2 and the Long-term Benefit of Adjuvant Chemotherapy in Lung Cancer

We sought to determine the long-term (median follow-up, 7.5 years) predictive power of human MutS homologue 2 (MSH2) immunohistochemical expression in patients who enrolled in the International Adjuvant Lung Trial. We tested the interaction between MSH2 and the allocated treatment (chemotherapy versus observation) in a Cox model adjusted on clinicopathologic variables. The significance level was set at 0.01. MSH2 levels were low in 257 (38%) and high in 416 (62%) tumors. The benefit from chemotherapy was likely different according to MSH2 (interaction test, P = 0.06): there was a trend for chemotherapy to prolong overall survival when MSH2 was low [hazard ratio (HR), 0.76; 95% confidence interval (95% CI), 0.59-0.97; P = 0.03], but not when MSH2 was high (HR, 1.12; 95% CI, 0.81-1.55; P = 0.48). In the control arm, the HR was 0.66 (95% CI, 0.49-0.90; P = 0.01) when MSH2 was high. When combining MSH2 with excision repair cross-complementing group 1 (ERCC1) into four subgroups, the benefit of chemotherapy decreased with the number of markers expressed at high levels (P = 0.01). A similar decrease was noted when combining MSH2 and P27 (P = 0.01). Chemotherapy prolonged overall survival in the combined low MSH2/low ERCC1 subgroup (HR, 0.65; 95% CI, 0.47-0.91; P = 0.01) and in the combined low MSH2/low P27 subgroup (HR, 0.65; 95% CI, 0.46-0.93; P = 0.01). MSH2 expression is a borderline significant predictor of a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with completely resected lung cancer. MSH2 combined with ERCC1 or P27 may identify patients most likely to benefit durably from chemotherapy.

MSH2 and adjuvant cisplatin-based chemotherapy in non-small cell lung cancer

CRA7502 Background: Adjuvant cisplatin-based chemotherapy improves survival among patients with non-small cell lung cancer. The human MutS homolog 2 (MSH2) protein is required to repair cisplatin-DNA lesions. Methods: We used immunohistochemistry to determine MSH2 expression in specimens from patients who had been enrolled in the International Adjuvant Lung Trial. The long-term (median follow-up 7.5 years) overall survival benefit was evaluated in a Cox model adjusted on clinical and pathological variables. Results: Among 673 evaluable tumors, 257 (38%) were MSH2 positive and 416 (62%) were MSH2 negative. The long-term survival benefit of chemotherapy was likely different according to MSH2 expression (test for interaction, P=0.06): chemotherapy compared with observation prolonged survival in the MSH2 negative group (adjusted hazard ratio for death, 0.76; 95%CI, 0.59 to 0.97; P=0.03), but not in the MSH2 positive group (adjusted hazard ratio for death, 1.12; 95%CI, 0.81 to 1.55; P=0.48). In the control arm, the adjusted hazard ratio for death associated with MSH2 positivity compared to MSH2 negativity was 0.66 (95%CI, 0.49 to 0.90; P=0.01). Among 658 patients with available excision repair cross-complementing group 1 (ERCC1) data, the benefit of chemotherapy decreased with the number of positive markers among MSH2 and ERCC1 (P=0.01). Chemotherapy compared with observation prolonged survival in the combined MSH2 negative/ERCC1 negative subgroup (adjusted hazard ratio for death, 0.65; 95%CI, 0.47 to 0.91; P=0.01). Conclusions: MSH2 appears to predict a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with non-small cell lung cancer and may be combined with ERCC1. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline Eli Lilly

MSH2 and adjuvant cisplatin-based chemotherapy in non-small cell lung cancer

CRA7502 Background: Adjuvant cisplatin-based chemotherapy improves survival among patients with non-small cell lung cancer. The human MutS homolog 2 (MSH2) protein is required to repair cisplatin-DNA lesions. Methods: We used immunohistochemistry to determine MSH2 expression in specimens from patients who had been enrolled in the International Adjuvant Lung Trial. The long-term (median follow-up 7.5 years) overall survival benefit was evaluated in a Cox model adjusted on clinical and pathological variables. Results: Among 673 evaluable tumors, 257 (38%) were MSH2 positive and 416 (62%) were MSH2 negative. The long-term survival benefit of chemotherapy was likely different according to MSH2 expression (test for interaction, P=0.06): chemotherapy compared with observation prolonged survival in the MSH2 negative group (adjusted hazard ratio for death, 0.76; 95%CI, 0.59 to 0.97; P=0.03), but not in the MSH2 positive group (adjusted hazard ratio for death, 1.12; 95%CI, 0.81 to 1.55; P=0.48). In the control arm, the adjusted hazard ratio for death associated with MSH2 positivity compared to MSH2 negativity was 0.66 (95%CI, 0.49 to 0.90; P=0.01). Among 658 patients with available excision repair cross-complementing group 1 (ERCC1) data, the benefit of chemotherapy decreased with the number of positive markers among MSH2 and ERCC1 (P=0.01). Chemotherapy compared with observation prolonged survival in the combined MSH2 negative/ERCC1 negative subgroup (adjusted hazard ratio for death, 0.65; 95%CI, 0.47 to 0.91; P=0.01). Conclusions: MSH2 appears to predict a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with non-small cell lung cancer and may be combined with ERCC1. [Table: see text]

Interpreting trial results in light of conflicting evidence: a Bayesian analysis of adjuvant chemotherapy for non-small-cell lung cancer.

