Quantitative Response Metrics for Lung Cancer
Clinician’s Perspective:
Lung cancer is the leading cause of cancer death in the United States and the second leading cause of death overall in our society {Jemal, 2008 #2} but mortality outcomes have improved only modestly over the last thirty years {Wakelee, 2006 #1}.
For these reasons lung cancer is an intense focus for pharmaceutical companies to develop better treatments but a number of challenges exist; significantly, the cost and time duration of the clinical trials required to establish the utility of a drug so that it can be formally approved by federal regulatory agencies {Mayburd, 2008 #3}.
The QIBA Volumetric CT group has proposed that quantitative spiral CT may increase the analytical power per subject enrolled in clinical trials to reduce:
- the number of total subjects enrolled in an arm of a clinical trial or
- the length of time that an individual needs to be followed to reliably establish drug response.
With the transition from conventional cytotoxic chemotherapy to new molecularly targeted therapeutics, a new trend has emerged in for drug response endpoints.
With certain molecularly targeted drugs, there may not be any appreciable shrinkage of the size of the tumor after drug exposure. Rather, the cancer stops growing which, in a clinical setting, is called stable disease (SD). In some instances, molecularly targeted drug therapy can result in disease stabilization lasting for years. In these cases, the success of the drug may be best measured with the clinical trial endpoint such as progression-free survival (PFS). With PFS, the interval is measured from the date of study entry until the date of disease progression. There are many nuances in interpreting the significance of this endpoint compared to other trial endpoints such as overall survival (OS). Overall survival is measured from the date of study entry to the time of patient death.
The focus of this discussion is on how accurately the measurement of these various parameters are made in clinical trials with imaging tools. Such measurement can be quite variable related to the manner of how disease progression occurs as well as how the imaging studies are performed. Depending on the study setting, volumetric imaging may or may not be informative. Lung cancer begins with a cancer arising within the cells of the airway of the lung. Localized cancer is called a primary lung cancer. Cancers are generally lethal to their hosts due to a predilection of spreading to other parts of the body. The first place a lung cancer typically spreads as it advances from localized disease is to the neighboring lymph nodal structures of the lung. This is called regional metastatic spread. In contrast, in the most advanced stage of cancer, the cancer spreads to a distant site such as a brain metastasis or liver metastasis. This is called distant metastatic spread.
In clinical trials, the discovery of a new site of metastatic dissemination is the basis for declaring failure of the efficacy of a new drug. This is a qualitative not quantitative determination. In virtually all lung cancer clinical trials there are situations when either a quantitative or a qualitative endpoint may be relevant but it is likely that quantitative endpoints will be most frequently informative in trials involving early stage lung cancer.