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Katherine Panageas, Dr.P.H., of Memorial Sloan-Kettering Cancer Center in New York, and colleagues examined the use of progression-free survival (PFS) as an endpoint measurement in clinical trials.
PFS is measured as the time from start of treatment to the first measurement of cancer growth. Disease progression is typically measured by radiologic tests, such as x-rays, at scheduled intervals. Most often, researchers do not know when progression actually occurs, so they can only estimate that it happened sometime between the test that showed progression and the previous one.
Methodological problems can arise when researchers define the date of progression as the date on which it was first detected, even though progression most likely occurred prior to that day. The researchers compared a variety of surveillance intervals using a simulated population to demonstrate how the evaluation schedule can affect the estimation of PFS.
The researchers found that the outcome of the trial can be heavily influenced by the surveillance interval and that comparing the PFS times of two studies with different evaluation schedules can lead to erroneous conclusions.
"The decision to use PFS as a primary endpoint should be considered carefully in the design phase of the trial. It is our intention to make researchers aware that estimates of PFS are highly dependent on when they look for progression. The clinical research community can address this concern by adopting consistent strategies for interval evaluations in the design phase," the authors write. -Journal of the National Cancer Institute
Posted March 23rd, 2007 by harminka
Flawed and Outdated Randomized Clinical Trials
Metastasis is an organism-wide phenomenon that may involve dozens of processes. It's hard to do replicable experiements when there are so many variables. So, instead, researchers opt for more straightforward experiments that generate plenty of reproducible results (like tumor shrinkage). This gives the illusion that researchers have done something meaningful.
Tens of thousands of scientists pushing a goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that fosters redundant problems and rewards academic achievement and publication above all else.
The manufacturers of cancer drugs use X-rays to determine a finding called progression-free survival (the cancer-free time that the drug induces before tumors grew substantially in number or size). However, to find whether a drug actually extends lives would have taken many more months to establish.
Groups of cancer patients, like the National Breast Cancer Coalition say they want better ways to measure success against cancer. Their president, Frances M. Visco, has said that it means we want better science, meaningful endpoints and drugs that have less toxicity and actually prolong survival.
One in 20 prospective cancer cures used in human tests reaches the market, the worst record of any medical category. Among those that gained approval in the last 20 years, fewer than one in five have been shown to extend lives, and life extensions usually are measured in weeks or months, not years.
The FDA released a report that lists more than 12 research areas that it will address to try to improve clinical trials. Among the efforts is a search for new ways to measure cancer progression. There is growing evidence that X-rays, long the standard, may not accurately assess a patient’s disease.
For decades, X-rays have been the principal means for researchers to judge whether a cancer drug works. If tumors appear to shrink or stop growing after therapy, the drug is thought to be working. But as the Dr. Katharina Pachmann, et al research presented at the 27th Annual San Antonio Breast Cancer Symposium reported, drugs like Taxol causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding helps explain that complete pathologic responses do not correlate well with improvements in survival.
There is growing evidence that tumor size may not matter much either. Small tumors can sometimes be as deadly as large tumors. That discovery has unmoored drug development. Researchers could track which patients live or die. But trials that measure life expectancy often take years and tens of millions of dollars to complete.
Researchers and companies would dearly love an interim measure akin to cholesterol or blood pressure readings. Testing the tumor first by cell cuture assay tests would help. The FDA is also encouraging tests of new imaging equipment. Officials are hopeful about research into PET scans. The scans show not only a tumor’s size, but also its vigor.
The most effective use of cytotoxic chemotherapy is in the first-line setting. The use of ineffective drugs at the time of initial therapy may lead to treatment failure. While some patients present with inherently resistant disease, it is possible that the resistance identified against one standard regimen may not be obtained with all regimens.
The responsibility of oncologists is to use every available resource at their disposal to select the most effective, least toxic drugs for their patients. Cell culture assay techniques can help them make the right choices for their patients whether at first-line therapy or thereafter.
(Oncol News Int'l, Vol 14, #5, May '05)