Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non-Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups

Duke University, Durham, North Carolina, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2008; 26(31):5043-51. DOI: 10.1200/JCO.2008.16.4855
Source: PubMed

ABSTRACT Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.
Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.
Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043).
Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.

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    • "Similarly, as seen in the IALT discussed above, in CALGB 9633 the benefit of adjuvant faded with time and emphasised the need for prolonged follow-up to establish the proof of benefit in adjuvant setting. Interestingly enough, a subgroup exploratory analysis was performed in CALGB 9633 according to tumour size P or <4 cm [8]. In the updated analysis with a 74 month followup the overall survival in stage IB was not improved in the intent-to-treat population, but an overall survival benefit was seen for patients with a tumour P4 cm with an HR of death = 0.69 and a P value = 0.043, a median overall survival of 99 months compared with 77 months in the surgery only arm. "
    EJC Supplements 09/2013; 11(2):131–136. DOI:10.1016/j.ejcsup.2013.07.024 · 9.39 Impact Factor
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    • "The IALT (International Adjuvant Lung Trial) shows that platinum-based chemotherapy for patients with NSCLC improves a 5-year survival rate by 4.1% (Arriagada et al., 2004), but there is no significant benefit after follow-up for 90 months (Arriagada et al., 2010). The CALGB 9633 trial results in a similar finding (Strauss et al., 2008). Furthermore, the ANITA (Adjuvant Navelbine International Trialist Association) and JBR-10 (National Cancer Institute of Canada Clinical Trial Group) trials also confirm the survival benefit of adjuvant cisplatinvinorelbine chemotherapy in patients with NSCLC at I-IIIA even after follow-up for 9.3 years (Winton et 4506 al., 2005; Douillard et al., 2006; Butts et al., 2010). "
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    ABSTRACT: Purpose: To determine the efficacy of post-operative chemotherapy with cisplatin plus vinorelbine (NP) in Chinese patients with non-small cell lung cancer (NSCLC). Methods: A total of 451 patients with NSCLCs at stages I, II, and IIIA after surgical resection were treated with cisplatin plus vinorelbine for 4 cycles or volunteers observed between January 2002 and November 2004 and were followed for five years. The therapeutic efficacy was evaluated with reference to overall survival (OS) and disease-free survival (DFS), and adverse effects were also recorded. Potential factors affecting the lengths of OS and DFS were analyzed by multivariate analysis. Results: Most patients (86.7%) completed at least 4 cycles of treatment. Patients with chemotherapy survived significantly longer than those in the observation group (p<0.001). The absolute improvements in the 2 and 5-year OS were 3.8% [hazard ratio (HR) =0.674, 95% confidence interval (CI): 0.554-0.820, P<0.0001] and 13.0% (HR=0.732, 95% CI: 0.579-0.926, P=0.009), respectively. The improvement at 4-year DFS was 2.1% (HR=0.327, 95% CI: 0.214-0.500, P<0.0001). Stratification analysis revealed that older age, histological type, pathological degree, but not the gender and smoking status, are independent factors affecting the length of survival in this population. Many patients (63.3%) had grade 1-III tolerable adverse effects, and there was no treatment-related death. Conclusions: Post-operative chemotherapy with NP regimen is effective and tolerable in Chinese patients with NSCLC.
    Asian Pacific journal of cancer prevention: APJCP 09/2012; 13(9):4505-10. DOI:10.7314/APJCP.2012.13.9.4505 · 2.51 Impact Factor
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    • "The reported positive results of adjuvant tegafur-uracil (UFT) in stage I NSCLC cannot be extrapolated to non-Asian patients [Hamada et al. 2005]. Also, it should be stressed that, although biologically plausible, the assumption of therapeutic benefit for stage IB disease with tumor size larger than 4 cm is based on an unplanned subgroup analysis [Strauss et al. 2008]; the revised classification of T1bN0 disease as stage II may resolve this controversy . Overall, in an alternative statistical "
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    ABSTRACT: Although surgery is the only potentially curative treatment for early-stage non-small cell lung cancer (NSCLC), 5-year survival rates range from 77% for stage IA tumors to 23% in stage IIIA disease. Adjuvant chemotherapy has recently been established as a standard of care for resected stage II-III NSCLC, on the basis of large-scale clinical trials employing third-generation platinum-based regimens. As the overall absolute 5-year survival benefit from this approach does not exceed 5% and potential long-term complications are an issue of concern, the aim of customized adjuvant systemic treatment is to optimize the toxicity/benefit ratio, so that low-risk individuals are spared from unnecessary intervention, while avoiding undertreatment of high-risk patients, including those with stage I disease. Therefore, the application of reliable prognostic and predictive biomarkers would enable to identify appropriate patients for the most effective treatment.This is an overview of the data available on the most promising clinicopathological and molecular biomarkers that could affect adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine practice. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information warranting further validation. On the other hand, real-time quantitative polymerase-chain reaction strategy involving relatively small number of genes offers a practical alternative, with high cross-platform performance. Although data extrapolation from the metastatic setting should be cautious, the concept of personalized, pharmacogenomics-guided chemotherapy for early NSCLC seems feasible, and is currently being evaluated in randomized phase 2 and 3 trials. The mRNA and/or protein expression levels of excision repair cross-complementation group 1, ribonucleotide reductase M1 and breast cancer susceptibility gene 1 are among the most potential biomarkers for early disease, with stage-independent prognostic and predictive values, the clinical utility of which is being validated prospectively. Inter-assay discordance in determining the biomarker status and association with clinical outcomes is noteworthing.
    rapeutic Advances in Medical Oncology, The 07/2011; 3(4):185-205. DOI:10.1177/1758834011409973
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