Adjuvant Cisplatin-based Chemotherapy Research Articles

Updates in non-small cell lung cancer--insights from the 2009 45th annual meeting of the American Society of Clinical Oncology.

We have reviewed the pivotal presentations in non-small cell lung cancer (NSCLC) from the 2009 annual meeting of the American Society of Clinical Oncology. We have discussed the scientific data, the impact on standards of care, and ongoing clinical trials.In patients with early-stage NSCLC, there is still no data to support the superiority of either neoadjuvant or adjuvant chemotherapy. However, adjuvant cisplatin-based chemotherapy has sustained the survival benefits after median follow-up of more than 9 years. The first-line treatment with inhibitors of epidermal growth factor receptor (EGFR) could be considered for the treatment of EGFR mutated patients with metastatic disease.Several maintenance studies with cytotoxic or biological agents have also demonstrated promising outcomes. Finally, novel targeted agents such as inhibitors of histone deacetylase and multi-targeted tyrosine kinase inhibitor have shown promising activity in NSCLC treatment.

Abstract 2995: MicroRNA expression and outcome of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: International Adjuvant Lung Cancer Trial Biologic Program (IALT-Bio)

Abstract The aim of our study was to assess whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic and/or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted so far of adjuvant chemotherapy in patients with radically resected NSCLC stage I-III. Expression of miR-21, miR-29b, miR-34a/b/c, miR-155 and Let-7a was determined by quantitative real-time PCR in paraffin embedded formalin fixed tumor specimens from 639 IALT patients, using small nuclear RNA U66 as the endogenous normalization control. From 79 patients sufficient tumor adjacent normal tissue was available as well. The prognostic and predictive value of microRNA expression and chemotherapy for survival were studied using a Cox model, which included every factor used in the stratified randomization plus clinical and histological prognostic factors as well as other factors statistically related to microRNA expression. Association of p53 mutation status and miR-34a/b/c expression was analyzed, as well as association of EGFR and K-Ras mutation status with miR-21 and Let-7a expression, respectively. Finally association of p16 and miR-29b expression was assessed. In situ hybridization was performed for validation and to determine histological expression patterns. Overall, we found that there was no significant association between the expression profile of any of the tested microRNAs and survival. However, for miR-21, miR-34b and miR-34c, there is a suggested deleterious prognostic effect of lower values on survival. No single microRNA expression profile or a combination of microRNA expression profiles, as determined by cluster analysis, predicted response to adjuvant cisplatin-based chemotherapy. Concluding, expression levels of the tested microRNAs were neither predictive nor prognostic in this patient cohort. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2995.

Adjuvant or neoadjuvant chemotherapy in minimal N2 stage IIIA nonsmall cell lung cancer

In the last decade, numerous randomized trials have evaluated the benefit of (neo-)adjuvant chemotherapy in nonsmall cell lung cancer. This article will review the recent data on perioperative chemotherapy in stage III A-N2 nonsmall cell lung cancer and future research opportunities are presented. Four retrospective series, two phase 2 and four phase 3 trials in the neoadjuvant setting and one retrospective series, two phase 2 trials and two phase 3 trials in the adjuvant setting are retrieved and discussed. The available evidence does not allow to change the current recommendation regarding the management of patients presenting with biopsy-proven clinical stage IIIA-N2 nonsmall cell lung cancer: their preferred treatment is chemoradiotherapy. Surgery with neoadjuvant or adjuvant chemotherapy is not proven superior to radiotherapy. The patient occasionally presenting with unforeseen pN2 despite adequate preoperative mediastinal staging should be offered adjuvant cisplatin-based chemotherapy and possibly postoperative radiotherapy.

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.

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.

Pharmacotherapy Update: Vinorelbine in the Treatment of non-small-cell Lung cancer

Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world. Vinorelbine is an active vinca-alkaloid with a broad spectrum of anti-tumour activity. In particular, it has high activity in NSCLC, where a synergy with cisplatin has been demonstrated. Recently, oral vinorelbine has shown a similar activity and efficacy as compared to the intravenous formulation, giving to the patient an easier way of administration and increasing his comfort. Although surgery remains the best chance of cure for patients with resectable NSCLC, it is now accepted that postoperative cisplatin-based adjuvant chemotherapy significantly improves survival in patients with NSCLC. The combination of cisplatin and vinorelbine is the most active among all the adopted schedules. Patients presenting with locally advanced disease at diagnosis benefit from concomitant chemotherapy with cisplatin-vinorelbine regimen in combination with thoracic radiotherapy. Platinum-based combinations have become the standard of care for treating NSCLC. Vinorelbine–cisplatin combination is one of the proposed doublets for treating advanced, metastatic, NSCLC. Because of its favorable toxicity profile, vinorelbine has become a major compound as a treatment for elderly patients with advanced NSCLC.

