Pre-operative Chemotherapy for Non-small Cell Lung Carcinoma
Pre-operative Chemotherapy for Non-small Cell Lung Carcinoma
The roll by the cytotoxic chemotherapy and its efficacy in the treatment of NSCLC was not clearly identified until the 1980s. Most first and second generation anti-cancer drugs evaluated in more than 20 randomized controlled trials (RCTs) did not contribute to the overall survival (OS) benefit. These medications frequently had trend toward harm especially when used for post-operative chemotherapy. However, the results of RCTs carried out in the 1980s constantly suggested benefit in the treatment of NSCLC from the use of cisplatin, the first platinum agent.
To our knowledge, the first RCT to evaluate the efficacy of post-operative chemotherapy using the cisplatin regimen for resectable NSCLC was reported by Sawamura in 1988. Since 1988, increasing numbers of RCTs have been performed to evaluate the possible therapeutic value of post-operative chemotherapy using cisplatin. Although most of these studies did not show a statistically significant benefit individual study basis, the majority of the studies suggested trend toward benefit from the addition of post-operative chemotherapy to curative surgery.
Two very sizable RCTs, reported in 2004, had a considerable impact on the consensus for the treatment of resectable NSCLC. The largest trial ever conducted by Arriagada with 1,867 NSCLC patients concluded that cisplatin-based post-operative chemotherapy improved OS among patients with completely resected NSCLC with a hazard ratio (HR) of 0.86 [95% confidence interval (CI), 0.76–0.98, P<0.03]. In the same year, Kato published results of a RCT with 979 stage I adenocarcinoma cases. Post-operative chemotherapy with uracil-tegafur improved OS among patients with completely resected pathological stage I adenocarcinoma of the lung with HR of 0.71 (95% CI, 0.52–0.98, P=0.04). The subgroup analysis of Kato's study indicated that post-operative chemotherapy was not beneficial in T1N0M0 (tumor size <3 cm, stage IA according to tumor nodule metastasis classification 7 edition) cases, but was of the great benefit in T2N0M0 cases. After the landmark publications by Arriagada and Kato, post-operative chemotherapy was accepted as part of the standard treatment for resectable NSCLC.
Further solid evidence supporting post-operative chemotherapy was provided by the Lung Adjuvant Cisplaitn Evaluation published in 2008 by Pignon. This individual patient data meta-analysis used data from five large-scale RCTs that compared surgery alone with the surgery plus cisplatin-based post-operative chemotherapy. In the meta-analysis of 4,584 patients with a median follow-up of 5.2 years, post-operative chemotherapy was associated with an improved OS with HR of 0.89 (95% CI, 0.82–0.96, P=0.005). Notably, this study suggested that post-operative chemotherapy might lead to a deterioration in the OS of stage IA (tumor size <3 cm) cases (HR 1.40, 95% CI, 0.95–2.06), although the treatment looked to be effective for stage IB-IIIA cases. The fact that post-operative chemotherapy was shown to have less benefit for stage IA disease (tumor size <3 cm) than stage IB disease is compatible with the observation in Kato's RCT. These observations are reasonable because cases with earlier stage NSCLC have a lower risk of micrometastasis and recurrence.
Pre-operative chemotherapy is a relatively newer treatment strategy, as the word "neo-adjuvant (pre-operative)" chemotherapy clearly indicates in contrast with "adjuvant (post-operative)" chemotherapy. Compared with post-operative chemotherapy, fewer RCTs were conducted to evaluate the pre-operative chemotherapy. Some of these studies have suggested promising results. However, once the RCTs by Arriagada and Kato in 2004 had confirmed the benefit of post-operative chemotherapy, treatment by surgery alone was no longer ethically acceptable. As a result, two large scale RCTs were closed prematurely, these being the Southwest Oncology Group Trial S9900 (Pisters et al.) and Chest Investigators (Scagliotti et al.). It should be emphasized that the two RCTs were not stopped because of any perceived ineffectiveness of pre-operative chemotherapy, but because surgery alone was seen as inferior to surgery plus post-operative chemotherapy. No clear evidence has suggested that pre-operative chemotherapy is inferior to post-operative chemotherapy.
Thereafter, to our knowledge, no new RCTs have been carried out to compare the surgery alone and the surgery plus pre-operative chemotherapy. However, the long-term follow-up results have been sporadically reported since 2004. In addition, meta-analyses that evaluated survival benefits from the pre-operative chemotherapy have been reported almost annually since 2005.
At least 12 meta-analyses have been published since the first one by Berghmans in 2005. Most of these meta-analyses reported HRs for OS in the range of 0.81 to 0.89 in favor of pre-operative chemotherapy. Cumulative meta-analysis indicates that pre-operative chemotherapy plus surgery could provide OS benefit with HRs of around 0.85 since 2003. Though the total sample size was has almost tripled from 1,312 by 2003 to 3,728 by 2012, RCTs after 2003 did not largely change the pooled HR.
