Future Directions in Non-Small-Cell Lung Cancer: A Continuing Perspective

Despite the absence of any highly visible breakthrough presentation, the 8th World Conference on Lung Cancer in Dublin, Ireland, was a true watershed event. Trends that have been developing over the last decade have now become clear, and the need for new approaches is compelling. In the context of a continuing perspective on these meetings,[1] enormous progress has been made in the treatment of non-small-cell lung cancer (NSCLC), in the understanding of the molecular events leading to lung cancer, and in the war against tobacco. Complacency based on these advances would, however, be folly. The continued lack of progress against small-cell lung cancer (SCLC), the absence of major progress in diagnostic imaging, and the continued slow pace of translating biologic understanding to clinical application are frustrating. Underlying all of this is our inability to complete pivotal randomized trials in a timely fashion.

Trends That Have Become Established Patterns

NSCLC Is, Stage for Stage, More Successfully Treated Than SCLC

Much of the past 2 decades has been absorbed with extolling the curability of SCLC and intensifying its treatment so as to increase the number of cures achieved.[2] The corollary to this was the ongoing denigration of any therapy other than surgery for NSCLC. Table 1 is a comparison, albeit an unconventional one, of outcomes for patients with SCLC and NSCLC. As a group, and for virtually any specific stage of disease, patients with NSCLC now clearly have an equal or superior outcome compared with patients with SCLC. The era during which we justified treating just about anyone with SCLC because “they do so well” and withheld treatment from patients with NSCLC because “they do so poorly” is now clearly at an end.

Adenocarcinoma Is Now the Most Common Histologic Subtype of Lung Cancer

Most investigators in lung cancer matured during the era when squamous cell carcinomas were the predominant form of non-small-cell lung cancer. With uncommon exceptions in certain nations, this trend has now been totally reversed.[3] Whether this represents a change in the spectrum of inhaled carcinogens due to increasing use of filtered products is speculative, albeit intriguing.

The emergence of adenocarcinomas, with their tendency for earlier metastasis, means that clinical practices—eg, screening for asymptomatic brain metastases and more frequent use of mediastinoscopy in patients with negative computed tomography scans—will have to be re-evaluated.

Multimodal Therapy Has Replaced Unimodal Therapy in Many Clinical Settings

With the exception of very early stage IA NSCLC and widespread NSCLC or SCLC, evidence suggests that combinations of treatment modalities are superior to single-modality treatment (Table 2). An adjunct to this is the emergence of the thoracic oncologist who may be trained in any of the modalities but is widely experienced in using all available modalities of treatment.

“Therapeutic Imperative” Has Triumphed Over Nihilism and Cost Cutting

Although highly variable across cultures, the concept that a patient wants to be treated, despite long odds against success (the “therapeutic imperative”) is now well established. Earlier objections to this approach, especially for patients with metastatic NSCLC, centered around the lack of a survival benefit and the worsening of quality of life due to treatment-related toxicity. It is now clear from randomized trials and meta-analyses that treatment for metastatic NSCLC improves survival, albeit modestly,[4-6] that patient symptoms are improved in most cases,[7-10] that the emetogenic side effects of therapy can be abrogated,[11,12] and that the cost-benefit ratio is clearly in favor of including chemotherapy for the treatment of locally advanced[13] and metastatic NSCLC.[14] One hopes that the era of studies comparing treatment vs best supportive care is now truly over.

Where Has Clear Progress Been Made?

Tobacco Control

Although the accumulated damage from decades of tobacco abuse will continue to plague us well into the next century, the tide appears to have finally turned. As a result of extraordinarily brave political action by former commissioner David Kessler, md, the Food and Drug Administration in the United States has recognized and documented the addictive nature of nicotine(Drug information on nicotine) and has moved to regulate its use as a drug.[15,16] It is expected that a similar action will ensue in Europe with the election of the Labour Party in England and a formal end to British opposition to an advertising ban in Europe.[17] Canada has passed legislation to restrict advertising and limit tar and nicotine content[17] and, most extraordinarily, the tobacco industry in the United States has been forced to its knees in court by several states, resulting in settlement agreements that reimburse tobacco-related health costs, end or restrict most advertising, and severely limit access to tobacco products for minors. As of this writing, at least one firm has admitted to covering up their knowledge of tobacco’s harmful effects, thus ending one of the longest scientific fantasies ever promulgated by an industry. For these efforts to have long-term success, the changes in consumer behaviors need to be sustained. The revelations of “doping” of cigarettes by manipulation of nicotine content[18] have had a clear impact on the glamour associated with smoking.