A critical appraisal of the adjuvant chemotherapy guidelines for patients with completely resected T3N0 non-small-cell lung cancer

Background. A Joint Expert Panel recently published guidelines for adjuvant cisplatin-based chemotherapy, recommending routine use in patients with completely resected stage II (T1-2N1 and T3N0) non-small-cell lung cancer (NSCLC). However, these two tumor subgroups should be considered as different entities. While the efficacy of adjuvant chemotherapy has been established in patients with T1-2N1 NSCLC, its benefit in patients with T3N0 tumor remains questionable. Material and methods. We performed an extensive review of the literature using the Joint Expert Panel guidelines as a start point. Altogether, we identified 76 potentially relevant articles. Basing on inclusion and exclusion criteria, 23 of the 76 articles were eventually included in this review. Results. After careful evaluation of the selected articles, we found no information on the effect of adjuvant chemotherapy in patients with T3N0 NSCLC. Discussion. In the absence of evidence-based data, we recommend that the lack of information on the efficacy of adjuvant chemotherapy for T3N0 tumors be discussed with patients and propose chemotherapy as an individual option. While the efficacy of adjuvant chemotherapy will be difficult to assess prospectively through a large randomized clinical trial, a pooled-analysis of the existing data would quickly and with a limited effort provide a preliminary answer.

Use of Adjuvant Chemotherapy in Non-small Cell Lung Cancer in Routine Practice

For many years, surgery has been the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC). Recent randomized trials demonstrated that cisplatin-based adjuvant chemotherapy increases overall survival. The aim of this study was to analyze the precise use of adjuvant chemotherapy in patients with resected NSCLC in routine practice. Between January 2004 and May 2005, we retrospectively analyzed 219 patients with early-stage NSCLC who had undergone surgery at one major surgical center in Paris, Institut Mutualiste Montsouris. Patient characteristics, the type of surgery, and indications for adjuvant chemotherapy were analyzed. Eighty-seven of the 219 patients (40%) in this study had been treated with adjuvant chemotherapy. Different factors were associated with doctors not prescribing this treatment: age, comorbidity, tumor, node, metastasis stage, and postoperative complications. More than eight different cisplatin-based regimens were used, highlighting considerable heterogeneity in the use of adjuvant chemotherapy in daily practice. There is an increase of adjuvant chemotherapy during the study period. Cisplatin-based chemotherapy is the standard treatment for patients with resected stage II and IIIA NSCLC. However, such therapy is used quite heterogeneously in daily practice and specific regimens, and the percentage of patients receiving adjuvant chemotherapy vary from standard recommendations. A prospective follow-up of daily practice regarding the use of adjuvant chemotherapy is warranted.

Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer

PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.

The feasibility of adjuvant carboplatin and docetaxel in patients with curatively resected locally advanced non-small cell lung cancer

Background Adjuvant cisplatin-based chemotherapy benefits selected patients with stages II and III non-small cell lung cancer (NSCLC). However, carboplatin being tolerated better than cisplatin, carboplatin-based adjuvant therapy may have better chemotherapy compliance. This study aimed to investigate the feasibility and toxicity of adjuvant carboplatin and docetaxel in patients with completely resected locally advanced NSCLC. Methods Eighty patients with completely resected locally advanced NSCLC were enrolled in this trial. Adjuvant chemotherapy was initiated between 1 and 4 weeks after surgery, and consisted of four cycles of carboplatin (AUC = 5), and docetaxel (Taxotere, 75 mg/m 2) every 3 weeks, after which patients received prophylactic G-CSF supportive therapy. Results Patient demographics were: Median age 55 years (range 34–73): gender ratio was 56.3% male/43.7% female: 72.5% of the patients were at stage IIIA and 27.5% were at stage IIIB. The two most common histologies were adenocarcinoma (62.5%) and squamous cell carcinoma (17.5%). Sixty-six patients (82.5%) received four cycles of therapy over a 12-week period. Fourteen patients (17.5%) did not complete therapy due to: patient refusal ( n = 12), severe adverse events ( n = 1) and bone metastases during chemotherapy ( n = 1). No treatment related deaths were observed and the primary adverse events were hematologic toxicity, alopecia, fatigue and gastointestinal reaction (nausea, vomiting and diarrhea). Conclusion Combination therapy with carboplatin and docetaxel with the use of G-CSF supportive therapy has an acceptable toxicity profile such that the majority of patients completed four cycles of therapy in 12 weeks.

