Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer — The Smoke Clears
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《新英格兰医药杂志》
Lung cancer has been the most common cancer in the world since 1985 and is today the leading cause of cancer-related death. In 2002, there were 1.35 million new cases and 1.18 million related deaths worldwide.1 Non–small-cell lung cancer, the most common form, accounts for 80 to 85 percent of cases. Given the size of the problem, the benefit of adjuvant chemotherapy for non–small-cell lung cancer, reported by Winton et al. in this issue of the Journal, has tremendous implications.2
Complete surgical resection is the best hope for cure in patients with operable non–small-cell lung cancer, yet the five-year overall survival rate is only 23 to 67 percent, depending on the size of the primary tumor and the presence or absence of invasion and lymph-node involvement.3 After surgery, relapse at distant sites occurs two to three times as frequently as local recurrence and is most often fatal. Postoperative radiotherapy decreases the rate of local recurrence in stage IIIA disease but has a detrimental effect on survival in patients with stage I or stage II disease.4 Adjuvant systemic chemotherapy directed at micrometastatic disease has an established role in the treatment of breast and colon cancer; however, its use in non–small-cell lung cancer has, until now, been controversial.
Decades ago, initial forays into adjuvant therapy for non–small-cell lung cancer failed — the trials were poorly designed and used relatively inactive chemotherapy. The next generation of studies incorporated cisplatin (an agent still considered a cornerstone of treatment), but the studies were too small to detect a benefit.
A 1995 meta-analysis of results from randomized trials of adjuvant therapy conducted between 1965 and 1991 showed that treatment with alkylating agents alone or in combination with radiation reduced overall survival (an absolute decrease in the rate of survival of 5 to 7 percent at five years, and an increase in the risk of death of 15 to 35 percent).5 Moreover, a cisplatin-based regimen in combination with radiation did not affect overall survival as compared with postoperative radiotherapy alone.5 The subsequent North American Intergroup (INT 0115) trial, which compared adjuvant etoposide plus cisplatin and radiation with adjuvant radiation alone, confirmed this lack of benefit.6 However, the 1995 meta-analysis did reveal that cisplatin-based chemotherapy without radiation improved the five-year overall survival rate by 5 percent and reduced the risk of death by 13 percent as compared with no adjuvant therapy.5 Although this improvement did not achieve statistical significance, it did rekindle interest in postoperative chemotherapy for non–small-cell lung cancer.
The Adjuvant Lung Project Italy (ALPI) trial was the first large study of adjuvant therapy to be reported after the meta-analysis.7 Among the 1088 patients with completely resected stage I, II, or IIIA non–small-cell lung cancer who could be evaluated and who were randomly assigned to three cycles of mitomycin plus vindesine plus cisplatin or observation, no statistically significant benefit in overall survival was seen with adjuvant therapy. In this study, postoperative radiotherapy was given to 43 percent of patients, 69 percent completed all three chemotherapy cycles, and there were more deaths during the first year in the chemotherapy group than in the observation group. These negative results echoed the findings of earlier trials and again dampened enthusiasm for adjuvant treatment.
The following year, the results of the largest trial of adjuvant chemotherapy for non–small-cell lung cancer reheated the debate.8 The randomized International Adjuvant Lung Cancer Trial (IALT) included 1867 patients with completely resected stage I, II, or IIIA non–small-cell lung cancer and showed an improvement of 4 percent in the five-year overall survival rate and a reduction of 14 percent in the risk of death after adjuvant chemotherapy with a cisplatin-based two-drug regimen. Postoperative radiotherapy was given to 25 percent of patients, and 74 percent received at least 240 mg of cisplatin per square meter of body-surface area.
Postulated reasons for the contradictory results of the ALPI study and IALT include a larger number of early deaths in the ALPI study and differences in numbers of participants, chemotherapy regimens, and the frequency of postoperative radiotherapy. Although IALT supported the use of adjuvant chemotherapy, patients with lung cancer and physicians were not enthusiastic, given the potential toxic effects of therapy, modest survival benefits, and conflicting results.
