AP Biotechnology Writer, Paul Elias, wrote an article this week that described how while the cost of cancer drugs have skyrocketed, the benefits are less apparent. It’s been more than 30 years since we declared a war on cancer and although there have been some real triumphs, and some great advances, the overall picture is not good. Tomorrow one of my closest friends is going into the local oncology center for the removal of what we all hope are some benign breast lumps. This post is dedicated to her, and to all those with cancer or at risk for cancer. Part of the issue is surely environmental, and we have much more to learn about what causes cancer and whether the toxins that we put into the planet are coming back to attack us. Part of the issue, though, is how we approach cancer care. THCB contributor Greg Pawelski has written before about the need for more chemosensitivity testing, and now writes on how we can use what we know to more effectively care for patients.
We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perform well-designed, prospective, randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination. The problem is not with using the prospective, randomized trial as a research instrument. The problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance (i.e. do most cancers prefer Pepsi or Coke?).
There are 60-80 different therapeutic drug regimens out there, any one or in combination can help cancer patients. The system is overloaded with drugs and underloaded with wisdom and expertise for using them. Government and academic clinical investigators have failed to support the individualization of chemotherapy through laboratory testing, in favor of attempts to identify "one size fits all treatments" through trial and error testing which has consumed tens of thousands of human lives. This entire effort has been a colossal failure and a colossal waste of human and financial resources.
One of the main problems in providing effective chemotherapy is the situation that every patient is unique. Tumors grow and spread in different ways and their response to treatment depends on these characteristics. The amount of chemotherapy that each patient can tolerate varies considerably from patient to patient. Therapeutic protocols currently in use are limited in their effectiveness because they are based on the results of clinical trials conducted on a general patient population, yet no two patients are alike. Chemosensitivity testing can help to improve the efficacy of cancer therapies on an individual patient basis.
Without the information provided by chemosensitivity testing, oncologists have the freedom to choose between multiple different drug regimens, all of which have approximately the same probability of working. Some of these regimens are highly profitable to oncologists. Other regimens are much less profitable. Pre-screen testing takes away a lot of this freedom to choose and narrows the selection to those drugs that have the highest probability to be successful but may have lower profitability for the oncologist. This cuts into the oncologist’s bottom line, though it benefits the patient.
The hallmark of the disease is heterogeneity, yet the powers that be insist on trying to homogenize it, rather than tailoring treatment to the individual nature of the disease. If we devoted 10% of the "one-size-fits-all" resources to developing and testing methods to individualize therapy, we’d have actually made some progress at lowering the costs of cancer drugs.
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Gregory – I read a post by you on some other site that stated that 34% of patients treated with Hereptin got brain metasteses 6 months after the start of Herceptin. Could you direct me to the article from whence these data came?
Thank you very much – Susan Mann
Cell-based Assay Associated with Survival in Ovarian Cancer Patients
http://cancerfocus.net/forum/showthread.php?t=1114&highlight=Rational+Therapeutics
Targeted Cancer Therapy Improved with Ex-Vivo Chemosensitivity Analysis
http://cancerfocus.net/forum/showthread.php?t=560&highlight=Rational+Therapeutics
Functional profiling with cell culture assays that predicts for patient survival in ovarian cancer
http://cancerfocus.net/forum/showthread.php?t=253&highlight=Weisenthal+Cancer+Group
Functional profiling with cell culture assays for targeted drug therapy
http://cancerfocus.net/forum/showthread.php?t=241&highlight=Weisenthal+Cancer+Group
Cancer and cancer care is a huge topic that weighs on the minds of many Americans. Having someone else determine your standard of care can be a scary experience for the one receiving the treatments. If you are a healthcare manager or case manager you know how hard it is to get consistent and fair external peer reviews and you also know that it is imperative to provide the patient with the best possible care while keeping costs down.
Allmed is hosting a webinar on the latest standards of care when it comes to oncology. Sign up for free here if you are interested.
http://www.allmedmd.com/resources/downloads/webinar4_download.html
Cancer and cancer care is a huge topic that weighs on the minds of many Americans. Having someone else determine your standard of care can be a scary experience for the one receiving the treatments. If you are a healthcare manager or case manager you know how hard it is to get consistent and fair external peer reviews and you also know that it is imperative to provide the patient with the best possible care while keeping costs down.