Sequential adjuvant chemotherapy after surgical resection of high‐risk urothelial carcinoma

Despite definitive surgery, the survival of patients with high-risk urothelial carcinoma (UC) is poor. Adjuvant cisplatin-based chemotherapy may be beneficial, but it is restricted by the need for normal renal function (RF). Sequential administration of adjuvant chemotherapy facilitates drug delivery and improves survival in patients with breast cancer. The objective of this study was to evaluate the feasibility and survival impact of adjuvant, sequential chemotherapy in patients with high-risk UC. Fifty patients were treated on 2 simultaneous protocols between 1997 and 2004. The patients on Protocol A (normal RF) received doxorubicin and gemcitabine (AG) followed by paclitaxel and cisplatin. The patients on Protocol B (impaired RF) received AG followed by paclitaxel plus carboplatin. Overall survival (OS) and disease-specific survival (DSS) were compared with a group of 203 contemporary control patients who had similar pathology and RF and who underwent surgery alone. The median follow-up of protocol patients was 6.5 years (range, 0.9-8.6 years), and 25 patients remained alive. The median follow-up of the control group was 4.7 years (0.0-9.2), and 68 patients remained alive. The median OS for patients on Protocol A was greater than that for controls who had good RF (4.6 years vs 2.5 years; P = .03). The median OS for patients on Protocol B was greater than that for controls who had impaired RF (3.4 years vs 2 years; P = .04). DSS for the protocol and matched control groups was similar (good RF: 4.6 years vs 3 years; P = .24; impaired RF: 3.4 years vs 3.3 years; P = .40). In this nonrandomized study, adjuvant, sequential chemotherapy for patients with high-risk UC did not improve DSS over that observed with surgery alone.

Expression of MRP1, BCRP, LRP and ERCC1 as prognostic factors in non-small cell lung cancer patients receiving postoperative cisplatin-based chemotherapy

The development of resistance to chemotherapy is one of the major obstacles in the treatment of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic value of multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance-related protein (LRP), and excision repair cross-complementing 1 (ERCC1) in NSCLC patients receiving cisplatin-based adjuvant chemotherapy (cisplatin plus vinorelbine or gemcitabine) after tumor resection. We used semiquantitative reverse-transcription polymerase chain reaction to detect the expression of MRP1, BCRP, LRP and ERCC1 mRNA in surgical resection specimens of 60 patients with stage IB through IIIA NSCLC. The expression level of each gene was analyzed in relation to clinicopathological factors, tumor-free survival (TFS), and overall survival. The results showed that stage IIIA (p=0.011), N1 and N2 status (p=0.008), high expression of MRP1 (p=0.034) and LRP (p=0.018) were associated with shorter TFS. Stage IIIA (p=0.0105), N1 and N2 status (p=0.009), high expression of MRP1 (p=0.021) and ERCC1 (p=0.012) were related to a shorter overall survival. Cox multivariate analyses revealed that early stage (p=0.013 and p=0.024), negative lymph node status (p=0.006 and p=0.011), and low MRP1 expression (p=0.022 and p=0.035) were independent predictors of favorable TFS and overall survival, respectively. Additionally, ERCC1 (p=0.019) was an independent predictor of favorable overall survival.

Adjuvant chemotherapy for completely resected non-small-cell lung cancer.

