Surgery remains the initial treatment for patients with early-stage non-small-cell lung cancer (NSCLC). Additional therapy is necessary because of high rates of distant and local disease recurrence after surgical resection. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. Since then, a new generation of randomized phase III trials have been conducted, some of which have reported a benefit for chemotherapy in the adjuvant setting. The role of postoperative radiation therapy remains to be defined. It may not be beneficial in early-stage NSCLC but still may have utility in stage IIIA disease. Improvement in survival outcomes from adjuvant treatment are likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Preliminary results with gene-expression profiles and lung cancer proteomics have been promising. These techniques may be used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. All of these innovations will hopefully increase cure rates for lung cancer patients by maximizing the efficacy of adjuvant therapy.
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:
(1) The potentially severe toxicity of our chemotherapeutics and the need for "kinder," more targeted agents
(2) The issue of increased treatment-related morbidity to the lung, especially in the postoperative setting, limiting our ability to administer adjuvant therapy
(3) Ineffective lung cancer screening resulting in more advanced stages at diagnosis
(4) Inadequate trial accrual and development in NSCLC
(5) Inadequate use of interdisciplinary evaluations to ensure multimodality assessment and treatment.
Although the adjuvant trials mentioned above are showing survival benefits that are helping to reduce lung cancer recurrence, the largely cisplatin-based regimens continue to be toxic and difficult to administer. Dr. Pepe et al presented data from JBR.10 at ASCO 2006 examining the administration of chemotherapy in the elderly (> 65 years old), where the difficulty of treating NSCLC patients is clearly borne out. The elderly received significantly fewer doses of cisplatin/vinorelbine chemotherapy and were more likely to refuse chemotherapy (40%) compared to their younger counterparts (23%). Despite this disparity in dose administration, the investigators were still able to detect a survival advantage in this population without significantly enhanced treatment-related toxicity.
As Dr. Joan Schiller commented in her review of this data at ASCO, perhaps the reason there was less toxicity is because these patients received less chemotherapy. Regardless, these provocative data raised the issue of giving toxic agents to the patients most frequently afflicted with lung cancer. Despite the demonstrated survival advantage, the awareness that adjuvant therapy adversely affects the quality of life of our at-risk patients continues to make physicians and patients less likely to undertake the adjuvant therapy approach.
We need to find ways to more effectively deliver adjuvant therapy and manage side effects. Drs. Wozniak and Gagdeel astutely point out that the advent of less toxic and more targeted therapies is increasing the palatability of adjuvant chemotherapy. As trastuzumab (Herceptin) therapy in breast cancer has consistently shown survival benefits in both the palliative and adjuvant settings, it has concurrently shown decreased treatment-related morbidity compared to older, more traditional cytotoxic therapies. Similarly, the report of a survival benefit for bevacizumab (Avastin) therapy in advanced NSCLC patients in ECOG 4599 has prompted great excitement over the use of this "kinder" agent in the adjuvant setting.
However, secondary to concerns over wound healing, the authors appropriately highlight the concern of using this endothelium-targeted therapy in the postoperative setting. We believe that greater perioperative interdisciplinary planning as well as protocol screening may select patients and clinical situations most likely to benefit from this approach. Continued development of novel therapeutics that are targeted and less toxic will only enhance the practicality of and need for adjuvant therapies.
The molecular pathways involved in the tumorigenicity of lung cancer cells are intricate, providing a rich trove of potential targets. However, the interactions between these pathways are complex, and inhibiting a single step may be inadequate for terminating the cancer cell's activity. This requires the development of multitargeted therapies that disrupt these pathways in a terminal and irreversible manner. Targeting a single step in the sequence may be overcome by the cancer cell's ability to consistently attain a growth advantage by utilizing various bypass mechanisms. The complexity of the EGFR pathway attests to this hypothesis. Activation of EGFR triggers several distinct pathways intracellularly, including the Ras/Raf/MAP kinase sequence and the PI3K/Akt sequence. These pathways downstream from EGFR signaling activate proliferation, survival, and transformation of the cancer cell.[11,12]
Attempts to target and inhibit EGFR with tyrosine kinase inhibitors (TKIs) such as gefitinib (Iressa) and erlotinib (Tarceva) have had mixed results in the treatment of advanced NSCLC.[13-19] The identification of EGFR somatic mutations that increase the susceptibility of some lung cancers to these TKIs has led to the possibility of tailoring a therapeutic approach for NSCLC patients based on their tumor's genetic profile. Studies are ongoing to refine this approach and make it clinically relevant. Further investigations based on treatment approaches that are driven by the DNA profile of a patient's lung cancer will help to develop targeted regimens that are better tolerated and easier to administer in the adjuvant setting.
