The Benefits of Achieving Stable Disease in Advanced Lung Cancer
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
(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
Stable Disease and
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 (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. 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.
2. Kelly K, Crowley J, Bunn PA, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19:3210- 3218, 2001.
3. Shepherd F, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000.
4. Fossella F, Devore R, RN K, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with plantinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000.
5. 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. In press.
6. Kris M, Natale R, Herbst R: A phase II trial of ZD1839 (“Iressa”) in advanced nonsmall cell lung cancer patients who had failed platinum- and docetaxel-based regimens (abstract 1166). Proc Am Soc Clin Oncol 21:292a, 2002.
7. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 19:265- 272, 2001
8. Arteaga CL, Baselga J: Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: Implications for drug development and practice. Clin Cancer Res 9:1579-1589, 2003.
9. Hoang T, Xu R, Schiller J, et al: Survival significance of achieving stable disease in chemonaive patients with advanced non-small cell lung cancer treated with standard chemotherapy: ECOG Data. Presented at the 10th World Conference on Lung Cancer in Vancouver, British Columbia, Canada, 2003.