Adjuvant Chemotherapy for Lung Cancer — A New Standard of Care
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《新英格兰医药杂志》
In patients with cancer who undergo surgery with curative intent but who are known to be at risk for a recurrence, postoperative chemotherapy increases the chance of a cure. The basis of this adjuvant therapy rests on demonstrations in animal models that the presence of a small residual tumor rather than a large tumor is associated with a greater fraction of tumor cells that are growing, a greater fractional rate of cell death, a lower likelihood that tumor cells are drug resistant, and a higher cure rate. Subsequent clinical investigations have established proof of these principles for adjuvant chemotherapy in cancers of the breast, colon, and stomach, among others. But in the case of lung cancer — which is of particular importance, given the high associated mortality rate worldwide — randomized trials have not, until now, shown a statistically significant benefit of adjuvant chemotherapy after complete resection of non–small-cell lung cancer.
In this issue of the Journal, the International Adjuvant Lung Cancer Trial (IALT) Collaborative Group unequivocally concludes that "cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non–small-cell lung cancer."1 In this study of 1867 patients who were randomly assigned to adjuvant treatment or observation, the primary end point of overall survival was significantly higher in the adjuvant-chemotherapy group (P<0.03), with a hazard ratio for death of 0.86 (95 percent confidence interval, 0.76 to 0.98) and an absolute increase in the five-year survival rate of 4.1 percent.
The study is valid from a statistical perspective — and for this reason it represents a new standard of care — but from a clinical perspective, a wider context is required, especially given a 25-year history of negative outcomes. Why did the IALT group find that cisplatin-based adjuvant therapy confers a significant survival benefit for patients with resected non–small-cell lung cancer, and what are the clinical implications of this study?
The open-choice design undoubtedly helped the IALT investigators enroll the largest number of patients to date in such a trial and thereby achieve statistically significant results. The design of the trial allowed physicians in 148 participating centers in 33 countries to choose which tumor stages to include, the dose of cisplatin used per cycle of adjuvant treatment, the chemotherapeutic agent to include with cisplatin, and the option of postoperative radiotherapy. The trial was terminated early, after approximately 60 percent of the predetermined number of patients had been enrolled, because of decreasing enrollment that was probably the result of a shift in clinical practice to the use of chemotherapy before surgery. Nevertheless, the results of the study reached statistical significance because of a higher than predicted rate of death.
The flexibility of the study design not only led to the enrollment of a sufficient number of patients for the purposes of statistical analysis but also highlighted the consistent benefit of chemotherapy with respect to all potential variables. Given the large number of variables included, it was virtually impossible for the study to achieve statistical significance by means of univariate or multivariate analyses, which are meant to account for potential imbalances between the chemotherapy and control groups and to identify factors that could influence the effect of adjuvant chemotherapy. The randomized nature and the size of the study make it unlikely that the results are due to an imbalance in one or more important prognostic variables. The variations allowed in the adjuvant treatment had the potential to mitigate the effect of the treatment, but this did not happen. Indeed, a significant effect of cisplatin treatment was observed.
This study raises issues regarding treatment decisions for individual patients and ongoing and future research. One matter is the chemotherapy regimen. A meta-analysis of chemotherapy for non–small-cell lung cancer2 and the IALT findings support the use of cisplatin. The choice of the agent to be used with cisplatin does not seem to be of major importance, assuming that the cisplatin dose is similar to that used in the IALT protocol. Lower doses may be less effective, and higher doses may be too toxic.
A second concern is the toxicity of adjuvant chemotherapy in patients with lung cancer who have undergone thoracotomy; they frequently have coexisting conditions and are more likely to be elderly. In the IALT, the rate of chemotherapy-associated mortality was 0.8 percent, and 23 percent of patients had at least one episode of life-threatening adverse effects, mostly attributable to myelotoxicity. Although the study stipulated the administration of a dose of 300 to 400 mg of cisplatin per square meter of body-surface area, in reality 26 percent of patients received less than 240 mg per square meter, mostly because of toxic effects.
