Focus on Early-stage Disease
After decades of increasing death rates, we have finally begun to make strides in reducing death from lung cancer in the United States. Reduction in tobacco use has led to a significant decline in lung cancer death rates among men and a stabilization of lung cancer death rates in women (Figure 1). However, even with these positive trends, lung cancer remains by far the leading cause of cancer-related death in the United States.
In 2007 an estimated 160,000 American men and women will die of lung cancer.1 The best chance for cure is treating lung cancer when it presents as early- stage disease. Recent studies have reported 2-year overall non-small cell lung cancer (NSCLC) survival of 90%, vs 47% for stage III to stage IV disease.2 Although this difference diminishes in the longer term, survival is still significantly affected by earlier intervention (Figure 2). Today, approximately a third of all patients diagnosed as having lung cancer present with early-stage disease. Advances in screening for lung cancer are likely to increase the proportion of patients who have early-stage disease and place additional importance on enhanced curative strategies.3 Curing lung cancer begins with effectively detecting and staging when the cancer is still amenable to local therapy. The next step is to optimize local therapies such as surgery and radiofrequency ablation (RFA). Finally, effective adjuvant therapy, incorporating novel agents, is essential if we are to make progress in controlling micrometastatic disease. All of these steps will be enhanced by gene expression profiling and oncogene mutational sequencing, which will allow more refined risk stratification and new target identification.
One of the important advances of the past decade has been the introduction of techniques to improve lung cancer staging. The introduction of brain imaging via contrast magnetic resonance imaging allows patients with small volume brain disease to be treated more aggressively and in some cases be spared major chest surgery. The most significant advance has been the positron emission tomography (PET) scan, particularly PET computer tomography (CT), which enhances detection of small regions of metastatic disease to identify patients appropriate for curative treatment.4 Other important advances have been made in interventional imaging of mediastinal disease, including fiberoptic bronchial ultrasound and endoscopic esophogeal ultrasound ablation (EUS)5, which provide pulmonologists with noninvasive means to determine operability.
During the past decade several surgical innovations have improved local treatment of lung cancer. Standard lobectomy is an effective procedure, yet it requires a full thoracotomy and has significant morbidities. Newer techniques such as sleeve resection and other parenchymal-sparing resections have proven helpful to patients who have limited lung reserve.6 The use of video-assisted thoroscopy (VATS) lobectomy has also increased, allowing more patients who might not tolerate a full thoracotomy to benefit from surgery. It also allows for quicker recovery from surgery for patients with standard risk disease, allowing them to get to adjuvant therapy sooner.7 Ongoing studies are determining the potential role of this approach in stage I and II disease. For patients whose disease is inoperable even with a parenchymal-sparing resection, a VATS approach, and aggressive physical therapy, new minimally invasive tools such as RFA can produce durable local control of disease.8 Trials are now under way to determine if cure is also possible from this approach. Ultimately, we may learn that RFA is applicable to patients who are medically fit, which would provide a less invasive alternative to open surgery that is associated with substantially better quality of life.
Perhaps the most significant recent advance in treating lung cancer has been the recognition that chemotherapy given after surgery is able to improve the cure rate. Cisplatin-based regimens have shown the most consistent benefit.9 Patients with stage II and III NSCLC appear to derive the greatest benefit from treatment, but even older patients appear to benefit. At the 2006 American Society of Clinical Oncology meeting, we learned that older patients experience more toxic effects from treatment but derive benefits similar to younger patients and that adjuvant treatment should be discussed with fit patients older than 70 years.10
Despite the widespread acceptance of cisplatin-based treatment for patients with stage II and III disease, a number of questions have not yet been answered: Are there patients with stage I disease who might benefit? Is there a role for regimens other than cisplatin? What are the optimal timing and duration of therapy? Are there markers that might predict benefit from adjuvant therapy? Many of these questions are being approached in ongoing clinical trials, and a study from Europe this year also suggests that we may have a useful biomarker, ERCCI, to assist us in finding answers.
Integrating novel agents into the adjuvant equation is also important. Data published in late 2006 showed that bevacizumab added to standard carboplatin and paclitaxel-based chemotherapy is able to improve outcome for patients who have metastatic adenocarcinoma of the lung.11 A major question is whether this advance for patients with stage IV disease can translate into an improved cure rate for patients in the adjuvant setting. A randomized Intergroup trial of carboplatin, paclitaxel, and bevacizumab compared with carboplatin and paclitaxel alone is about to begin to address this question. To learn more about this and other trials that may be available and appropriate for your patients, go to http://www.clinicaltrials.gov.
Finally, we must explore new ways to identify patients who are most likely going to experience disease relapse. Analysis of tumor specimens using gene expression profiling is providing new insights into the molecular profiles of individual tumors, drug response, and risk of cancer recurrence.12,13,81 Perhaps the biggest potential win from molecular profiling is that these approaches might uncover as yet unrecognized targets for new drug development. Ultimately, this would be the big "payoff" from the genomics revolution, and there is great hope and excitement that this may actually be able to improve patient outcomes in the near future.
The purpose of this educational monograph is to provide a succinct but thorough review of the most current approaches for assessing and treating stage I and II NSCLC, important studies and data that physicians should be aware of, perspectives of academic experts on each topic, and references for further reading. We hope you find this to be a valuable resource, both for continuing medical education and as a reference for your practice.