For many years, surgery alone was the standard treatment for patients with stage I-IIIA non-small-cell lung cancer (NSCLC). However, recent studies have demonstrated that adjuvant chemotherapy provides a survival benefit. The first adjuvant chemotherapy for NSCLC was performed in the 1960s using a key drug known as cyclophosphamide. In the 1980s and early 1990s, a new anti-cancer drug, cisplatin, was developed. The first meta-analysis of this drug was conducted by the Non-small Cell Lung Cancer Collaborative Group in 1995. This analysis comparing surgery with surgery plus chemotherapy containing cisplatin produced a hazard ratio of 0.87 and suggested an absolute benefit of chemotherapy of 5% at 5 years;this difference was not statistically significant (p0.08). Several clinical trials of adjuvant chemotherapy were planned after the meta-analysis conducted in 1995, but the efficacy of adjuvant chemotherapy remained a matter of controversy. However, useful evidence was reported after 2003. The International Adjuvant Lung Cancer Collaborative Group Trial (IALT) demonstrated a 4.1% improvement in survival for patients with stage I to III NSCLC. The JBR. 10 trial demonstrated a 15% improvement in 5-year survival for the adjuvant chemotherapy arm in stage IB or II (excluding T3N0) patients. The Adjuvant Navelbine International Trialist Association (ANITA) trial reported that the overall survival at 5 years improved by 8.6% in the chemotherapy arm and that this survival rate was maintained at 7 years (8.4%) in stage II and IIIA patients. A meta-analysis based on collected and pooled individual patient data from the 5 largest randomized trials was conducted by the Lung Adjuvant Cisplatin Evaluation (LACE). This analysis demonstrated that cisplatin-based adjuvant chemotherapy improved survival in patients with stage II or III cancer. Alterna-tively, uracil-tegafur has been developed and tested in Japan. The Japan Lung Cancer Research Group (JLCRG) on Postsurgical Adjuvant Chemotherapy reported a 5-year overall survival advantage of 11% in the uracil-tegafur group patients with stage IB cancer. The efficacy of adjuvant chemotherapy with uracil-tegafur was confirmed in a meta-analysis. In conclusion, the results of phase III trials and a meta-analysis have confirmed the benefit of adjuvant chemotherapy for resected stage IB, II, and IIIA NSCLC.

Favourable outcomes of patients with clinical stage T3N0M0 bladder cancer treated with induction low‐dose chemo‐radiotherapy plus partial or radical cystectomy vs immediate radical cystectomy: a single‐institutional retrospective comparative study

To address the role of neoadjuvant concurrent chemo-radiotherapy (CRT) in muscle-invasive bladder cancer, by comparing retrospectively the oncological outcomes between a low-dose CRT (LCRT) plus partial cystectomy (PC) or radical cystectomy (RC) protocol and an immediate RC protocol. From 1997 to 2007, 119 patients with clinical stage T2-4aN0M0 bladder cancer received LCRT consisting of RT of 40 Gy in 4 weeks concurrently with two cycles of chemotherapy with cisplatin (20 mg/day for 5 days) during the first and fourth week of RT. Subsequently, 24 (20%) and 65 patients (55%) had PC and RC, respectively, while 30 (25%) had no curative surgery; the median follow-up was 36 months. From 1983 to 1997, 73 patients had an immediate RC; 29 (41%) received cisplatin-based adjuvant chemotherapy, and the median follow-up was 46 months. Oncological outcomes were compared retrospectively between these groups. The cancer-specific survival (CSS) rate at 5 years was 75% and 61% for the LCRT protocol and immediate RC protocol, respectively (P = 0.11). In patients with clinical stage T3N0M0 the LCRT protocol gave significantly better survival rates than the immediate RC protocol, with 5-year CSS rates of 62% vs 27% (P = 0.006), while being comparable in those with clinical stage T2N0M0 disease (89% vs 88%, P = 0.84). In patients with clinical stage T3N0M0 the LCRT protocol provided a lower 5-year recurrence rate at distant sites than the immediate RC protocol (31% vs 62%, P = 0.09). The LCRT plus PC or RC protocol gave significantly better survival rates than the historical, immediate RC protocol in patients with clinical stage T3N0M0 bladder cancer, suggesting that neoadjuvant CRT possibly has survival benefits for such patients.

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]

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

CRA7502 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]

Prognostic Analysis of ERCC1, RRM1 and p53 Expressions in Postoperative Stage I-II Lung Cancer.