Winton and colleagues add considerable fuel to the fire with results that favor adjuvant chemotherapy after complete resection of non–small-cell lung cancer. In their trial (JBR.10), 482 patients with stage IB (T2N0) or stage II (T1N1 or T2N1) non–small-cell lung cancer were randomly assigned to four cycles of adjuvant vinorelbine plus cisplatin or to observation. This is the first trial to treat all patients with a "third generation" chemotherapy agent (vinorelbine), omit postoperative radiotherapy, and focus on a narrow subgroup of patients with operable tumors. All patients began adjuvant therapy within six weeks after surgery and had a performance status score of 0 or 1 (fully ambulatory, minimal symptoms, and good general health). Chemotherapy was not excessively toxic (there were two treatment-related deaths). Compliance with chemotherapy was typical for a trial of adjuvant therapy for non–small-cell lung cancer — 58 percent of patients receiving treatment completed three cycles, and 48 percent completed four cycles of chemotherapy. With a median follow-up of more than five years, the results are astonishing: adjuvant chemotherapy improved the five-year overall survival rate by 15 percentage points as compared with observation alone (69 percent vs. 54 percent, P=0.03) and decreased the risk of death by 31 percent (P=0.04).
Supportive findings come from Cancer and Leukemia Group B (CALGB).9 The CALGB protocol 9633 trial included a "modern" chemotherapy regimen (paclitaxel plus carboplatin), omitted postoperative radiotherapy, and focused on an even narrower subgroup of patients (only those with stage IB disease). The 344 patients were randomly assigned to four cycles of adjuvant chemotherapy or observation. Chemotherapy was well tolerated, with no treatment-related deaths and 85 percent of patients completing all planned cycles. The four-year overall survival rate was improved by 12 percentage points in the patients assigned to chemotherapy as compared with those assigned to observation alone (71 percent vs. 59 percent), with a 38 percent decrease in the risk of death. Moreover, the rate of death from lung cancer was reduced by almost half. At this year's annual meeting of the American Society of Clinical Oncology, further evidence of the benefits of adjuvant chemotherapy for non–small-cell lung cancer was presented.10 The Adjuvant Navelbine International Trialist Association (ANITA) study randomly assigned 840 patients with completely resected stage IB, stage II, or stage IIIA non–small-cell lung cancer to four cycles of vinorelbine plus cisplatin or to observation. As in the JBR.10 trial, the level of toxic effects was acceptable, and with a median follow-up of more than 70 months, adjuvant chemotherapy increased the 5-year overall survival rate by 8 percentage points (51 percent vs. 43 percent) and decreased the risk of death by 21 percent.
Both the JBR.10 and ANITA trials performed subgroup analyses according to stratification, and neither trial showed a statistically significant survival benefit for patients with stage IB disease. This is in marked contrast to the findings of the CALGB study. These conflicting data may reflect differences in sample size, number of events, or other factors. Furthermore, insufficient numbers of patients with stage IA disease have been studied to allow conclusions to be made about the efficacy of adjuvant therapy in this subgroup. Other encouraging results of adjuvant therapy come from Japan, where investigators have focused on the use of oral uracil–tegafur after resection of non–small-cell lung cancer.11,12 Although a meta-analysis showed a significant improvement in overall survival among patients treated with uracil–tegafur, as compared with those who did not receive adjuvant therapy,12 these data have not been confirmed outside of Japan, and the benefits of uracil–tegafur as compared with platinum-based regimens have not been studied.
On the basis of the data reported by Winton et al. and the supporting trials, the controversy surrounding adjuvant chemotherapy for resectable non–small-cell lung cancer is over. Adjuvant platinum-based chemotherapy should be recommended after complete resection of non–small-cell lung cancer in patients with a good performance status. Additional research will enable us to select those patients most likely to benefit from adjuvant therapy, to customize the therapy on the basis of the biology of the tumor, to lessen toxicity and increase compliance, to identify more effective regimens, and to further improve survival.
Source Information
From the Department of Thoracic and Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston.
References
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589-2597.
Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710-1717.
Burdett S, Stewart L. Postoperative radiotherapy in non-small-cell lung cancer: update on an individual patient data meta-analysis. Lung Cancer 2005;47:81-83.
Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899-909.
Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small cell lung cancer. N Engl J Med 2000;343:1217-1222.
Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003;95:1453-1461.
The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-360.(Katherine M.W. Pisters, M)
Complete surgical resection is the best hope for cure in patients with operable non–small-cell lung cancer, yet the five-year overall survival rate is only 23 to 67 percent, depending on the size of the primary tumor and the presence or absence of invasion and lymph-node involvement.3 After surgery, relapse at distant sites occurs two to three times as frequently as local recurrence and is most often fatal. Postoperative radiotherapy decreases the rate of local recurrence in stage IIIA disease but has a detrimental effect on survival in patients with stage I or stage II disease.4 Adjuvant systemic chemotherapy directed at micrometastatic disease has an established role in the treatment of breast and colon cancer; however, its use in non–small-cell lung cancer has, until now, been controversial.
Decades ago, initial forays into adjuvant therapy for non–small-cell lung cancer failed — the trials were poorly designed and used relatively inactive chemotherapy. The next generation of studies incorporated cisplatin (an agent still considered a cornerstone of treatment), but the studies were too small to detect a benefit.
A 1995 meta-analysis of results from randomized trials of adjuvant therapy conducted between 1965 and 1991 showed that treatment with alkylating agents alone or in combination with radiation reduced overall survival (an absolute decrease in the rate of survival of 5 to 7 percent at five years, and an increase in the risk of death of 15 to 35 percent).5 Moreover, a cisplatin-based regimen in combination with radiation did not affect overall survival as compared with postoperative radiotherapy alone.5 The subsequent North American Intergroup (INT 0115) trial, which compared adjuvant etoposide plus cisplatin and radiation with adjuvant radiation alone, confirmed this lack of benefit.6 However, the 1995 meta-analysis did reveal that cisplatin-based chemotherapy without radiation improved the five-year overall survival rate by 5 percent and reduced the risk of death by 13 percent as compared with no adjuvant therapy.5 Although this improvement did not achieve statistical significance, it did rekindle interest in postoperative chemotherapy for non–small-cell lung cancer.
The Adjuvant Lung Project Italy (ALPI) trial was the first large study of adjuvant therapy to be reported after the meta-analysis.7 Among the 1088 patients with completely resected stage I, II, or IIIA non–small-cell lung cancer who could be evaluated and who were randomly assigned to three cycles of mitomycin plus vindesine plus cisplatin or observation, no statistically significant benefit in overall survival was seen with adjuvant therapy. In this study, postoperative radiotherapy was given to 43 percent of patients, 69 percent completed all three chemotherapy cycles, and there were more deaths during the first year in the chemotherapy group than in the observation group. These negative results echoed the findings of earlier trials and again dampened enthusiasm for adjuvant treatment.
The following year, the results of the largest trial of adjuvant chemotherapy for non–small-cell lung cancer reheated the debate.8 The randomized International Adjuvant Lung Cancer Trial (IALT) included 1867 patients with completely resected stage I, II, or IIIA non–small-cell lung cancer and showed an improvement of 4 percent in the five-year overall survival rate and a reduction of 14 percent in the risk of death after adjuvant chemotherapy with a cisplatin-based two-drug regimen. Postoperative radiotherapy was given to 25 percent of patients, and 74 percent received at least 240 mg of cisplatin per square meter of body-surface area.
Postulated reasons for the contradictory results of the ALPI study and IALT include a larger number of early deaths in the ALPI study and differences in numbers of participants, chemotherapy regimens, and the frequency of postoperative radiotherapy. Although IALT supported the use of adjuvant chemotherapy, patients with lung cancer and physicians were not enthusiastic, given the potential toxic effects of therapy, modest survival benefits, and conflicting results.