Advances in perioperative management have led to improved outcomes in patients undergoing pulmonary resection for cancer. This progress has been achieved despite the fact that the majority of patients referred for surgical consideration are elderly and have multiple comorbidities. Mortality following anatomic resection of lung cancer is reported to be less than 3% in many series. However, significant respiratory and, to a lesser extent, cardiac complications are seen in as many as 20% of patients following surgery. Complications resulting from surgical resection limit multimodality treatment approaches. Decreased patient performance status following surgery increases the risk of adjuvant cisplatin-based chemotherapy and reduces the likelihood of treatment compliance, as previously described.
The advent and application of less toxic chemotherapeutic regimens will be required for this group of lung cancer patients suffering significant cardiorespiratory compromise as a result of their surgical therapy. Continued advances in surgical outcomes, including less invasive thoracoscopic surgical procedures that may limit morbidity and preserve performance status, are being actively studied.
Lung Cancer Screening
The absence of cost-effective and clinically useful screening methods further differentiates lung cancer from other malignancies such as breast and cervical cancer. As effective screening methods for lung cancer are developed and thoracic malignancies are discovered at earlier stages, there will be an advancing need for adjuvant therapies. Though mammograms in the early detection of breast tumors have led to a significant decrease in the incidence of more advanced stages of breast cancer (with a coincident increase in early-stage and noninvasive breast malignancies), the search for a cost-effective lung cancer screening tool has been elusive. Previously published studies in the 1970s failed to show efficacy for radiographic screening of at-risk populations such as tobacco users. Due to the paucity of randomized, controlled data to support routine screening in asymptomatic patients, the US Preventive Services Task Force has recommended against screening this at-risk population.
The recent publication of the International Early Lung Cancer Action Program (I-ELCAP) study has added valuable but inconclusive evidence as to the efficacy of low-dose computed tomography (CT) scanning of high-risk patients for thoracic malignancies. Nearly 30,000 patients deemed at high risk for lung cancer due to a history of exposure to tobacco or another known carcinogenic exposure were screened with low-dose CT scans of the chest. Screening detected lung cancer in 484 patients, of whom 85% had stage I disease. Among the 302 stage I patients who went on to surgical resection, the 5-year survival rate was 92% (confidence interval = 88%-95%), which is well above the expected stage I survival of approximately 70%.
As remarkable as this may sound, there was no discussion in the final publication as to the cost-effectiveness of this approach, and, as clearly brought out by Dr. Unger in his accompanying editorial, factors such as lead-time bias and overdiagnosis complicate the clinical usefulness of these findings. However, this study is an important step toward the improved screening of high-risk patients, for whom adjuvant therapies are the most relevant. Until an inexpensive and sensitive method of screening high-risk populations for lung cancer is developed, adjuvant therapies will continue to have a lower priority for investigational purposes, compared with salvage and palliative therapies.
Clinical Trial Development in NSCLC
An ongoing impediment to the effective accrual of data in the arena of NSCLC has much to do with physician and patient reluctance to enroll in protocols. Recently, meta-analyses such as the LACE review have helped to broaden the palatability of adjuvant therapy. However, the use of statistical tools to interpret results from trials with differing characteristics is always subject to limitations. Whereas adjuvant breast cancer trials routinely accrue 1,500 to 8,000 patients at a time, the IALT study was hailed for its ability to accrue nearly 2,000 patients largely due to its less stringent enrollment criteria. This study was an anomaly in lung cancer trials, as most protocols have difficulty accruing patients. The factors involved are beyond the scope of this discussion but include societal biases about lung cancer patients, funding difficulties, and patient/physician preferences. The position of all physicians who treat lung cancer should be to advocate and encourage trial participation for all patients regardless of disease stage or clinical situation.
Multidisciplinary Patient Evaluation
In order to increase screening of lung cancer patients for adjuvant therapies, adequate and prompt referral for multidisciplinary assessment is paramount. This is well highlighted by Drs. Wozniak and Gagdeel's review, in their discussion of neoadjuvant treatment strategies. Several studies, including the Bimodality Lung Oncology Team (BLOT) trial, the French Thoracic Study Group, and Southwest Oncology Group (SWOG) 9900, show inconclusive but promising results for this approach. A notable factor is the significant difficulty in delivering postoperative chemotherapy, perhaps secondary to surgical complications, raising the need for preoperative therapies to hopefully decrease the occurrence of subsequent local and distant relapses. However, the key to this paradigm is interdisciplinary collaboration to appropriately screen and treat these patients, preferably on protocol. These cooperative approaches improve staging assessments through the appropriate use of mediastinoscopies and emerging technologies such as positron-emission tomography (PET)/CT scanning.
