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© Oxford University Press 2006.
NEWS |
Sometimes Size Doesn't Matter: Reevaluating RECIST and Tumor Response Rate Endpoints
If you give a cancer patient a drug and then the tumor's growth screeches to a halt or a hole appears in its middle, most people would say the drug was working. But on the basis of the response criteria most widely used for solid tumors, these changes mean nothing.
Standardized response criteria are critical for directing individual patient care, evaluating new therapies, and communicating risk to family and patients. Yet just what those criteria should be for solid tumors is up for debate. Although some groups are looking for new ways to physically measure success, others are moving away from tumor measurements altogether and strictly examining survival.
"I think standardizing response assessment is generally a good thing because people speak the same language when they are reporting studies," said Primo N. Lara, M.D., associate professor of medicine at the University of California at Davis in Sacramento, who presented on the topic at the American Society of Clinical Oncology annual meeting. "Some people misinterpret a tumor response as being an end-all or be-all for a particular study, but our study showed that even if you don't have a [measurable] response, having stable disease or nonprogression at a certain time point is a good predictor of outcome. You may not need to have a nice 30% reduction in tumor size to benefit from a treatment."
Choi Criteria Trump RECIST?
In 2000, an international group agreed on standard criteria for measuring tumor response, called Response Evaluation Criteria in Solid Tumors (RECIST). A complete response was the disappearance of all target tumors. A partial response was a 30% or larger decrease in the sum of the longest diameter of the tumors. And progressive disease was a 20% or more increase in the sum of the diameter. Stable disease was everything between 30% decrease and 20% growth of tumor size.
In recent years, however, two developments have called RECIST into question. First, imaging techniques that allow smaller changes in tumor size to be detected and reliably reproduced have improved. The techniques also show changes in tumor density, which can be an important indicator of therapeutic response even without the tumor shrinking. Second, an increasing number of drugs in development inhibit cell growth (cytostatic) and thus do not shrink the tumor like conventional chemotherapy drugs, which kill cells (cytotoxic). If judged by RECIST criteria alone, these new drugs would not show antitumor activity in a clinical trial, despite providing substantial benefit in terms of progression-free or overall survival.
A prime example of these limitations is seen in evaluating gastrointestinal stromal tumor (GIST) patients treated with imatinib. The drug prolongs survival in these patients but rarely shrinks the tumor by the required 30% to be called a partial response by RECIST criteria. Positron emission tomography (PET) scans indicate that the tumors become less dense, suggesting that the number of cancer cells is decreasing. Moreover, progression in GIST often occurs within the boundaries of the original tumor, which would not be considered progression by RECIST.
| A New Look at Tumor Response Researchers have recognized problems with the current system of measuring drug response, given that tumor cells may react differently to new drugs, and new imaging techniques allow more accurate measurements of tumor density. The old RECIST A complete response is the disappearance of all target lesions; a partial response is a 30% decrease in the sum of the longest dimension (LD) of target lesions, relative to baseline measurement; progressive disease is an increase of 20% or more in the sum of the LD of target lesions; and stable disease is a decrease in tumor size of less than 30% or increase of less than 20%. The new Choi criteria A response is a 10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced computed tomography scan. SWOG's lung cancer response criteria A response is anything that is not progression, including stable disease and tumor shrinkage. They define this concept as the disease control rate. NCCTG and NSABP's metastatic colorectal cancer criteria A response is the proportion of patients progression free at a specific time point. NSABP's locally advanced breast cancer criteria A response is a pathologic complete response instead of tumor shrinkage.
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A more recently developed standard, called the Choi criteria, appears to better predict survival in a small series of patients than RECIST, said Robert S. Benjamin, M.D., chair of sarcoma medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston, at the ASCO meeting. A good response by the Choi criteria is defined as a 10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced computed tomography (CT) scan.
The benefit of using the Choi criteria was confirmed in a second series of GIST patients, Benjamin reported. By RECIST, 28 (48%) of patients showed response and 30 (52%) were nonresponders. Yet there was no statistical difference in time to progression between the two groups (P = .2). By the Choi criteria, however, 49 (84%) were good responders and 9 (16%) were not. The good responders had a longer time to progression than the poor responders (P = .0002). The Choi criteria also more accurately predicted disease-specific overall survival than the RECIST criteria.
"RECIST did not predict for survival in any way. Choi criteria did," Benjamin said.
Although the Choi criteria were developed to evaluate GIST patients, Benjamin showed that the criteria potentially have value in other diseases by reanalyzing previously published clinical trial data testing sorafenib in renal cell cancer patients.
"By using 10% rather than 30% as a cutoff for response, the Choi criteria really does allow for a more sensitive assessment," said Richard Pazdur, M.D., head of the Office of Oncology Drug Products at the FDA's Center for Drug Evaluation and Research. "Also, the criteria aim to rectify the incorrect premise of response rate, as defined by RECIST, that tumor size is directly proportional to the number of tumor cells. ... The Choi criteria try to take this into account."