Winton and colleagues add considerable fuel to the fire with results that favor adjuvant chemotherapy after complete resection of non–small-cell lung cancer. In their trial (JBR.10), 482 patients with stage IB (T2N0) or stage II (T1N1 or T2N1) non–small-cell lung cancer were randomly assigned to four cycles of adjuvant vinorelbine plus cisplatin or to observation. This is the first trial to treat all patients with a "third generation" chemotherapy agent (vinorelbine), omit postoperative radiotherapy, and focus on a narrow subgroup of patients with operable tumors. All patients began adjuvant therapy within six weeks after surgery and had a performance status score of 0 or 1 (fully ambulatory, minimal symptoms, and good general health). Chemotherapy was not excessively toxic (there were two treatment-related deaths). Compliance with chemotherapy was typical for a trial of adjuvant therapy for non–small-cell lung cancer — 58 percent of patients receiving treatment completed three cycles, and 48 percent completed four cycles of chemotherapy. With a median follow-up of more than five years, the results are astonishing: adjuvant chemotherapy improved the five-year overall survival rate by 15 percentage points as compared with observation alone (69 percent vs. 54 percent, P=0.03) and decreased the risk of death by 31 percent (P=0.04).
Supportive findings come from Cancer and Leukemia Group B (CALGB).9 The CALGB protocol 9633 trial included a "modern" chemotherapy regimen (paclitaxel plus carboplatin), omitted postoperative radiotherapy, and focused on an even narrower subgroup of patients (only those with stage IB disease). The 344 patients were randomly assigned to four cycles of adjuvant chemotherapy or observation. Chemotherapy was well tolerated, with no treatment-related deaths and 85 percent of patients completing all planned cycles. The four-year overall survival rate was improved by 12 percentage points in the patients assigned to chemotherapy as compared with those assigned to observation alone (71 percent vs. 59 percent), with a 38 percent decrease in the risk of death. Moreover, the rate of death from lung cancer was reduced by almost half. At this year's annual meeting of the American Society of Clinical Oncology, further evidence of the benefits of adjuvant chemotherapy for non–small-cell lung cancer was presented.10 The Adjuvant Navelbine International Trialist Association (ANITA) study randomly assigned 840 patients with completely resected stage IB, stage II, or stage IIIA non–small-cell lung cancer to four cycles of vinorelbine plus cisplatin or to observation. As in the JBR.10 trial, the level of toxic effects was acceptable, and with a median follow-up of more than 70 months, adjuvant chemotherapy increased the 5-year overall survival rate by 8 percentage points (51 percent vs. 43 percent) and decreased the risk of death by 21 percent.
Both the JBR.10 and ANITA trials performed subgroup analyses according to stratification, and neither trial showed a statistically significant survival benefit for patients with stage IB disease. This is in marked contrast to the findings of the CALGB study. These conflicting data may reflect differences in sample size, number of events, or other factors. Furthermore, insufficient numbers of patients with stage IA disease have been studied to allow conclusions to be made about the efficacy of adjuvant therapy in this subgroup. Other encouraging results of adjuvant therapy come from Japan, where investigators have focused on the use of oral uracil–tegafur after resection of non–small-cell lung cancer.11,12 Although a meta-analysis showed a significant improvement in overall survival among patients treated with uracil–tegafur, as compared with those who did not receive adjuvant therapy,12 these data have not been confirmed outside of Japan, and the benefits of uracil–tegafur as compared with platinum-based regimens have not been studied.
On the basis of the data reported by Winton et al. and the supporting trials, the controversy surrounding adjuvant chemotherapy for resectable non–small-cell lung cancer is over. Adjuvant platinum-based chemotherapy should be recommended after complete resection of non–small-cell lung cancer in patients with a good performance status. Additional research will enable us to select those patients most likely to benefit from adjuvant therapy, to customize the therapy on the basis of the biology of the tumor, to lessen toxicity and increase compliance, to identify more effective regimens, and to further improve survival.
Source Information
From the Department of Thoracic and Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston.
References
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589-2597.
Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710-1717.
Burdett S, Stewart L. Postoperative radiotherapy in non-small-cell lung cancer: update on an individual patient data meta-analysis. Lung Cancer 2005;47:81-83.
Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899-909.
Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small cell lung cancer. N Engl J Med 2000;343:1217-1222.
Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003;95:1453-1461.
The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-360.(Katherine M.W. Pisters, M)