Adjuvant chemotherapy for non-small cell lung cancer

Nearly half of all patients who undergo surgical resection of localized non-small cell lung cancer (NSCLC) will develop and ultimately die of recurrent disease. The postoperative radiotherapy (PORT) meta-analysis showed adjuvant thoracic radiotherapy to have a detrimental effect on survival in this patient population. A meta-analysis of early trials of adjuvant chemotherapy by the Non-Small Cell Lung Cancer Collaborative Group showed that while chemotherapy with alkylating agents was also detrimental, chemotherapy with cisplatin-based adjuvant chemotherapy was associated with an improved hazard ratio for death (HR = 0.87), equating to a 5 percent survival benefit at 5 years. However, the result was not statistically significant (p = 0.08). Recently, results have been reported for several large Phase III trials of adjuvant chemotherapy which differed with respect to the stage of resected disease included, the type of chemotherapy used and the use of post-operative radiotherapy. Three trials (IALT, JBR 10, and ANITA) that utilized cisplatin-based doublets showed a significantly positive survival benefit of adjuvant chemotherapy in patients with Stage II-IIIA NSCLC. The magnitude of this benefit, which was suggested to be 4-5 percent at 5 years in the meta-analysis and by the IALT study, may be as large as 8-15 percent as indicated by more recent studies with modern platinum-based doublet chemotherapy. These data indicate that medically fit patients with resected Stage II-IIIA NSCLC should be offered adjuvant chemotherapy with a modern cisplatin-based doublet.     

Lung cancer

Based on several landmark studies and meta-analyses, the standard of care for stage II - III A NSCLC patients has been adjuvant cisplatin-based doublet chemotherapy performed after appropriate surgical resection. The benefit of this therapy for patients with stage I B NSCLC is less apparent, likely because of the heterogeneity of this population. In Japan, however, many randomized clinical studies have assessed the effectiveness of postoperative adjuvant chemotherapy with tegafur-uracil (UFT)in patients with completely resected NSCLC. Based on these studies and a meta-analysis, UFT is used as the standard postoperative adjuvant chemotherapy for stage I NSCLC patients with a tumor larger than 2 cm. It is necessary to re-evaluate adjuvant chemotherapy strategies according to the new seventh edition of the tumor-nodemetastasis classification system. The role of postoperative radiotherapy(PORT)is also explored there. Recently, several tumor markers such as ERCC1 may have had a predictive value for selecting patients who will benefit from adjuvant platin-based chemotherapy. Targeted agents and vaccine therapy are also being evaluated as adjuvant treatments for use after the resection of NSCLC. Randomized studies are ongoing. If these results are confirmed, we will enter an era of personalized care for resected NSCLC.     

Adjuvant therapy for resected non-small cell lung cancer

Surgery remains the initial treatment for patients with early-stage non-small cell lung cancer (NSCLC). The frequent occurrence of distant metastases and local regional failure after surgical resection would indicate that additional treatment is necessary. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. This was followed by a new generation of randomized phase III trials some of which have reported a benefit for chemotherapy in the adjuvant setting. Based on the results of these trials, platin-based chemotherapy has become the standard of care for resected stages II and IIIA NSCLC. The role of postoperative radiation therapy remains to be defined. In the future, improvement in survival outcomes from adjuvant treatment is likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Gene expression profiles and proteomics are techniques being used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. Increasing the understanding of the molecular makeup of lung cancer will hopefully increase cure rates for patients by maximizing the efficacy of the adjuvant therapy.     

Adjuvant chemotherapy for resected non-small-cell lung cancer

Because of the high rate of distant disease recurrence, the 5-year survival of patients who have undergone complete surgical resection of localized non-small-cell lung cancer (NSCLC) is approximately 50%. Initial results from early studies of adjuvant postoperative chemotherapy reported an adverse effect of alkylating agent and older chemotherapy regimens on survival. Cisplatin-based combinations were the first to show a survival advantage. A 1995 meta-analysis of these studies suggested a 13% reduction in the hazard ratio for death (HR = 0.87), leading to a 5% survival benefit at 5 years. Still, these trials involved limited numbers of patients (N = 1,394), and the results failed to reach statistical significance (P = .08). Of the five largest subsequent randomized trials of platinum-based adjuvant therapy, three showed a significant survival advantage. Although it is impossible to determine the reasons for the differing outcomes of these studies, several key features distinguish them, and the data suggest that medically fit patients with resected stage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.     