Historical Backgrounds of the Peri-operative Chemotherapy
Post-operative Chemotherapy
The roll by the cytotoxic chemotherapy and its efficacy in the treatment of NSCLC was not clearly identified until the 1980s. Most first and second generation anti-cancer drugs evaluated in more than 20 randomized controlled trials (RCTs) did not contribute to the overall survival (OS) benefit. These medications frequently had trend toward harm especially when used for post-operative chemotherapy. However, the results of RCTs carried out in the 1980s constantly suggested benefit in the treatment of NSCLC from the use of cisplatin, the first platinum agent.
To our knowledge, the first RCT to evaluate the efficacy of post-operative chemotherapy using the cisplatin regimen for resectable NSCLC was reported by Sawamura in 1988. Since 1988, increasing numbers of RCTs have been performed to evaluate the possible therapeutic value of post-operative chemotherapy using cisplatin. Although most of these studies did not show a statistically significant benefit individual study basis, the majority of the studies suggested trend toward benefit from the addition of post-operative chemotherapy to curative surgery.
Two very sizable RCTs, reported in 2004, had a considerable impact on the consensus for the treatment of resectable NSCLC. The largest trial ever conducted by Arriagada with 1,867 NSCLC patients concluded that cisplatin-based post-operative chemotherapy improved OS among patients with completely resected NSCLC with a hazard ratio (HR) of 0.86 [95% confidence interval (CI), 0.76–0.98, P<0.03]. In the same year, Kato published results of a RCT with 979 stage I adenocarcinoma cases. Post-operative chemotherapy with uracil-tegafur improved OS among patients with completely resected pathological stage I adenocarcinoma of the lung with HR of 0.71 (95% CI, 0.52–0.98, P=0.04). The subgroup analysis of Kato's study indicated that post-operative chemotherapy was not beneficial in T1N0M0 (tumor size <3 cm, stage IA according to tumor nodule metastasis classification 7 edition) cases, but was of the great benefit in T2N0M0 cases. After the landmark publications by Arriagada and Kato, post-operative chemotherapy was accepted as part of the standard treatment for resectable NSCLC.
Further solid evidence supporting post-operative chemotherapy was provided by the Lung Adjuvant Cisplaitn Evaluation published in 2008 by Pignon. This individual patient data meta-analysis used data from five large-scale RCTs that compared surgery alone with the surgery plus cisplatin-based post-operative chemotherapy. In the meta-analysis of 4,584 patients with a median follow-up of 5.2 years, post-operative chemotherapy was associated with an improved OS with HR of 0.89 (95% CI, 0.82–0.96, P=0.005). Notably, this study suggested that post-operative chemotherapy might lead to a deterioration in the OS of stage IA (tumor size <3 cm) cases (HR 1.40, 95% CI, 0.95–2.06), although the treatment looked to be effective for stage IB-IIIA cases. The fact that post-operative chemotherapy was shown to have less benefit for stage IA disease (tumor size <3 cm) than stage IB disease is compatible with the observation in Kato's RCT. These observations are reasonable because cases with earlier stage NSCLC have a lower risk of micrometastasis and recurrence.
Pre-operative Chemotherapy
Pre-operative chemotherapy is a relatively newer treatment strategy, as the word "neo-adjuvant (pre-operative)" chemotherapy clearly indicates in contrast with "adjuvant (post-operative)" chemotherapy. Compared with post-operative chemotherapy, fewer RCTs were conducted to evaluate the pre-operative chemotherapy. Some of these studies have suggested promising results. However, once the RCTs by Arriagada and Kato in 2004 had confirmed the benefit of post-operative chemotherapy, treatment by surgery alone was no longer ethically acceptable. As a result, two large scale RCTs were closed prematurely, these being the Southwest Oncology Group Trial S9900 (Pisters et al.) and Chest Investigators (Scagliotti et al.). It should be emphasized that the two RCTs were not stopped because of any perceived ineffectiveness of pre-operative chemotherapy, but because surgery alone was seen as inferior to surgery plus post-operative chemotherapy. No clear evidence has suggested that pre-operative chemotherapy is inferior to post-operative chemotherapy.
Thereafter, to our knowledge, no new RCTs have been carried out to compare the surgery alone and the surgery plus pre-operative chemotherapy. However, the long-term follow-up results have been sporadically reported since 2004. In addition, meta-analyses that evaluated survival benefits from the pre-operative chemotherapy have been reported almost annually since 2005.
At least 12 meta-analyses have been published since the first one by Berghmans in 2005. Most of these meta-analyses reported HRs for OS in the range of 0.81 to 0.89 in favor of pre-operative chemotherapy. Cumulative meta-analysis indicates that pre-operative chemotherapy plus surgery could provide OS benefit with HRs of around 0.85 since 2003. Though the total sample size was has almost tripled from 1,312 by 2003 to 3,728 by 2012, RCTs after 2003 did not largely change the pooled HR.
