Management of Early-Stage Lung Cancer: Past, Present, and Future Adjuvant Trials
Management of Early-Stage Lung Cancer: Past, Present, and Future Adjuvant Trials
The standard of care with regard to adjuvant chemotherapy of lung cancer has changed remarkably over the past 3 years. Until the initial report of the International Adjuvant Lung Trial in 2003, there was no real evidence from any individual randomized clinical trial (RCT) that adjuvant chemotherapy improves survival in resectable non-small-cell lung cancer. However, five RCTs that have now been reported indicate that adjuvant chemotherapy is effective, at least in certain subgroups of resectable patients. Moreover, numerous meta-analyses have also reported a positive effect from adjuvant treatment. Nonetheless, because of methodologic issues and conflicting results, the question of who should be treated and what constitutes optimal adjuvant therapy remains controversial. This article reviews the recent randomized trials that have contributed to a change in the state of the art, as well as some of the methodologic problems that may have confounded their proper interpretation. It also considers newer approaches to adjuvant therapy, with a particular focus on strategies that incorporate our growing knowledge of molecular medicine and predictive factors to the field of adjuvant chemotherapy of lung cancer.
Lung cancer remains the most frequent cause of cancer death both in the United States and worldwide.[1,2] The American Cancer Society (ACS) estimates that lung cancer is the third most common cancer in the US, ranking behind prostate cancer and breast cancer (Table 1). However, in terms of cancer mortality, it is in a league of its own.
Indeed, the ACS estimates that lung cancer will be responsible for 162,460 cancer deaths in the US in 2006. By way of comparison, an estimated 156,250 deaths were expected from colorectal cancer, breast cancer, pancreatic cancer, and prostate cancer combined. These diseases represent the second through fifth leading causes of cancer mortality, respectively (Table 1). It is estimated that lung cancer will be responsible for 28.8% of all cancer deaths in the US in 2006, despite the fact that it represents only 12.5% of all new cancers. Overall, 5-year survival in the US is currently estimated to be approximately 15%.
On a worldwide basis, lung cancer is both the most common cancer and most common cause of cancer mortality. In the year 2002, there were an estimated 1,350,000 new cases of lung cancer, and an estimated 1,179,000 lung cancer deaths. Globally, lung cancer represents 12.4% of all new cancers, and 17.6% of all cancer deaths. Overall, 5-year survival is estimated to be 10% in Europe and 9% in developing countries.
Among patients with early-stage non-small-cell lung cancer (NSCLC), the most powerful predictor of long-term survival is the ability to achieve complete surgical resection. Nonetheless, patients remain at substantial risk for recurrence and death despite an apparent complete surgical excision. For example, data reported by Mountain in 1986 that were used to establish the International Staging System for lung cancer included 5-year survival rates of 64% and 45% for patients with pathologic stage I or II disease, respectively (Table 2). High recurrence rates among those with resected lung cancer underscore the potential role of adjuvant chemotherapy in this setting.
While a considerable risk of recurrence and death following resection has long provided a powerful rationale for adjuvant treatment, research in the area of adjuvant chemotherapy has never received the same priority in NSCLC as it has in other common cancers, particularly breast and colorectal cancer. Nonetheless, several influential randomized clinical trials on adjuvant chemotherapy in lung cancer and an important meta-analysis of trials did appear in the literature prior to 2003, when the first positive report from a large randomized trial was published, helping to change the standard of care.
I will briefly review the most influential of these older randomized trials along with the meta-analysis. Subsequently, I will address recent randomized trials that have led to a change in clinical practice in resectable NSCLC. In the discussion section, I will attempt to define the current state of the art in adjuvant therapy and to articulate major unanswered questions. Finally, I will consider newer approaches to adjuvant therapy in lung cancer.
Randomized Trials and Meta-Analysis Published Prior to 2003
Three cisplatin-based adjuvant randomized trials sponsored by the Lung Cancer Study Group (LCSG) are among the best known older studies in the area of adjuvant chemotherapy of lung cancer. Each trial utilized an adjuvant chemotherapy regimen consisting of the CAP (cyclohphosphamide, doxorubicin [Adriamycin], and cisplatin [Platinol]) regimen in various stages of NSCLC.