A third point is the role of adjuvant radiotherapy, which this study did not investigate. Given the continuing debate over the value of adjuvant radiotherapy, especially when it is combined with chemotherapy, and to avoid limiting enrollment because of a strong investigator preference, the IALT left the option of radiotherapy to the investigator. Randomization minimized the potential effect of radiotherapy as a variable. The benefits and risks of radiotherapy in patients with resectable non–small-cell lung cancer remain to be determined.
Finally, there is the controversy over the sequence of surgery and chemotherapy. In the IALT, surgery was followed by chemotherapy. Among the arguments for the use of chemotherapy before surgery are better tolerance, earlier institution of systemic therapy, and reduced tumor volume at surgery. Preoperative chemotherapy combined with radiotherapy has also been reported to be beneficial in patients with disease that has metastasized to mediastinal lymph nodes.3 The question of whether this approach will benefit all patients with resectable disease, not just those with stage IIIA disease, is being addressed in randomized trials comparing chemotherapy before resection with surgery alone. Furthermore, randomized clinical trials are being initiated to study the relative benefit of chemotherapy followed by surgery as compared with surgery followed by chemotherapy.
The results of the IALT must be corroborated, because this is the only trial that has shown a significant prolongation of survival with the use of adjuvant chemotherapy. Every effort must be made to complete ongoing studies. In the future, decisions about adjuvant chemotherapy will probably be influenced by the improved assessment of the risk of recurrence made possible by the availability of better imaging methods and more precise surgical staging and the application of molecular diagnostic techniques. Advances in systemic therapy, particularly therapy targeted to specific properties of lung cancer, will lead to further prolongation of survival.
The finding in the IALT that cisplatin-based adjuvant therapy confers an absolute increase in survival of 4.1 percent among patients with resected non–small-cell lung cancer is consistent with the benefit achieved with the use of adjuvant therapy for other cancers and represents a new standard of care, but not necessarily the only standard of care. For individual patients, the potential benefits of adjuvant chemotherapy must be balanced against the risks and the inherent and understandable preferences of physicians and patients. Only a continued commitment to well-designed, adequately powered clinical trials will allow us to gather the data necessary to make evidence-based decisions. Given the advances in cancer treatment and the increasing demand on limited resources, integration of the IALT findings into clinical practice is a task that should ultimately yield rich rewards.
Source Information
From Cancer Centers and Programs, Beth Israel Medical Center; and St. Luke's–Roosevelt Hospital Center — both in New York.
References
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.
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.
Rosell R, Gómez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-158.(Ronald H. Blum, M.D.)
In this issue of the Journal, the International Adjuvant Lung Cancer Trial (IALT) Collaborative Group unequivocally concludes that "cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non–small-cell lung cancer."1 In this study of 1867 patients who were randomly assigned to adjuvant treatment or observation, the primary end point of overall survival was significantly higher in the adjuvant-chemotherapy group (P<0.03), with a hazard ratio for death of 0.86 (95 percent confidence interval, 0.76 to 0.98) and an absolute increase in the five-year survival rate of 4.1 percent.
The study is valid from a statistical perspective — and for this reason it represents a new standard of care — but from a clinical perspective, a wider context is required, especially given a 25-year history of negative outcomes. Why did the IALT group find that cisplatin-based adjuvant therapy confers a significant survival benefit for patients with resected non–small-cell lung cancer, and what are the clinical implications of this study?
The open-choice design undoubtedly helped the IALT investigators enroll the largest number of patients to date in such a trial and thereby achieve statistically significant results. The design of the trial allowed physicians in 148 participating centers in 33 countries to choose which tumor stages to include, the dose of cisplatin used per cycle of adjuvant treatment, the chemotherapeutic agent to include with cisplatin, and the option of postoperative radiotherapy. The trial was terminated early, after approximately 60 percent of the predetermined number of patients had been enrolled, because of decreasing enrollment that was probably the result of a shift in clinical practice to the use of chemotherapy before surgery. Nevertheless, the results of the study reached statistical significance because of a higher than predicted rate of death.