The Choi Criteria fit the response requirements set forth by David A. Karnofsky in his 1961 paper in Clinical Pharmacology and Therapeutics. It is objective, quantifiable, reproducible, and a surrogate marker for survival. Also, response—or progression—could be detected early and help direct treatment.
"I think we need to start employing multiple modalities" for detecting response, Benjamin said. "Based on CT [scans], the Choi criteria are very effective, but I would add in PET or whatever else you have. If you see evidence of response by any criteria, that trumps nonresponse. And more likely, unless there is evidence that the tumor is growing when you take it out, I would call these patients responders."
Another Group's Search
The Southwest Oncology Group's (SWOG) lung cancer committee is also looking for a better measure of response. At a practical level there are problems using RECIST in non–small-cell lung cancer (NSCLC) because not all patients have measurable disease at the beginning of therapy. Moreover, some patients who do have measurable disease and respond to treatment don't show tumor shrinkage per se; the tumor density may change without substantial changes in the edges of the tumor. This finding would not be considered response by RECIST. Finally, traditional tumor response may not predict survival in this disease, said Lara, who presented the SWOG data.
By contrast, progression in NSCLC is often less equivocal than response. Therefore, Lara and his colleagues hypothesized that if they used nonprogression as a measure of response, as opposed to tumor shrinkage, they could predict survival more effectively. To test this idea, they pooled data from three prior phase III randomized, controlled SWOG trials, which included 984 patients, and examined the data by using a landmark analysis, which asks how many patients are progression free at a set time point. They found that of the 886 alive at 2 months, 62% had stable disease and 19% had complete or partial responses by RECIST, for an overall disease control rate of 81%. The other 18% had progressive disease. They showed that RECIST's partial and complete response criteria correlated statistically significantly with improved survival (P<.001), but the disease control rate was a much stronger predictor (P<.0001).
The group concluded that disease control rate is a more powerful predictor of survival than RECIST response rate.
"Employing disease control rate instead of response rate may enhance clinical trial interpretation and guide clinical practice," he said. SWOG will test the value of this predictor of clinical outcome in prospective trials.
Resisting Tumor Measures
"People criticize RECIST, but they are not clear in their thinking from my opinion. They confuse two issues," said Daniel Sargent, Ph.D., a biostatistician at the Mayo Clinic in Rochester, Minn. "The first is, if we are going to measure a tumor response, let's do it correctly. The second is, is tumor response even worth measuring."
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With that in mind, several clinical trials groups are also moving away from RECIST and other response criteria altogether. Sargent, who specializes in gastrointestinal cancers, said several colorectal cancer studies have indicated that tumor response is a poor surrogate for survival. Therefore, the North Central Cancer Treatment Group (NCCTG) will use the proportion of patients progression free at a specific time point to measure clinical benefit in upcoming trials. Similarly, clinical researchers in the National Surgical Adjuvant Breast and Bowel Project (NSABP) are moving away from RECIST criteria.
"We are using progression-free survival, rather than objective tumor response, as the primary endpoint for our metastatic colorectal cancer clinical trials," said Michael O'Connell, M.D., associate chairman of NSABP and director of Allegheny General Hospital in Pittsburgh. "This is because of the emphasis on new targeted monoclonal antibodies and tyrosine kinase inhibitors in our studies, which may substantially decrease tumor growth rate without causing a shrinkage of tumor." They have already used different criteria in studies testing drugs for locally advanced breast cancer: Pathologic complete response rate was the endpoint rather than tumor shrinkage, as set by the RECIST criteria.
Pazdur emphasized the need for consistency in clinical trials, regardless of which response criteria are used. But Sargent is careful to point out that using progression-free survival (PFS) or time to progression as an endpoint does not negate the need to measure tumors or tumor burden. "PFS is not the answer to RECIST. PFS as an endpoint may make more sense than tumor response as an endpoint, but we still need a methodology to measure PFS and a methodology to measure tumor response. If we use PFS, we will still need a methodology to measure tumor response, and it is going to be, I expect, very similar to what exists for RECIST," but including newer techniques such as PET scans and more precise tumor measurements.
An important benefit of using PFS or time to progression as an endpoint is that each demonstrates the therapeutic benefit for the whole population rather than for individual patients, Pazdur said. But no measure is perfect. "All of these criteria have some degree of subjectivity to it. Obviously if there was such great objectivity here, we would not need expert panels to review these x-rays and determine what is the underlying true response rate," Pazdur said.
He noted that response, as a measure of treatment success, is attractive because it provides immediate gratification to everyone involved, including patients. "I would like to caution that although we have this tremendous love affair with response rates, it is a tremendously dangerous disco that we are dancing here," he said.
As more cytostatic drugs enter the clinic, stable disease will become an increasing issue in both trials and patient care, the importance of which must be established in randomized, controlled trials where clinical benefit can be clearly established by measures of survival.
"Pick your response criteria and stick to it," Pazdur concluded. "The FDA has no dog in this fight."
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