LCSG-772 randomized 141 patients with resected stage II or III adenocarcinoma or large-cell carcinoma of the lung to six cycles of CAP chemotherapy or to a control group that received no chemotherapy. (It should be noted that control participants did receive an immunotherapy regimen, consisting of intrapleural bacillus Calmette-Guérin (BCG) and levamisole, for which there is no other evidence for efficacy.) While early results indicated a 15% survival advantage at 1 year (77% vs 62%), continued follow-up failed to reveal any significant long-term survival advantage.
LCSG-791 randomized 172 patients with incompletely resected NSCLC, as defined either by the presence of tumor in the highest resected mediastinal node, or by a positive margin. Patients were randomized to either adjuvant CAP chemotherapy with postoperative radiation (40 Gy) or to postoperative radiation therapy alone. This study also showed significantly better survival at 1 year in the CAP arm (68% vs 54%), although with longer follow-up the significant survival advantage disappeared.
LCSG-801 randomized 283 patients with T2, N0 or T1, N1 NSCLC to either four cycles of CAP or no adjuvant therapy. Overall, 85% of participants had T2, N0 and 15% had T1, N1 tumors. Five-year survival was 55% in both groups. While compliance and delivery of the intended therapy was problematic, the results of this trial were clearly negative.
In contrast, however, a smaller study conducted at Helsinki University Central Hospital in Finland, with a very similar design to LCSG-801, was the only individual randomized trial to report a significant survival advantage. In this trial, 110 patients with T1-3, N0 NSCLC were randomized to surgery followed by six cycles of CAP chemotherapy or to surgery alone. Stage distribution included 31% with T1, N0 disease, 62% with T2, N0 disease, and 7% with T3, N0 NSCLC.
The investigators found a statistically significant 5-year survival advantage favoring the adjuvant chemotherapy arm (67% vs 56%; P = .050). However, problems with randomization appear to have confounded interpretation of this trial: Those randomized to surgery alone included almost twice as many patients who required pneumonectomy as was true in the adjuvant chemotherapy arm (39% vs 20%; P = .038). As would be expected, pneumonectomy patients had a significantly worse survival than those requiring lobectomy (P = .002).
Two randomized trials conducted in predominantly stage II and III NSCLC failed to demonstrate a survival benefit for adjuvant chemotherapy and radiation compared to adjuvant radiation alone. In a French trial conducted by the Groupe D'etude et de Traitement des Cancer Bronchiques (GETCB), 267 patients were randomized to either adjuvant chemotherapy with COPAC (cyclophosphamide, vincristine [Oncovin], cisplatin, doxorubicin, lomustine [CeeNU]), followed by 60 Gy of postoperative radiation therapy (PORT) over 6 weeks or to PORT alone. Stage distribution included 70% with stage III, 26% with stage II, and 3% with stage I disease. With a minimum follow-up of 6 years, survival was similar in the two groups (P = .68).
Finally, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial comparing adjuvant chemoradiation vs PORT alone in completely resected stage II or IIIA NSCLC. In this study, 488 patients were randomized to receive four cycles of adjuvant chemotherapy with cisplatin and etoposide and concurrent radiation (50.4 Gy) or to a similar PORT regimen. Survival was virtually identical within the two groups (hazard ratio [HR] = 0.93; 95% confidence interval [CI] = 0.74-1.18).
While none of these or other older randomized trials demonstrated a clear and unequivocal survival advantage associated with randomization to adjuvant chemotherapy, a meta-analysis of chemotherapy in NSCLC published in 1995 did suggest a survival benefit for those randomized to cisplatin-based adjuvant chemotherapy regimens. Eight trials utilizing a cisplatin-based adjuvant chemotherapy regimen showed an overall 13% proportional reduction in the risk of death among those receiving adjuvant chemotherapy. This translated into an absolute 5% improvement in the probability of long-term survival among those receiving adjuvant treatment. However, the difference favoring cisplatin-based adjuvant chemotherapy was not statistically significant (HR = 0.87; 95% CI = 0.74-1.02; P = .08).
Nonetheless, the 5% survival advantage observed in the 1995 meta-analysis with cisplatin-based chemotherapy provided an incentive for conducting additional randomized trials in this area. Several of these studies have now been reported and have dramatically changed the practice of medicine as it relates to adjuvant chemotherapy for NSCLC. On the other hand, numerous important questions remain. The next several sections review key recent trials that have begun to answer these questions.