Dr. Kelly has written an excellentarticle demonstrating theclinical significance of achievingstable disease in advanced non–small-cell lung cancer (NSCLC)patients. This hypothesis is supportedby clinical data from two phase IItrials (Iressa Dose Evaluation in AdvancedLung Cancer [IDEAL-1 andIDEAL-2]) of the epidermal growthfactorreceptor (EGFR) inhibitor gefitinib(ZD1839, Iressa) in previouslytreated patients. She appropriatelypoints out that although tumor shrinkageis a conventionally used end pointfor cytotoxic drugs, it may not be appropriatefor the “novel” cytostaticagents. For these agents, stabilizationof disease without obvious tumorshrinkage may result in a clinicalbenefit.
Dr. Kelly has written an excellentarticle demonstrating theclinical significance of achievingstable disease in advanced non-small-cell lung cancer (NSCLC)patients. This hypothesis is supportedby clinical data from two phase IItrials (Iressa Dose Evaluation in AdvancedLung Cancer [IDEAL-1 andIDEAL-2]) of the epidermal growthfactorreceptor (EGFR) inhibitor gefitinib(ZD1839, Iressa) in previouslytreated patients. She appropriatelypoints out that although tumor shrinkageis a conventionally used end pointfor cytotoxic drugs, it may not be appropriatefor the "novel" cytostaticagents. For these agents, stabilizationof disease without obvious tumorshrinkage may result in a clinicalbenefit.Stable Disease andCytotoxic Agents
Cytotoxic chemotherapy is still thestandard treatment for chemonaivepatients with advanced NSCLC, resultingin a response rate of 19% to26% and median and 1-year survivalrates of 8 months and 33% to 37%,respectively.[1,2] As seen in Table 1,a significant numbers of patients (asmany as 29% of all previously untreatedpatients) achieved so-calledstable disease after receiving first-linedoublet chemotherapy. Although stabledisease is almost always reported,it has not been considered a clinicalend point of interest. In fact, by currentdefinition, patients with stabledisease are those who neither respondnor have disease progression.In the docetaxel (Taxotere) armsof two randomized phase III trials,previously treated patients whoachieved stable disease outnumberedresponders by a ratio of 5:1 or 7:1(Table 1).[3,4] Despite the low responserate of roughly 7%, patientslived longer and had improved qualityof life. Presumably, those benefitswere not seen only in the small percentageof patients who achieved aresponse, but also in those whoachieved stable disease.Stable Disease andCytostatic Agents
Anti-EGFR agents have been investigatedextensively in the treatmentof lung cancer. Of all molecularly targetedagents, gefitinib, an EGFRtyrosinekinase inhibitor is the firstand so far the only one approved bythe Food and Drug Administration foruse in NSCLC patients who havefailed two prior chemotherapyregimens.In two phase II trials (Table 2), 10%to 19% of previously treated patientsresponded to gefitinib, for an overallmedian survival of 6 to 7.8 months.[5,6]In addition, a significant number ofpatients (29%-34%) achieved stabledisease. As pointed out by Dr. Kelly,the investigators found that 40% to80% of patients who experiencedstable disease enjoyed an improvementin symptoms, and 30% to 60%had improvement in quality of life,whereas only a small percentageof patients with disease progressiondid so.
Should Stable Disease Be aClinical End Point in Trials?
In addition to survival, tumor responsehas been used as a primary orsecondary objective in clinical trialsof cytotoxic therapies. In many trials,tumor response by imaging criteria isused to evaluate the efficacy of aninvestigational treatment. However,this "traditional" end point is beingchallenged with the emergence of anew class of drugs-the molecularlytargeted agents. These novel agents,such as the anti-EGFR agents, mayexert a predominantly cytostatic effecton cancer cells rather than thecytotoxic mechanism seen with conventionalchemotherapeutic agents.As shown in the IDEAL trials andas discussed by Dr. Kelly, cytostaticagents may produce disease stabilization,and as a result, improve bothsymptoms and quality of life, whichare important to patients who sufferfrom this disease. Using complete andpartial response as the primary endpoints in screening phase II trials carriesthe risk of overlooking a cytostaticdrug with a low response rate butwith clinical benefit.Does Stable Disease Result inProlonged Survival?
What is not clear is whether, inaddition to symptom relief or improvementin quality of life, patients withdisease stabilization also have an improvedsurvival. "Softer" end pointssuch as progression-free survival ortime to progression are sometimesused in clinical trials of novelagents.[7,8] Preliminary data from theEastern Cooperative Oncology Groupsuggest that chemonaive patients withadvanced NSCLC who achieved stabledisease with standard chemotherapymay also have a survivalbenefit. Thus, in this new era ofmolecularly targeted therapy, the clinicalimportance of stable diseaseshould be investigated as an additionalclinical end point in trial designs.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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Shepherd F, Dancey J, Ramlau R, et al:Prospective randomized trial of docetaxel versusbest supportive care in patients with nonsmallcell lung cancer previously treated withplatinum-based chemotherapy. J Clin Oncol18:2095-2103, 2000.
Fossella F, Devore R, RN K, et al: Randomizedphase III trial of docetaxel versus vinorelbineor ifosfamide in patients withadvanced non-small-cell lung cancer previouslytreated with plantinum-containing chemotherapyregimens. The TAX 320 Non-SmallCell Lung Cancer Study Group. J Clin Oncol18:2354-2362, 2000.
Fukuoka M, Yano S, Giaccone G, et al:Multi-institutional randomized phase II trial ofgefitinib for previously treated patients withadvanced non-small-cell lung cancer. J ClinOncol. In press.
Kris M, Natale R, Herbst R: A phase IItrial of ZD1839 (“Iressa”) in advanced nonsmallcell lung cancer patients who had failedplatinum- and docetaxel-based regimens (abstract1166). Proc Am Soc Clin Oncol 21:292a,2002.
Korn EL, Arbuck SG, Pluda JM, et al:Clinical trial designs for cytostatic agents: arenew approaches needed? J Clin Oncol 19:265-272, 2001
Arteaga CL, Baselga J: Clinical trial designand end points for epidermal growth factorreceptor-targeted therapies: Implications fordrug development and practice. Clin CancerRes 9:1579-1589, 2003.
Hoang T, Xu R, Schiller J, et al: Survivalsignificance of achieving stable disease inchemonaive patients with advanced non-smallcell lung cancer treated with standard chemotherapy:ECOG Data. Presented at the 10thWorld Conference on Lung Cancer in Vancouver,British Columbia, Canada, 2003.