Adjuvant chemotherapy in resected non-small cell lung cancer

There is still a high mortality ratio in completely resected non-small cell lung cancer patients either due to local or, more often, to metastatic recurrence. The NSCLC Collaborative Group Meta-analysis demonstrated a not statistically significant advantage in patients treated with cisplatin-based regimens. Many subsequent trials were unable to demonstrate the real effectiveness of cisplatin-based adjuvant chemotherapy with a significant rate of toxicity. The IALT trial demonstrated little advantage in overall and disease-free survival with acceptable toxicity. A recent meta-analysis of trials including 5716 patients demonstrated the role of cisplatin-based chemotherapy as adjuvant treatment of resected non-small cell lung cancer even if results shoud be carefully examined. At present, adjuvant chemotherapy in non-small cell cancer should not be reserved to experimental trials.     

Adjuvant therapy of resected non-small-cell lung cancer

Surgical resection of early-stage non-small-cell lung cancer (NSCLC) remains the standard of care in patients fit for surgery. Careful preoperative staging is imperative, as is pathologic documentation of the mediastinal nodal contents. Adjuvant postoperative thoracic radiation therapy (RT) clearly has an impact in reducing locoregional recurrence but has no clear impact on survival. The Postoperative RT (PORT) metaanalysis raised concerns about PORT, particularly in stage I/II NSCLC, suggesting it may negatively impact survival. This was not a concern in stage III NSCLC, in which the risk of locoregional recurrence is higher. However, distant recurrence remains the dominant pattern in resected NSCLC, suggesting that the majority of patients with early-stage resected NSCLC harbor occult micrometastatic disease. Historically, the role of adjuvant chemotherapy has been controversial, and its routine use was not supported by the published data, which consisted of a small number of underpowered trials using inadequately delivered, antiquated chemotherapy. More recently, larger trials have been reported with conflicting results. Like adjuvant PORT, chemotherapy combined with RT has not improved survival over PORT alone. The use of adjuvant cisplatin-based therapy did not show a survival advantage in the Adjuvant Lung Project Italy study but did in the International Adjuvant Lung Trial, creating controversy in the routine implementation of adjuvant therapy in all patients. Recently completed randomized trials by the Cancer and Leukemia Group B and the National Cancer Institute of Canada provide convincing evidence of a substantial benefit from adjuvant therapy in well-staged and completely resected stage I/II NSCLC. Currently, the totality of the data supports a discussion with patients with resected NSCLC regarding the potential benefits of adjuvant therapy.     

Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials.

PURPOSE: The role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials. METHODS: We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy. RESULTS: Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P =.001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P =.012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P =.015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild. CONCLUSION: This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.     

Adjuvant treatment of lung cancer: current status and potential applications of new regimens

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancers diagnosed worldwide. Surgical resection offers the best chance for cure for those patients diagnosed with early-stage disease; however, the vast majority of patients will eventually relapse. Despite complete surgical resection, recurrences are likely due to undetectable microscopic disease at diagnosis, making these patients potential candidates for effective adjuvant therapy. Postoperative radiation therapy may actually have a detrimental effect in patients with NO-N1 disease and has been shown to possibly prevent local recurrences in patients with N2 disease. Although results from a large meta-analysis of data on adjuvant chemotherapy suggested an absolute benefit of 5% at 5 years from cisplatin-based chemotherapy, a rate similar to that seen in breast and colon cancers where adjuvant chemotherapy is a standard of care, the use of adjuvant therapy in NSCLC remained controversial. In addition, results of the International Adjuvant Lung Cancer Trial (IALT), which compared adjuvant cisplatin-based chemotherapy to observation in patients with resected stage-I-IIIA NSCLC, suggested that adjuvant therapy had the potential to prevent a substantial number of deaths each year. Two recently reported landmark studies have demonstrated the survival advantages of adjuvant therapy for patients with early-stage NSCLC. Docetaxel, one of the most active agents for advanced NSCLC, is also regularly used for locally advanced disease as part of neoadjuvant or combined-modality regimens. As recent findings have established the value of adjuvant chemotherapy for early-stage NSCLC, agents such as docetaxel warrant rigorous evaluation in this setting.     

