Adjuvant Chemotherapy in NSCLC: State-of-the-Art
Adjuvant chemotherapy (AC) plays now a significant role in the treatment of resected non-small cell lung cancer (NSCLC) patients and has become standard in clinical practice. It took more than two decades of clinical research to show its value, but it is has been well established that its benefit translates into a 4–5% absolute increase in 5-year survival according to published meta-analysis. This improvement is obtained with two-drug, Cisplatin-based regimens (multiples choices are acceptable but vinorelbine is the drug with more reported evidence) and usually four courses are recommended. Survival increase is restricted to cases in which there is involvement of lymph nodes (both N1 and N2 levels). For N0 cases AC might be considered, with a lower level of evidence, for tumors larger than 4 cm in diameter. At the present time, molecular predictive factors and gene signatures are investigational. Patient selection is of paramount importance. Proper recovery from surgery and the absence of major comorbidities are essential features. Toxicity is significant, but manageable and transient. Neutropenia is the most relevant side effect due to the risk of febrile neutropenia. The role of timing of administration, adjuvant radiotherapy (RT) and of newer drugs under evaluation is also reviewed.
Surgery remains the basic treatment for patients with localized non-small cell lung cancer (NSCLC). Nonetheless, even after an apparently complete resection procedure the risk of recurrence remains substantial. The benefit of adjuvant chemotherapy (AC) was not demonstrated until one decade ago with the repot of trial exploring the value of active cisplatin combinations along with optimal supportive care measures.
Pathological stage is the single most relevant prognostic factor for recurrence and death after NSCLC surgery. For patients with pathological stage II the 5-year survival rate after surgery alone is under 50% (stage IIA 46%, and IIB 36%) and it drops as low as to 24% for stage IIIA. Significant efforts have been made to refine prognostic information with molecular markers (such as K-ras mutations and ERCC-1 expression) or gene expression signatures, but up to the present they remain investigational and need to be confirmed in prospective trials which are currently active.
AC is currently recommended for patients with pathologic stages II and III after surgery with curative intent. It is not for stage IA and its role in stage IB is limited and based on lower evidence. Theoretical considerations make postoperative chemotherapy appealing: i.e., the percentage of relapse in these tumors is high, and most of the relapses are systemic (lung, CNS, bone, adrenal and liver being the commonly involved organs) as well as the earlier proof of benefit in other common primary tumors such as breast or colorectal carcinomas. However it took a longer time to demonstrate its benefit in NSCLC.
Trials conducted prior to 2000 were small and had several methodological flaws that did not permit to reach any conclusion and lead to a nihilistic attitude. A meta-analysis published in 1995 showed that alkylating-based regimens were detrimental in terms of survival (a 15% increased risk of death existed). On the contrary, for eight trials that used cisplatin-based regimens a 5% absolute benefit in 5-year survival was found (albeit without statistical significance due to small size). This finding gave new thrust to AC and several new trials with Cisplatin combinations were started.
Besides of the intrinsic effectiveness of chemotherapy a second factor had to be taken into consideration. Compliance of patients with the scheduled chemotherapy was poor. A thoracotomy is a significant surgical procedure and requires some time to recover. Besides, by the time when those trials were conducted supportive measures (antiemetic therapy and colony-stimulating stimulating factors mainly) were suboptimal.
Abstract and Introduction
Abstract
Adjuvant chemotherapy (AC) plays now a significant role in the treatment of resected non-small cell lung cancer (NSCLC) patients and has become standard in clinical practice. It took more than two decades of clinical research to show its value, but it is has been well established that its benefit translates into a 4–5% absolute increase in 5-year survival according to published meta-analysis. This improvement is obtained with two-drug, Cisplatin-based regimens (multiples choices are acceptable but vinorelbine is the drug with more reported evidence) and usually four courses are recommended. Survival increase is restricted to cases in which there is involvement of lymph nodes (both N1 and N2 levels). For N0 cases AC might be considered, with a lower level of evidence, for tumors larger than 4 cm in diameter. At the present time, molecular predictive factors and gene signatures are investigational. Patient selection is of paramount importance. Proper recovery from surgery and the absence of major comorbidities are essential features. Toxicity is significant, but manageable and transient. Neutropenia is the most relevant side effect due to the risk of febrile neutropenia. The role of timing of administration, adjuvant radiotherapy (RT) and of newer drugs under evaluation is also reviewed.
Introduction
Surgery remains the basic treatment for patients with localized non-small cell lung cancer (NSCLC). Nonetheless, even after an apparently complete resection procedure the risk of recurrence remains substantial. The benefit of adjuvant chemotherapy (AC) was not demonstrated until one decade ago with the repot of trial exploring the value of active cisplatin combinations along with optimal supportive care measures.
Pathological stage is the single most relevant prognostic factor for recurrence and death after NSCLC surgery. For patients with pathological stage II the 5-year survival rate after surgery alone is under 50% (stage IIA 46%, and IIB 36%) and it drops as low as to 24% for stage IIIA. Significant efforts have been made to refine prognostic information with molecular markers (such as K-ras mutations and ERCC-1 expression) or gene expression signatures, but up to the present they remain investigational and need to be confirmed in prospective trials which are currently active.
AC is currently recommended for patients with pathologic stages II and III after surgery with curative intent. It is not for stage IA and its role in stage IB is limited and based on lower evidence. Theoretical considerations make postoperative chemotherapy appealing: i.e., the percentage of relapse in these tumors is high, and most of the relapses are systemic (lung, CNS, bone, adrenal and liver being the commonly involved organs) as well as the earlier proof of benefit in other common primary tumors such as breast or colorectal carcinomas. However it took a longer time to demonstrate its benefit in NSCLC.
Trials conducted prior to 2000 were small and had several methodological flaws that did not permit to reach any conclusion and lead to a nihilistic attitude. A meta-analysis published in 1995 showed that alkylating-based regimens were detrimental in terms of survival (a 15% increased risk of death existed). On the contrary, for eight trials that used cisplatin-based regimens a 5% absolute benefit in 5-year survival was found (albeit without statistical significance due to small size). This finding gave new thrust to AC and several new trials with Cisplatin combinations were started.
Besides of the intrinsic effectiveness of chemotherapy a second factor had to be taken into consideration. Compliance of patients with the scheduled chemotherapy was poor. A thoracotomy is a significant surgical procedure and requires some time to recover. Besides, by the time when those trials were conducted supportive measures (antiemetic therapy and colony-stimulating stimulating factors mainly) were suboptimal.
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