The Benefits of Achieving Stable Disease in Advanced Lung Cancer

Dr. Kelly has written an excellent article demonstrating the clinical significance of achieving stable disease in advanced non- small-cell lung cancer (NSCLC) patients. This hypothesis is supported by clinical data from two phase II trials (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL-1 and IDEAL-2]) of the epidermal growthfactor receptor (EGFR) inhibitor gefitinib(Drug information on gefitinib) (ZD1839, Iressa) in previously treated patients. She appropriately points out that although tumor shrinkage is a conventionally used end point for cytotoxic drugs, it may not be appropriate for the "novel" cytostatic agents. For these agents, stabilization of disease without obvious tumor shrinkage may result in a clinical benefit. Stable Disease and Cytotoxic Agents
Cytotoxic chemotherapy is still the standard treatment for chemonaive patients with advanced NSCLC, resulting in a response rate of 19% to 26% and median and 1-year survival rates of 8 months and 33% to 37%, respectively.[1,2] As seen in Table 1, a significant numbers of patients (as many as 29% of all previously untreated patients) achieved so-called stable disease after receiving first-line doublet chemotherapy. Although stable disease is almost always reported, it has not been considered a clinical end point of interest. In fact, by current definition, patients with stable disease are those who neither respond nor have disease progression. In the docetaxel(Drug information on docetaxel) (Taxotere) arms of two randomized phase III trials, previously treated patients who achieved stable disease outnumbered responders by a ratio of 5:1 or 7:1 (Table 1).[3,4] Despite the low response rate of roughly 7%, patients lived longer and had improved quality of life. Presumably, those benefits were not seen only in the small percentage of patients who achieved a response, but also in those who achieved stable disease. Stable Disease and Cytostatic Agents
Anti-EGFR agents have been investigated extensively in the treatment of lung cancer. Of all molecularly targeted agents, gefitinib, an EGFRtyrosine kinase inhibitor is the first and so far the only one approved by the Food and Drug Administration for use in NSCLC patients who have failed two prior chemotherapy regimens. In two phase II trials (Table 2), 10% to 19% of previously treated patients responded to gefitinib, for an overall median survival of 6 to 7.8 months.[5,6] In addition, a significant number of patients (29%-34%) achieved stable disease. As pointed out by Dr. Kelly, the investigators found that 40% to 80% of patients who experienced stable disease enjoyed an improvement in symptoms, and 30% to 60% had improvement in quality of life, whereas only a small percentage of patients with disease progression did so. Should Stable Disease Be a Clinical End Point in Trials?
In addition to survival, tumor response has been used as a primary or secondary objective in clinical trials of cytotoxic therapies. In many trials, tumor response by imaging criteria is used to evaluate the efficacy of an investigational treatment. However, this "traditional" end point is being challenged with the emergence of a new class of drugs-the molecularly targeted agents. These novel agents, such as the anti-EGFR agents, may exert a predominantly cytostatic effect on cancer cells rather than the cytotoxic mechanism seen with conventional chemotherapeutic agents. As shown in the IDEAL trials and as discussed by Dr. Kelly, cytostatic agents may produce disease stabilization, and as a result, improve both symptoms and quality of life, which are important to patients who suffer from this disease. Using complete and partial response as the primary end points in screening phase II trials carries the risk of overlooking a cytostatic drug with a low response rate but with clinical benefit. Does Stable Disease Result in Prolonged Survival?
What is not clear is whether, in addition to symptom relief or improvement in quality of life, patients with disease stabilization also have an improved survival. "Softer" end points such as progression-free survival or time to progression are sometimes used in clinical trials of novel agents.[7,8] Preliminary data from the Eastern Cooperative Oncology Group suggest that chemonaive patients with advanced NSCLC who achieved stable disease with standard chemotherapy may also have a survival benefit.[9] Thus, in this new era of molecularly targeted therapy, the clinical importance of stable disease should be investigated as an additional clinical end point in trial designs.