The remaining clouds on this horizon are significant, however. Cigar smoking has regained its cachet and, though less dangerous than cigarette smoking, it threatens the societal pressures against smoking behaviors. Finally, the legislation and legal actions in Europe and North American have had little or no impact on sales or marketing in Central and South America, Eastern Europe, and Asia.

Understanding the Molecular Changes Leading to Development and Progression of Lung Cancer

Initial studies demonstrating the presence of autocrine and paracrine growth control in lung cancer[19-22] have been followed by the recognition that these receptors are generally tyrosine kinases, and that the growth signal is transferred to the nucleus by a complex signal transduction machinery that includes activation of vital proteins such as Ras, GTPase, Raf, and MAP kinase, which in turn translocate to the nucleus and activate transcription factors.[23] Receptor tyrosine kinases (RTKs) can also signal more directly to the nucleus by activating signal transducers and transcription activators (STATs) that dimerize, bind directly to DNA, and activate transcription.[24] Cell division is stimulated by RTKs through activation of cyclin-dependent kinases that allow cells to progress through the cell cycle.[25] Overexpression or inappropriate expression of several RTKs and constitutive overexpression of cyclin-dependent kinases and signal transducers and transcription activator proteins appear to be involved in sustaining the growth of malignant cells.[26]

Although not yet fully characterized, the sequence of genetic changes leading to development of lung carcinogenesis also is being unraveled. Mutations in up to 10 to 20 recessive or dominant oncogenes appear common in each cancer and may be related to abnormalities of DNA repair.[27]

Abnormal p53, myc, and Rb genes and gene products have been described as having a series of recessive oncogenes (FHIT homozygous deletion region FRA3B fragile site, BAP-1, ACL5 homozygous deletion region, and the VHL gene region) exposed during 3p allelic loss, a common finding in lung cancer.[28] What is less clear is how these aberrations directly affect cell-signaling mechanisms that lead to continued cell proliferation.

Real Progress Has Been Made Against NSCLC

Because of the enormous numbers of NSCLC patients, even small changes in long-term outcome affect thousands of individuals. Progress in the past several years, however, has been far more than incremental. In the management of metastatic NSCLC, the introduction of paclitaxel(Drug information on paclitaxel) (Taxol),[29,30] docetaxel (Taxotere),[31,32] vinorelbine (Navelbine),[33,34] gemcitabine(Drug information on gemcitabine) (Gemzar),[35,36] and the topoisomerase I inhibitors topotecan(Drug information on topotecan) (Hycamtin)[37] and irinotecan (Camptosar)[38] led to a series of doublet studies incorporating cisplatin(Drug information on cisplatin) (Platinol) or carboplatin(Drug information on carboplatin) (Paraplatin), resulting in now-routine 1-year survival rates of 40% and better, with measurable 2-year survival rates.[39] Paclitaxel/cisplatin,[40] vinorelbine/cisplatin,[41,42] and gemcitabine/cisplatin[43] have all proven superior to older regimens, and comparisons between and among them are under way. The combination of paclitaxel/carboplatin has become a de-facto community standard in the United States. Despite the fact that only phase II trial results are available,[44] this combination has become the comparative arm in each of the cooperative group trials currently under way in the United States (Table 3). Combinations of these new agents with surgery and/or radiation are now under active investigation and may represent our first real impact on systemic disease.[45,46]

Previous expectations that patients with locally advanced NSCLC would have only a 5% 5-year survival rate with radiation alone have now been eclipsed by regular expectations of 20% to 30% 5-year survivals with various permutations of sequential and concurrent chemotherapy, radiation, and possibly surgery.[47,48]