Cisplatin is an important drug in lung cancer chemotherapy. It has been proven that ERCC1, RRM1, p53 expressions were related to resistance to platinum and prognosis of the patcents with lung cancer. The aim of this study is to analyze the association of the expression of ERCC1, RRM1, p53 with postoperative survival in patients with stage I-II non-small-cell lung cancer (NSCLC), and to explore the relationship between the expression of ERCC1, RRM1, p53 and resistance to cisplatin. A total of 75 patients with stage I-II NSCLC receiving radical resection from Feb. 1992 to Jan. 1994 were followed up. Postoperative patients with stage I were randomized two groups (chemo and non-chemo groups). All patients with stage II received adjuvant cisplatinbased chemotherapy. Immunohistochemical staining was used to detect the expression of ERCC1, RRM1, p53 in paraffinembedded specimens. In stage I NSCLC, the prognosis of the patients with high expression of ERCC1 (High-ERCC1) was better than those with low expression of ERCC1 (Low-ERCC1). 1, 3, 5-year survival rate in the patients with high expression of ERCC1 was 100.00%, 91.30%, 86.74% and in those with Low-ERCC1 was 96.43%, 60.71%, 57.14%, respectively (P =0.0058). The patients with High- ERCC1 had a better survival rate than those with Low-ERCC1 in stage I NSCLC without chemotherapy. MST in high and low expression of ERCC1 was 72.00(+) months and 64.67 months, respectively (P =0.0327). In contrary to stage I NSCLC, the patients with had a better survival rate than those with in stage II. MST was 60.00(+) months in stage II patients with low expression of ERCC1, but MST was only 25.50 months with (P =0.0442). The postoperative survival of NSCLC patients was not any statistical different between with high expression and low expression of RRM1 and p53. High expression of ERCC1 is a better independent prognostic factor in stage I NSCLC patients. Cisplatin-base chemotherapy prolongs survival in stage II NSCLC patients with. Adjuvant chemotherapy regimen is determined according to ERCC1 expression levels in resected NSCLC.

Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor epidermal growth factor receptor (EGFR) mutations

7523 Background: Patients with stage IV adenocarcinoma whose tumors harbor EGFR mutations have high rates of response (∼ 75%) and prolonged progression free survival after EGFR tyrosine kinase inhibitor (TKI) treatment. Adjuvant cisplatin-based chemotherapy improves disease free survival (DFS) and overall survival (OS) in patients with resected stages IB-IIIA NSCLC. To see if adjuvant treatment with EGFR TKI (gefitinib or erlotinib) improves DFS in patients with EGFR mutation NSCLC, we conducted a retrospective review of patients with resected lung adenocarcinoma harboring EGFR mutations, some of whom received EGFR TKIs postoperatively. Methods: With Institutional Review Board approval, clinical information was obtained on all patients with stage I-III lung adenocarcinoma harboring EGFR exon 19 or 21 mutations that underwent resection at MSKCC between May 2002 and August 2008. Age, gender, type of surgery, histology, EGFR mutation status (exon 19 deletions and exon 21 L858R), stage, perioperative therapy and survival were recorded. Kaplan-Meier analysis and Cox regression analysis were performed. Results: We studied 150 patients (112 women, 38 men) with completely resected stage I-III lung adenocarcinoma whose resection specimens contained EGFR activating mutations in exon 19 or 21. Median age was 69. Forty two patients (28%) received cytotoxic chemotherapy. Forty eight (32%) received either erlotinib (n=26) or gefitinib (n=22) postoperatively. The median time on TKI was 16 months. The median DFS was 43 months in the group that received a TKI vs. 31 months for those that did not. After controlling for stage, individuals who received adjuvant gefitinib or erlotinib had a better DFS (HR=0.38, 95%CI: 0.16–0.90) than the non-TKI group (p=0.03). The median overall survival has not been reached. Conclusions: These data indicate that the adjuvant use of either gefitinib or erlotinib improves DFS in patients with completely resected stage I -III lung adenocarcinomas with mutations in EGFR exons 19 and 21. These data justify a randomized trial in similar patients. [Table: see text]

Adjuvant Treatment of Resected Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide, and efforts to improve outcomes of patients with this disease require a multidisciplinary approach. While surgical resection is the optimal treatment for early stage lung cancer, the high rates of recurrence after resection pose a distinct challenge. In recent years, substantial evidence has accumulated to support adjuvant chemotherapy in Stage II and III non-small cell lung cancer (NSCLC). A recent meta-analysis of large clinical trials of cisplatin-based adjuvant chemotherapy for resected NSCLC showed that the 5-year survival benefit in favor of chemotherapy was 5.3% (hazard ratio for death, 0.89; 95% confidence interval, 0.82-0.96; P = 0.005). The use of adjuvant chemotherapy in Stage I NSCLC remains controversial. Current and future efforts are being directed toward identification of prognostic and predictive markers to select patients at highest risk for recurrence, and of chemotherapeutic agents to which their tumors are most likely to respond. The role of targeted therapies, including those directed at the epidermal growth factor receptor and vascular endothelial growth factor in adjuvant treatment, is currently under investigation. At this time, there are no data to support the routine use of adjuvant radiation treatment, except in cases in which surgical margins are positive.