Drs. Novello and Le Chevalier have produced a comprehensive summary of a large number of trials of chemotherapy for all stages of non-small-cell lung cancer (NSCLC). This is a broad subject area, constantly changing and rife with controversy; selecting the key trials with international relevance is no small feat. Nonetheless, the review highlights many salient issues in the treatment of lung cancer.
Advanced Disease
One-third of all patients with lung cancer present with advanced NSCLC. Thus, even small improvements in survival could have largescale global effects. The historical reticence to give chemotherapy to patients with advanced disease should be abandoned, as multiple international studies have shown chemotherapy to be beneficial with respect to quality and quantity of life and costeffectiveness.[ 1-3] For roughly 2 decades, chemotherapy regimens have been cisplatin(Drug information on cisplatin)-based; however, studies combining newer less toxic drugs have demonstrated similar therapeutic end points. Emerging data suggest that a variety of doublet combinations of "new" chemotherapies are effective, and that doublet therapy is superior to monotherapy and equivalent to triplet combinations. Therefore, doublet therapy can, to a certain extent, be tailored to a given patient, community, or country without deleterious effects on outcome.
Although the benefits of chemotherapy are real, it is important to remember that lung cancer therapy should be individualized. Patients who have lost a significant amount of weight or those with an impaired performance status may not realize the same benefits from chemotherapy.[ 4] That being said, advanced age alone should not be a deterrent to treatment and fit patients over 70 have been shown to benefit from both single-agent and doublet chemotherapy.
Despite the progress in first-line therapy for advanced disease, there is still a need for effective secondline treatments, as the vast majority of patients go on to develop progressive disease. Single-agent docetaxel(Drug information on docetaxel) (Taxotere) has been approved for use in second-line therapy, but patients should be encouraged to enroll in clinical trials whenever possible.
Adjuvant and Neoadjuvant Therapy
Novello and Le Chevalier also outline the myriad of trials that have investigated the use of adjuvant chemotherapy, radiation, and combinedmodality therapy in early-stage (I-IIIA) NSCLC. It becomes clear from these studies that different chemotherapy regimens and radiation doses, and more importantly, different stages of lung cancer were involved, making comparisons across trials extremely difficult.
It is not surprising that both positive and negative results have been reported. There may well be patient subgroups, such as those with N2 disease, that will benefit; the results of ongoing studies in this population and other subgroups are awaited with interest. At this point, there is no consensus in the literature that adjuvant chemotherapy or radiation improves overall survival, and thus, these approaches should not be regarded as the standard of care.
It is well established that patients with locally advanced (stage IIIB) disease benefit from combinedmodality neoadjuvant therapy. Ongoing trials will hopefully clarify the role of induction vs consolidative chemotherapy and the optimal dose and timing of thoracic radiation. It is tempting to extrapolate these results to less advanced disease.
Another area of active investigation and debate is the role of neoadjuvant chemotherapy and/or radiation for resectable NSCLC (stage I-IIIA). Unfortunately, no consistent evidence has shown that neoadjuvant therapy has a positive impact on survival. Promising phase II trials have led to ongoing phase III trials and, again, these will hopefully identify the subpopulations most likely to benefit from neoadjuvant treatment.
Biologically Targeted Therapy
Despite shuffling and rearranging traditional cytotoxic chemotherapies and radiation, we have come to a therapeutic plateau in the management of NSCLC. The appeal of systemic treatments that preferentially and effectively target cancer cells with minimal toxicity to normal tissues is obvious. Promising preclinical data have led to the investigation of several different ways to specifically target lung cancer cells, including angiogensis inhibitors, receptor-targeted therapy, vaccines, gene therapy, and signal transduction inhibitors.
Studies of cyclooxygenase-2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, and epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors are furthest along in clinical testing. These therapies have been used in patients with advanced NSCLC in combination with cytotoxic chemotherapy and/or radiation. EGFR-TK inhibitors have been used as single agents in patients who progress after standard chemotherapy, and they have demonstrated good response rates and a positive impact on quality of life.[5,6] Disappointingly, these benefits were not extended when one of the EGFR-TK inhibitors, ZD1839 (Iressa), was used in combination with chemotherapy as first-line therapy in the Iressa NSCLC Trial Assessing Combination Therapy (INTACT) study.
The results of similar studies are eagerly anticipated. Overall, the results of the trials of targeted therapies have been a "mixed bag," but such agents certainly warrant further examination.
Several uses of targeted agents are currently under investigation. Adjuvant chemotherapy has not yet proven to be of benefit, and it may represent a niche for targeted therapy. EGFRTK inhibitors are being tested as maintenance therapy. Various other agents are being tested in combination with standard chemotherapy. For example, the Eastern Cooperative Oncology Group trial E4599 is a phase III study of carboplatin(Drug information on carboplatin) and paclitaxel with or without bevacizumab(Drug information on bevacizumab) (a recombinant humanized monoclonal antibody to VEGF) that is currently accruing patients.
The concept of combining multiple targeted therapies is intuitively attractive and, in a way, analogous to using non-cross-resistant chemotherapy combinations. This idea is also being explored in NSCLC. For example, an ongoing trial at Vanderbilt University, in collaboration with M. D. Anderson Cancer Center, involves the treatment of patients with recurrent, previously treated advanced NSCLC with a combination of a VEGF inhibitor (the monoclonal antibody bevacizumab) and an EGFR-TK inhibitor (erlotinib [OSI-774, Tarceva]). By targeting two sites concurrently, we hope to take advantage of the natural interactions between these two growth stimulatory pathways and simultaneously inhibit cell growth and tumor angiogenesis, and perhaps even overcome tumor resistance.
The role of biologically targeted therapy is still actively being studied. It is likely that we will discover that certain tumors respond preferentially to specific agents or combinations of agents, and treatment may evolve to be more tailored to pathologic subgroups of lung cancers. As we expand our knowledge of tumor biology, targeted agents will find their place in the mosaic of lung cancer treatment.
Conclusions
Novella and Le Chevalier have constructed a comprehensive chronologic summary of trials of chemotherapy in NSCLC. They review areas of controversy that have centered on dose, schedule, toxicity, and general therapeutic philosophy. The next decade of trials will help define the timelines and combinations of chemotherapeutic agents for lung cancer, and will hopefully generate many more compelling research questions.