Allmed is hosting a webinar on the latest standards of care when it comes to oncology. Sign up for free here if you are interested.
http://www.allmedmd.com/resources/downloads/webinar4_download.html
Cell Culture Drug Resistance Tests (CCDRTs) are laboratory tests in which fresh specimens of human neoplasms are cultured in the presence and absence of anti-cancer drugs. At the conclusion of the cell culture, measurements are made to determine whether the drugs are effective in either killing the neoplastic cells and in/or preventing their growth. Test results correlate with drug effects in the patient, with respect to both treatment response (tumor reduction) and patient survival.
The logic is that if the drug kills tumor cells from an individual patient in a test tube, then the drug is more likely to be effective when administered to a patient. Conversely, a drug that does not kill the patient’s cancer cells, even at concentrations significantly higher than can be achieved in the patient, then it is unlikely to be effective.
The concept is to isolate cells from a fresh specimen obtained from a viable neoplasm. These cells are cultured in the continuous presence or absence of a drug, most often for 3 to 7 days. At the end of the culture period, a measurement is made of cell injury, which correlates directly with cell death (apoptosis).
The general measurements of cell death are the DISC assay method, the MTT assay method, the ATP assay method, and the flurescein diacetate assay method. These four endpoints produce valid and reliable measurements of cell death. They also correlate well with each other on direct comparisons of the different methods.
As with other laboratory tests, the determination of the efficacy of CCDRT is based on comparisons of laboratory tests with patient response (clinical correlations). The hypothesis to be tested with clinical correlations is that above-average drugs effects in the assays correlate with above-average drug effects in the patient, as measured by both response rates and patient survival.
Patients with test results in the “sensitive” range were more likely to respond than the total patient population as a whole. Conversely, patients with test results in the “resistant” range were less likely to respond than the patient population as a whole. On average, patients with assays in the “sensitive” range were 3.5-fold more likely to respond than patients with assays in the “resistant” range.
New “Targeted” drugs
Several new “targeted” drugs have been introduced during the last few years. Most of them have been developed for use in solid tumors but some have also emerged for hematological maligancies. These new “targeted” drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.
Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. Given the technical and conceptual advantages of CCDRTs together with their performance and the modest efficacy of therapy prediction based on analysis of genome expression as published so far, there is reason for a renewal in the interest for CCDRTs for optimized use of medical treatment of malignant disease.
There was a recent study using an angiogenesis assay, describing correlations between cell culture assay results (cell death in response to Iressa exposure) and survival of 31 patients with non-small cell lung cancer who had received extensive prior chemotherapy. These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered the assay laboratory tests. There were striking correlations between test results and patient survival.
By inhibiting anti-apoptosis with Iressa (or even Tarceva), the cells undergo apoptosis and die. And it is detected at the whole cell level in the cell culture assays and reported out — prospectively — that this correlates strikingly with patient survival. Not only is it a very important predictive test, but it is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a “gold standard” to develop new DNA, RNA, and protein-based tests of drug activity.
Gene Expression Profiling
Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of CCDRT. CCDRTs can actually integrate all the gene expression into one convenient test result.
In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.
What are the data supporting the use of testing DNA, RNA and Protein expression? Two retrospective studies from two Harvard-affiliated hospitals, showing response, but not survival advantages, with a grand total of twenty six correlations. And a subsequent study, presented in the July 14, 2005 issue of the New England Journal of Medicine from another laboratory that did not show correlations between gene mutations and patient survival (Volume 353:133-144 Number 2).
Laboratory, Clinical and Radiographic Tests
The traditional criteria ever used to evaluate laboratory, clinical and radiographic tests have been the performance characteristics (predictive accuracy, sensitivity and specificity) and perceived utility in the judgement of the clinician who orders the tests.
None of the available tests used in clinical decisions regarding treatment selection have ever been tested for there ‘efficacy.’ This includes estrogen receptor, progesterone receptor, Her2/neu, Oncotype DX, EGFR amplification/mutation, immunohistochemical staining for tumor classification, bacterial culture and sensitivity testing, CT, MRI, FDG Pet Scans to measure tumor response to treatment.
The only data supporting any of them relate to test ‘accuracy,’ and there is a total lack of information regarding test ‘efficacy’ (randomized trials with outcome measurements for diagnostic tests).
