Drs. Wozniak and Gadgeel present a cogent and thorough review of the available data evaluating the usefulness of adjuvant therapies in non-small-cell lung cancer (NSCLC). They emphasize the urgent need for multimodality treatment of early-stage lung cancer, in view of the high recurrence rates that lead to increased morbidity and mortality in lung cancer patients. They pointedly ask the question, "How do we improve the cure rates further?" However, we believe that an important corollary question is, "Why do most lung cancer patients not receive multimodality evaluation and therapy, especially in view of the poor long-term outcomes?" The answer to the latter question may identify mechanisms by which multimodality clinical evaluation and therapy of these patients could be brought in line with those for other malignancies such as breast cancer. Let us examine the impetus for such a shift in the paradigm of lung cancer clinical research.
Limitations of Early Trials
Lung cancer represents the single largest cancer burden on our society. According to the US Cancer Statistics Working Group in 2002, lung cancer was the second leading cause of death after heart-related illnesses. Lung cancer caused more deaths than breast cancer, prostate cancer, and colon cancer combined. The numbers are astounding, with over 90,000 males and 67,000 females expected to die of lung cancer each year. The continued high morbidity and mortality of patients with early-stage disease, as noted in the article (30%-40% relapse rate in stage I patients, 50%-60% relapse rate in stage II patients),[2-4] demonstrates the need for effective adjuvant therapies. Early trials in adjuvant therapy showed no significant benefit to additional chemotherapy or radiation therapy. Yet, as cited in the review by Drs. Wozniak and Gagdeel, these trials were limited by the use of ineffective drugs (eg, bacillus Calmette-Gurin [BCG], alkylating agents), small sample sizes, inadequate staging, and insufficient drug delivery.
Some of these limitations are highlighted by the influential Adjuvant Lung Project Italy (ALPI) trial. Though this trial showed no significant survival difference in patients treated with an adjuvant regimen of mitomycin, vindesine, and cisplatin vs observation, the article appropriately indicates that only 69% of patients completed the designated chemotherapy. It should be noted that this trial was closed early and did not meet its statistical goals for sample size (accrued 93% of goal), with 11 patients deemed ineligible secondary to questions over data integrity. Furthermore, the chemotherapy used included first-generation agents not commonly used in the United States for NSCLC, with increased toxicity compared to modern regimens. Given such a dubious context, the clinical relevance of these results must be viewed cautiously, and yet many physicians have viewed such evidence as conclusive in deciding against adjuvant therapy.
Current analyses have done much to refute this position. The International Adjuvant Lung Cancer Trial (IALT) is a landmark study that changed the thinking of many practicing oncologists. As noted in the article, the "user-friendly" approach allowed the use of modern agents (platinum-based doublets) and significantly increased enrollment efforts. With the benefit seen in overall survival (14% at 5 years), the race was on to find more evidence to support this approach. As presented in Drs. Wozniak and Gagdeel's review, multiple trials (eg, the Adjuvant Navelbine International Trialist Association [ANITA] trial, JBR.10) increased the evidence that adjuvant therapy in lung cancer was effective and reasonable as a new standard of care.
The disappointing recent report of Cancer and Leukemia Group B (CALGB) 9633 at the 2006 annual meeting of the American Society of Clinical Oncology (ASCO) may have tempered some of our enthusiasm for adjuvant therapy, but these results must be carefully interpreted with a focus on the trial's context. Since CALGB 9633 only examined stage IB patients and used a carboplatin-based regimen (unlike the other trials), our conclusions should not be extrapolated beyond this specific patient population and treatment approach.
The capstone of the evidence for adjuvant therapy should be the Lung Adjuvant Cisplatin Evaluation (LACE) analysis—also presented at ASCO 2006—which clearly demonstrated an overall survival benefit from adjuvant chemotherapy, with smaller gains in earlier-stage disease. With the pooling of data from five disparate trials as outlined in the article, the results of this analysis become more relevant and promising as a new standard for our NSCLC patients. Though survival benefits for this approach are small (5%-15% at 5 years), they are similar to gains in other malignancies with adjuvant therapy. For example, in breast cancer, patients with very early-stage disease receive comparably toxic regimens (anthracycline- and taxane-based), with similarly small gains in survival benefit. This approach is not only common but is considered the standard of care in many arenas. This brings us back to our original corollary question, "Why do most lung cancer patients not receive multimodality evaluation and therapy, especially in view of poor long-term outcomes?"
We believe the answer is complex and relates to the limitations of our ability to treat NSCLC patients as well as to subtle biases in society's approach to this patient population. The five factors that we believe may shed light on this ongoing dilemma include:
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