When successive randomized trials contradict prior evidence, clinicians may be unsure how to evaluate them: Does accumulating evidence warrant changing practice? An increasingly popular solution, Bayesian statistics quantitatively evaluate new results in context. This study provides a clinically relevant example of Bayesian methods. Three recent non-small-cell lung cancer adjuvant chemotherapy trials were evaluated in light of prior conflicting data. Results were used from International Adjuvant Lung Trial (IALT), JBR.10, and Adjuvant Navelbine International Trialist Association (ANITA). Prior evidence was sequentially updated to calculate the probability of each survival benefit level (overall and by stage) and variance. Sensitivity analysis was performed using expert opinion and uninformed estimates of survival benefit prior probability. The probability of a 4% survival benefit increased from 33% before IALT to 64% after IALT. After sequential updating with JBR.10 and ANITA, this probability was 82% (hazard ratio = 0.84; 95% CI, 0.77 to 0.91). IALT produced the largest decrease in variance (61%) and decreased the chance of survival decrement to 0%. Sensitivity analysis did not support a survival benefit after IALT. However, sequential updating substantiated a 4% survival benefit and, for stage II and III, more than 90% probability of a 6% benefit and 50% probability of a 12% benefit. When evaluated in context with prior data, IALT did not support a 4% survival benefit. However, sequential updating with JBR.10 and ANITA did. A model for future assessments, this study demonstrates the unique ability of Bayesian analysis to evaluate results that contradict prior evidence.

Patterns of co-expression of ERCC1 and p27 in resected non-small cell lung cancer by immunohistochemistry

7595 Background: Excision repair cross-complementation group 1 protein (ERCC1) and p27Kip1 have emerged as biomarkers which predict a lack of benefit from cisplatin-based adjuvant therapy in patients with resected non-small cell lung cancer (NSCLC). Retrospective analysis of tumor tissue from patients enrolled in the International Adjuvant Lung Trial (IALT) suggests that co-expression of these proteins is a stronger predictor of a lack of benefit than either marker independently (Pirker, JTO 2007 (abstract D3–03);2:S397–8). We analyzed in parallel the distribution of these markers in a series of patients with NSCLC. Methods: Surgical resection specimens from 18 patients with NSCLC were analyzed by immunohistochemistry (IHC) for ERCC1 (8F1; Lab Vision) and p27Kip1 (Dako). In addition, IHC expression profiles were correlated with clinicopathologic parameters, including tumor type, grade, and stage. Results: Of 18 tumors, 7 (39%) were ERCC1-positive, and 3 (17%) were p27Kip1-positive. Co-expression of ERCC1 and p27Kip1 was as follows: 1 case (6%) double-positive, 9 cases (50%) double-negative, 6 cases (33%) ERCC1-positive/p27Kip1-negative, and 2 cases (11%) ERCC1-negative/p27Kip1-positive. p27Kip1 expression correlated with better differentiated adenocarcinoma, as previously reported. There was no correlation of ERCC1 or p27Kip1 with other clinicopathologic parameters. Conclusions: The most common pattern of ERCC1 and p27Kip1 expression is double negativity, characteristic of 50% of NSCLC, predicting the patient is more likely to benefit from cisplatin-based adjuvant chemotherapy. Only 6% of patients show co-expression of these markers, which would predict the lowest likelihood of benefit. A significant proportion of patients (44%) show discordant reactivity for ERCC1 and p27Kip1. The value of these biomarkers has not been validated in a prospective trial or retrospective case series other than IALT and should not override pathologic stage as the major criteria for selection of adjuvant therapy until more data are available. Our results suggest that concurrent analysis of p27 and ERCC1 is most likely to bolster a clinical decision to treat a patient with adjuvant chemotherapy. No significant financial relationships to disclose.

Patterns of systemic chemotherapy in resectable non-small cell lung cancer

7590 Background: The International Adjuvant Lung Trial presented in May 2003 was followed by several trials and meta-analyses that demonstrated a clear benefit of adjuvant chemotherapy in stage II ...