The flexibility of the study design not only led to the enrollment of a sufficient number of patients for the purposes of statistical analysis but also highlighted the consistent benefit of chemotherapy with respect to all potential variables. Given the large number of variables included, it was virtually impossible for the study to achieve statistical significance by means of univariate or multivariate analyses, which are meant to account for potential imbalances between the chemotherapy and control groups and to identify factors that could influence the effect of adjuvant chemotherapy. The randomized nature and the size of the study make it unlikely that the results are due to an imbalance in one or more important prognostic variables. The variations allowed in the adjuvant treatment had the potential to mitigate the effect of the treatment, but this did not happen. Indeed, a significant effect of cisplatin treatment was observed.
This study raises issues regarding treatment decisions for individual patients and ongoing and future research. One matter is the chemotherapy regimen. A meta-analysis of chemotherapy for non–small-cell lung cancer2 and the IALT findings support the use of cisplatin. The choice of the agent to be used with cisplatin does not seem to be of major importance, assuming that the cisplatin dose is similar to that used in the IALT protocol. Lower doses may be less effective, and higher doses may be too toxic.
A second concern is the toxicity of adjuvant chemotherapy in patients with lung cancer who have undergone thoracotomy; they frequently have coexisting conditions and are more likely to be elderly. In the IALT, the rate of chemotherapy-associated mortality was 0.8 percent, and 23 percent of patients had at least one episode of life-threatening adverse effects, mostly attributable to myelotoxicity. Although the study stipulated the administration of a dose of 300 to 400 mg of cisplatin per square meter of body-surface area, in reality 26 percent of patients received less than 240 mg per square meter, mostly because of toxic effects.
A third point is the role of adjuvant radiotherapy, which this study did not investigate. Given the continuing debate over the value of adjuvant radiotherapy, especially when it is combined with chemotherapy, and to avoid limiting enrollment because of a strong investigator preference, the IALT left the option of radiotherapy to the investigator. Randomization minimized the potential effect of radiotherapy as a variable. The benefits and risks of radiotherapy in patients with resectable non–small-cell lung cancer remain to be determined.
Finally, there is the controversy over the sequence of surgery and chemotherapy. In the IALT, surgery was followed by chemotherapy. Among the arguments for the use of chemotherapy before surgery are better tolerance, earlier institution of systemic therapy, and reduced tumor volume at surgery. Preoperative chemotherapy combined with radiotherapy has also been reported to be beneficial in patients with disease that has metastasized to mediastinal lymph nodes.3 The question of whether this approach will benefit all patients with resectable disease, not just those with stage IIIA disease, is being addressed in randomized trials comparing chemotherapy before resection with surgery alone. Furthermore, randomized clinical trials are being initiated to study the relative benefit of chemotherapy followed by surgery as compared with surgery followed by chemotherapy.
The results of the IALT must be corroborated, because this is the only trial that has shown a significant prolongation of survival with the use of adjuvant chemotherapy. Every effort must be made to complete ongoing studies. In the future, decisions about adjuvant chemotherapy will probably be influenced by the improved assessment of the risk of recurrence made possible by the availability of better imaging methods and more precise surgical staging and the application of molecular diagnostic techniques. Advances in systemic therapy, particularly therapy targeted to specific properties of lung cancer, will lead to further prolongation of survival.
The finding in the IALT that cisplatin-based adjuvant therapy confers an absolute increase in survival of 4.1 percent among patients with resected non–small-cell lung cancer is consistent with the benefit achieved with the use of adjuvant therapy for other cancers and represents a new standard of care, but not necessarily the only standard of care. For individual patients, the potential benefits of adjuvant chemotherapy must be balanced against the risks and the inherent and understandable preferences of physicians and patients. Only a continued commitment to well-designed, adequately powered clinical trials will allow us to gather the data necessary to make evidence-based decisions. Given the advances in cancer treatment and the increasing demand on limited resources, integration of the IALT findings into clinical practice is a task that should ultimately yield rich rewards.
Source Information
From Cancer Centers and Programs, Beth Israel Medical Center; and St. Luke's–Roosevelt Hospital Center — both in New York.
References
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.
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.
Rosell R, Gómez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-158.(Ronald H. Blum, M.D.)