The surgical treatment of lung cancer patients in the United States varies considerably. Simple concepts such as complete preoperative and intraoperative staging and confirmation of cancer-free surgical margins are neglected in the majority of patients. Having concomitant thoracic surgery, radiation oncology, and medical oncology evaluations through mechanisms such as tumor boards and collaborative clinical practices allows discussion and adherence to national guidelines in addition to perioperative protocols and treatment plans that maximize outcome and minimize toxicity.
Obtaining an optimal outcome for our patients demands greater advocacy for some of the issues discussed above. Although Drs. Wozniak and Gagdeel expertly review the available data on adjuvant therapy in NSCLC, we need to translate these data into practice and treat our patients appropriately in a multidisciplinary setting. This effort involves increased protocol development for screening methodologies and novel therapeutics with less toxicity. As these initiatives are realized, we come closer to answering the authors' primary question, "How do we improve cure rates in non-small-cell lung cancer?"
-Thomas A. Samuel, MD
-Kevin P. Landolfo, MD, MSc
-Kapil Bhalla, MD
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. US Cancer Statistics Working Group: United States Cancer Statistics: 1999-2002 Incidence and Mortality (Web-based report version). Atlanta, Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute, 2005.
2. Unger M: A pause, progress, and reassessment in lung cancer screening. N Engl J Med 355:1822-1824, 2006.
3. van Rens MT, de la Riviere AB, Elbers HR, et al: Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II, and IIIA. Chest 117:374-379, 2000.
4. Adebonojo SA, Bowser AN, Moritz DM, et al: Impact of revised stage classification of lung cancer on survival. A military experience. Chest 115:1507-1513, 1999.
5. 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 95:1453-1461, 2003.
6. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004.
7. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients (abstract 7008). J Clin Oncol 24(18S):366s, 2006.
8. Pepe C, Hasan B, Winton T et al: Adjuvant chemotherapy in elderly patients: An analysis of NCIC Clinical Trials Group and Intergroup BR.10 (abstract 7009). J Clin Oncol 24(18S):366s, 2006.
9. Lynch TJ, Leighl NB: Lung Cancer I. ASCO 2006: Annual Meeting Summaries, p 150. Alexandria, Va; American Society of Clinical Oncology; 2006.
10. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group trial E4599 (abstract 4). J Clin Oncol 23(16S):2s, 2005.
11. Maione P, Gridelli C, Troiani T, et al: Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist 11:274-284, 2006.
12. Pao W, Miller VA: Epidermal growth factor receptor mutations, small molecule kinase inhibitors, and NSCLC: Current knowledge and future directions. J Clin Oncol 23:2556-2568, 2005.
13. Kris M, Natale RB, Herbst R, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. JAMA 290:2149-2158, 2003.
14. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003.
15. Herbst R, Giaccone G, Schiller J, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 2. J Clin Oncol 22:785-794, 2004.
16. Giaccone G, Herbst R, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 1. J Clin Oncol 22:777-784, 2004.
17. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC) (abstract 7010). Proc Am Soc Clin Oncol 23:617, 2004.
18. Herbst R, Prager D, Hermann R, et al: TRIBUTE-A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC) (abstract 7011). Proc Am Soc Clin Oncol 23:617, 2004.
19. Shepherd F, Pereira J, Ciuleanu T, et al: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial (abstract 7022). J Clin Oncol 22(suppl 14):622s, 2004.
20. Little AG, Rusch VW, Bonner JA, et al: Patterns of surgical care of lung cancer patients. Ann Thorac Surg 80:2051-2056, 2005.
21. Ginsberg RJ: Lung cancer surgery: Acceptable morbidity and mortality, expected results and quality control. Surg Oncol 263-266, 2002.
22. Early lung cancer detection: Summary and conclusions. Am Rev Respir Dis 130:565-570, 1984.
23. US Preventive Services Task Force: Screening for lung cancer. Available at www.ahrq.gov/clinic/uspstf/uspslung.htm. Accessed January 19, 2007.
24. The International Early Lung Cancer Action Program Investigators: Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 355:1763-1771, 2006.