Referral Patterns for Adjuvant Chemotherapy in Patients with Completely Resected Non-small Cell Lung Cancer

Lung cancer remains a leading cause of cancer-related mortality in North America. Despite potentially curative resection, non-small cell lung cancer (NSCLC) patients remain at high risk of relapse and death, with a 5-year survival rate of less than 67%. Several randomized trials now confirm a survival benefit with adjuvant platinum-based chemotherapy seen in the NSCLC Collaborative Group meta-analysis, including the International Adjuvant Lung Trial, National Cancer Institute of Canada BR.10, and Adjuvant Navelbine International Trialist Association (ANITA) trials, with absolute improvements in 4- and 5-year survival rates of 4% to 15%. This study examines whether referral patterns for adjuvant therapy in NSCLC have changed since the presentation of confirmatory trials. Retrospective chart review was undertaken at a major tertiary care center, identifying patients with completely resected stages I-IIIA NSCLC from May 2003 to May 2005. A total of 204 patients were identified (59 IA, 77 IB, 8 IIA, 41 IIB, and 19 IIIA). Institutional policy before May of 2003 was not to administer adjuvant therapy outside a clinical trial. After presentation of the International Adjuvant Lung Trial in May 2003, 31% (36/115) of patients with completely resected NSCLC from May 2003 to May 2004 were referred for adjuvant chemotherapy. After presentation of the BR.10 and Cancer and Leukemia Group B 9633 results in June 2004, 63% (56/89) were referred between June 2004 and May 2005. Reasons for not referring to a medical oncologist included stage IA disease, surgeon thought adjuvant therapy inappropriate, patient declined, comorbidities, postoperative complications, and advanced age. Of 92 patients referred to medical oncology, 42 (46%) received adjuvant chemotherapy. Reasons for not prescribing adjuvant chemotherapy included patient refusal (50%), comorbidities (14%), stage IA (10%), and advanced age (4%). Vinorelbine/cisplatin was the regimen most commonly used (67%). The presentation of positive adjuvant therapy trials in NSCLC has changed clinical practice substantially, doubling the number of patients with completely resected NSCLC referred for adjuvant chemotherapy since May 2004 (31% versus 63%). Although new evidence to support adjuvant chemotherapy in lung cancer is being disseminated to and accepted by physicians, more patient education and decision support may be required to increase uptake of adjuvant therapy in the early stage NSCLC population.

Adjuvant and Neoadjuvant Therapy for Early-Stage Non–Small-Cell Lung Cancer

Early-stage non-small-cell lung cancer (NSCLC) carries with it an unfavorable prognosis even in patients who have undergone surgical intervention. Efforts to improve the outcome of patients with early-stage NSCLC have focused on adjuvant or neoadjuvant chemotherapy. The role of adjuvant therapy in NSCLC has been clarified by the recent publication of several large randomized trials. The International Adjuvant Lung Trial was the first prospective trial to report that adjuvant chemotherapy following complete surgical resection of NSCLC improved absolute overall survival by approximately 5% at 5 years. This result has subsequently been confirmed by several other trials. As a result, adjuvant chemotherapy following complete resection of stage IB-III NSCLC can now be considered the standard of care. Neoadjuvant chemotherapy, which has long been investigated for stage III NSCLC, was also recently explored in stage I/II NSCLC. Although neoadjuvant chemotherapy seems promising, more work is needed to comprehensively evaluate and optimize this approach. The current evidence for adjuvant and neoadjuvant therapy in early-stage NSCLC is reviewed in this article.

Adjuvant Chemotherapy for Non–Small Cell Lung Cancer: Contribution of the International Adjuvant Lung Trial

The recently reported International Adjuvant Lung Cancer Trial (IALT) was designed to assess the potential benefit of three to four cycles of adjuvant cisplatin-based chemotherapy after complete resection of non-small cell lung cancer (NSCLC). Each center predetermined the cisplatin dose (total 300-400 mg/m(2)), the combined drug (etoposide or a Vinca alkaloid), and the radiotherapy policy. From 1995 to 2000, 1,867 patients were randomized in 148 centers from 33 countries. On September 1, 2002, median follow-up was 56 months and >98% of patients had an updated follow-up. Overall survival was significantly different between the two arms: 5-year survival rate was 44.5% in the chemotherapy arm versus 40.4% in the control arm [relative risk = 0.86 (0.76-0.98), P < 0.03]. Disease-free survival, incidence of local recurrence, and incidence of distant metastases (but not brain metastases) were likewise significantly different, with an advantage for the chemotherapy arm. We concluded that adjuvant cisplatin-based chemotherapy in resected NSCLC should become part of the standard management of operable NSCLC. Two other recently reported randomized prospective studies also showed a significant benefit for postoperative platin-based doublets in stage IB and II NSCLC and confirmed the role of adjuvant chemotherapy as part of the treatment of these patients. The Lung Adjuvant Cisplatin Evaluation program, a pooled analysis of all recent platin-based adjuvant trials, and the IALT-Bio study, which will investigate over 30 markers in the IALT patients' specimens, should allow us to better define the populations more likely to benefit from postoperative chemotherapy.