If you compare/contrast papers published so far trying to relate EGRF by IHC, EGFR mutations, EGFR expression, etc. All of the prior studies, published in places like Science and the New England Journal of Medicine, were entirely retrospective, not always consistent, often showed only response correlations (not survival correlations) in patients.
Choices in Drug Selection
It is within each practitioner’s prerogative to order CCDRT, providing that he/she specifies to the patient what the treatment would be in the absence of the assay and be clear if and how the information will be used to inform treatment decision making. Until the clinical trial approach has delivered curative results with a high success rate, the clinical autonomy to integrate promising insights and methods, like CCDRT, remains an essential component of patient advocacy.
One conservative application of the assays would be to identify the most active of the otherwise equally acceptable regimens. Another would be to eliminate the most inactive of the regimens and chose from among the rest on the basis of other clinical factors, including cost. In the setting of relapsed, refractory disease, CCDRT provides a mechanism for choosing from an even larger number of potential drug choices, many of which will not be tested in prospective, randomized trials for years to come.
If test results are used to assist in the selection of a regimen chosen from a series of otherwise reasonable alternatives, then patients will never be harmed by using the test result, and best available evidence strongly indicates that they will often be helped.
CCDRTS have been well proven to have predictive ‘accuracy’ with that of estrogen receptor, progesterone receptor, Her2/neu and the newer molecular tests. These are diagnostic tests and should be held to that criteria, and not to that of therapy.
In light of the precious little in the way of guidance from clinical trials with respect to best empiric therapy (where the only thing that has been proven to correlate with treatment decisions is reimbursement to the prescribing oncologist) and the importance of basing cancer treatment at least in part on patient preferences, it is entirely reasonable to support judicious application of laboratory tests which have been well characterized with respect to test ‘accuracy.’
An abstract on chemosensitivity testing from the American Society of Clinical Oncologists Annual Conference in 1998, summarized a paper from a National Cancer Institute study which looked at thirteen different studies that searched into assay-directed drug sensitivity testing for patients with cancer. It was noted that there were many different cancers represented in these studies, however, it was seen that the chemotherapy response rates went up using assay-directed therapy, as compared to using physician-directed therapy, and patient survival increased using assay-directed therapy, as compared to using physician-directed therapy.
A prospective, randomized clinical trial of physician’s choice chemotherapy versus ATP assay-directed chemotherapy in non-surgically debulked, platinum-resistant ovarian cancer was presented by Ian Cree, M.D., Ph.D., Director, Translational Oncology Research Centre, Portsmouth, England at the May, 2005 ASCO meeting in Orlando, Florida. The results were highly suggestive of an effect due to the assay, and the most successful drug regimens used were nearly all developed using the assay. UK results in cancer are always lower than in the US for a variety of reasons. Part of this is probably lead time bias, but data on surgical debulking may be part of the explanation. Patients in the US get a whole lot more surgery along the way than in Europe.
The Gynecologic Oncology Group (GOG) has decided to move forward with a study in platinum-resistant ovarian cancer, utilizing the “EDR” assay to direct chemotherapy. However, this assay is specifically designed to identify “inactive” drugs, and not “active” drugs. In this light, the EDR assay has the advantage of telling you who will “not respond” but cannot in any way change the negative outcome by selecting an “active” alternative. At least it’s a start.
There are other medical oncologists that are making proposals for a separate study, a first-line, no prior therapy, randomized trial with “head to head” comparison of several assays (EDR, ATP, DISC, MTT, as well as Caspase 3/7). These assays correlate very well with each other on direct comparisons of different methods. Different methods of assay results should be applied in choosing a particular drug regimen to be used in treating an individual patient’s cancer.
http://weisenthal.org/ova_1.htm aswell
Here are five studies on the correlation between the results of assay-directed chemotherapy and patient survival in ovarian cancer:
http://weisenthal.org/ov_surv.htm
Other studies of assay-directed chemotherapy in ovarian cancer:
http://weisenthal.org/assay_directed_therapy_in_ovarian_cancer.htm
Can you cite a study showing the correlation between in-vitro cancer cell sensitivity and patient survival?
Can you cite a study showing the correlation between in-vitro normal cell (such as fibroblast) sensitivity and adverse side effects?
It is my impression that such correlations are low, at least using current testing techniques.