The Rationale for Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer

The past decade has witnessed renewed interest in studies exploring the benefits of adjuvant (postoperative) chemotherapy (± radiation therapy) in patients with resected non-small cell lung cancer (NSCLC). Recently completed adjuvant trials have included a heterogeneous group of patients with resected stages I to IIIA NSCLC. With rare exception, the published results of these studies indicate adjuvant chemotherapy imparts a significant overall survival advantage. Subset analyses suggest survival benefit occurs primarily in patients with resected stage II or IIIA and is less likely to occur in stage I patients. This apparent lack of survival benefit in stage I patients was seemingly validated in a prospective trial conducted by the Cancer and Leukemia Group B in which stage IB patients were randomized to observation or adjuvant carboplatin and paclitaxel. Survival at 5 -years was identical in the two arms of this trial. By contrast, two contemporary postoperative chemotherapy trials also conducted exclusively in stage I NSCLC patients yielded positive survival results. The divergent outcome of the prospective trials along with the negative subset analyses has created uncertainty as to the utility of postoperative adjuvant chemotherapy in stage I NSCLC. Herein we review the data underlying this controversy and offer a proposed algorithm to aid the clinician in selecting patients whom we believe may benefit from adjuvant chemotherapy. The treatment algorithm is based on currently available tumor- and host-related factors that affect prognosis.     

Chemotherapy in stage I+II non-small cell lung cancer

Although surgical resection offers the best chance for long-term survival for patients with non-small cell lung cancer (NSCLC), the limited number of resectable patients and the presence of micrometastatic disease is limiting the effectiveness of this modality as sole treatment. Results of randomized trials demonstrated a survival benefit for preoperative (neoadjuvant) cisplatin-based chemotherapy in patients with stage IIIA NSCLC compared to surgery alone. In stage I+II NSCLC preoperative chemotherapy, although still experimental, clearly offers encouraging results. However, there is no evidence of its superiority over adjuvant chemotherapy. Moreover, for adjuvant therapy a benefit has not been established yet. Possibly current ongoing or recently finished trials may change the recommendations on adjuvant or neoadjuvant therapy for completely resected or resectable early disease in the future.     

Advances in our understanding of postoperative adjuvant chemotherapy in resectable non-small-cell lung cancer

PURPOSE OF REVIEW: After publication in 1995 of a meta-analysis of adjuvant chemotherapy in the treatment of NSCLC, a number of randomized trials investigated adjuvant chemotherapy using more active chemotherapeutic regimens and larger numbers of accrued patients per trial. This review will focus on recent clinical trials for adjuvant chemotherapy, and will help to interpret the applicability of these results to daily clinical practice. RECENT FINDINGS: Four large-scale randomized trials that used platinum-based chemotherapy have reported positive results during the last 3 years. These trials included cisplatin-based chemotherapy [the International Adjuvant Lung Cancer (IALT) trial], cisplatin plus vinorelbine [the National Cancer Institute of Canada (NCIC) BR10 trial], and carboplatin plus paclitaxel [the Cancer and Leukemia Group B (CALGB) 9633 trial]. More recently, another adjuvant trial [Adjuvant Navelbine International Trialist Association (ANITA)] was reported, which has added greatly to our understanding of the potential role of adjuvant treatment. Regarding adjuvant UFT (tegafur and uracil) chemotherapy, an individual patient data-based meta-analysis demonstrated its significant effect on survival in selected patients with completely resected non-small-cell lung cancer. SUMMARY: Recent trials indicate a survival benefit of postoperative adjuvant chemotherapy. These findings are anticipated to change the clinical management of patients with completely resectable non-small-cell lung cancer.     

Optimal adjuvant therapy for non-small cell lung cancer--how to handle stage I disease

The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.     

Adjuvant chemotherapy in early-stage non-small cell lung cancer

Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.     

Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer.

PURPOSE: Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC. METHODS: Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis. RESULTS: Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001). CONCLUSION: This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.     

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 earlystage 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.     

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.     

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.     

Adjuvant chemotherapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer death in France. Nearly 80% of lung tumors are non-small cell lung cancers (NSCLC). Surgery is the best curative approach, but it only concerns 30% of NSCLC, since the diagnosis is frequently made in patients with locally advanced or metastatic disease. Even when surgery is performed relapse occurs in up to 50% of patients. Several adjuvant trials have been led in the late 90's after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the IALT study, with 1 867 patients included, confirms the benefit of post-operative chemotherapy in resected NSCLC. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.     

非小细胞肺癌术后辅助化疗研究进展

完全切除的非细胞肺癌(NSCLC)是否需要术后辅助化疗是多年来肺癌治疗领域的研究热点,随着各种新药及新的联合化疗方案的出现,几项大型随机临床试验论证了含铂类药物术后辅助化疗可以延长患者生存期,从而奠定了肺癌术后辅助化疗的地位,但目前术后辅助化疗的预后和其疗效预测仍有很多末知因素.