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.

Adjuvant chemotherapy and radiotherapy in non-small cell lung cancer

Although surgical resection remains the best potentially curative treatment for non-small cell lung cancer (NSCLC), more than half the patients undergoing resection will eventually die of recurrent disease. Approximately two thirds of relapses occur outside the chest, indicating a potential role for adjuvant chemotherapy. Indeed, a meta-analysis has suggested an absolute survival benefit of 5% at 5 years with adjuvant cisplatin-based regimens. This finding has incited several large-scale randomized trials, the largest of which, the International Adjuvant Lung Trial, has confirmed a similar survival advantage. Conversely, a meta-analysis on postoperative radiotherapy has suggested a detrimental effect, especially for stage I and II patients, that is related most probably to a poor radiation technique. Its value for stage III remains controversial: the observed reduction in local failure did not translate into a survival benefit. In this article, the current status of adjuvant chemotherapy and radiotherapy are reviewed, and future prospects are discussed.

Impact of adjuvant chemotherapy (CT) on survival and local-control in non-small cell lung cancer (NSCLC): Results of the international adjuvant lung cancer trial (IALT)

Survival results of the International Adjuvant Lung Trial (IALT) which was designed to question the role of 3 to 4 cycles of adjuvant cisplatin-based CT after complete resection of NSCLC have been recently reported (NEJM, 2004). Our objective is to present results on patterns of failure and especially local control.

Impact of adjuvant chemotherapy (CT) on survival and local-control in non-small cell lung cancer (NSCLC): Results of the international adjuvant lung cancer trial (IALT)

Survival results of the International Adjuvant Lung Trial (IALT) which was designed to question the role of 3 to 4 cycles of adjuvant cisplatin-based CT after complete resection of NSCLC have been recently reported (NEJM, 2004). Our objective is to present results on patterns of failure and especially local control.

Adjuvant therapy for resected non-small-cell lung cancer: recent advances, emerging agents, and lingering questions.

Survival rates for all stages of non-small-cell lung cancer (NSCLC) are dismal. Despite complete resection of early-stage NSCLC, many patients have recurrence at distant metastatic sites, reinforcing the need for effective systemic adjuvant therapy. Chemotherapy, and more recently, targeted therapies, have been evaluated in the adjuvant setting. Although initial trials did not suggest improved survival, a 1995 meta-analysis favored adjuvant cisplatin-based chemotherapy. The recently published International Adjuvant Lung Trial confirms this finding and suggests a new standard of care. In this paper we review data on adjuvant chemotherapy and limitations of recent clinical trials, including those with targeted therapies. We also address the most effective and least toxic regimens for adjuvant chemotherapy and the subsets of patients likely to derive the most benefit.

Bayesian analysis of the International Adjuvant Lung Trial (IALT): Should it change practice?

6038 Background: IALT (2003) demonstrated that cisplatin-based adjuvant chemotherapy (CBAC) provides a 4% absolute survival benefit at 5 years for patients with resected stages I-III non-small cell lung cancer (NSCLC). These results must be interpreted in the context of conflicting data from prior randomized trials. We used Bayesian analysis to determine if the IALT results are convincing enough to change clinical practice or if additional trials are required. Methods: We developed three curves that estimate the probabilities of survival benefit prior to IALT's results. These estimates were based on: 1) a formal survey of 18 thoracic oncology experts; 2) a 1995 meta-analysis of adjuvant chemotherapy; and 3) a ‘skeptical’ curve, which downweights prior positive trials. The primary endpoint was difference in five-year survival. Analysis using Bayes Theorem incorporated IALT results into each curve to yield updated probabilities of survival benefit. Results: Survey respondents estimated a CBAC survival benefit, prior to IALT, of 2.94% (95% CI: 1.78–4.11%); only 11% of the experts offered CBAC at that time. The table shows the probability for each level of survival benefit before and after prior estimates were updated by IALT. Each updated curve supports an overall survival benefit for CBAC in NSCLC. However, the level of benefit supported varies. The probability of at least a 3% survival advantage was 80%, 71%, and 54%, for the meta-analysis, survey, and skeptical curve, respectively. The chance of a survival decrement for CBAC was below 1% for each curve. Conclusions: The preponderance of evidence supports at least a 3% survival advantage for CBAC. It is, therefore, ethically difficult to support additional randomized trials that include an observation-only arm. Future efforts should focus on incorporating targeted agents into adjuvant regimens for NSCLC as well as selecting patients most likely to benefit. No significant financial relationships to disclose.