The purpose of CCDRT is to take drugs, all of which have an "average" chance of working, and then to sort these drugs into 4 groups (with respect to an individual patient's cancer). Without CCDRT, the drugs have an "average" probability of providing clinical benefit, where "average" is the historical experience or the "clinically-expected" probability of benefit for a given drug in a given clinical situation. With CCDRT, drugs are sorted into categories: above-average, average, below-average, and very-much below average.
CCDRT results are reported out as either: "Sensitive," "Intermediate," "Resistant," or "Extremely Resistant" (labeled "EDR," which is an acronym for "extreme drug resistance"). A tumor which is "sensitive" to a given drug will have an above-average probability of being destroyed or damaged by the drug, and the patient will have an above-average probability of deriving benefit from treatment with the drug, all other factors being equal (where "all other factors" includes whether or not the patient's medical condition is consistent with the patient being able to safely receive the drug in question). A tumor which is "intermediate" to a given drug will have an average probability of being destroyed or damaged by the drug, and the patient will have an average probability of deriving clinical benefit. A tumor which is "resistant" to a given drug will have a below-average probability of being destroyed or damaged by the drug, and the patient will have a below-average probability of deriving clinical benefit. A tumor which has "EDR" has a considerably below-average probability of being destroyed or damaged by the drug, and the patient will have a considerably below-average probability of deriving clinical benefit.
Note that being "sensitive" to a drug does not guarantee clinical benefit for treatment with the drug. Likewise, being "resistant" to a drug does not guarantee a lack of clinical benefit. And the probability (e.g. 10%, 20%, 40%, 60%, 80%, etc.) of a drug working depends on both the "clinically expected" historical experience and upon the drug resistance category (sensitive, intermediate, resistant, EDR) in which each drug falls, as determined by CCDRT. For example, if a given drug has a "clinically expected" response rate of 40% and the CCDRT result is "sensitive," then the drug has a 68% probability of providing clinical benefit (a clinically meaningful reduction in the amount of cancer). If, however, the CCDRT result is "resistant," then the drug would have only an 8% probability of providing clinical benefit. If the CCDRT result is "EDR," then the drug would have only a 4% probability of providing clinical benefit.
The above indicates how the CCDRT results should be applied in choosing a particular drug regimen to be used in treating an individual patient's cancer. The oncologist should be guided by (1) historical experience with different drug regimens and (2) the patient's general medical condition (including age, kidney function, prior treatment history, etc.). Based on (1) and (2), it is determined which types of drug regimens are reasonable to use (typically, there will be a half dozen or more treatment regimens which would all have about the same chance of working, if chosen empirically). Then (3) the results of CCDRT are considered. CCDRT will sort the different reasonable treatment regimens into the different groups (above-average, average, below-average, and very-below-average), and this will direct attention away from regimens less likely to provide benefit and toward regimens which are more likely to provide benefit.
Following are three repesentative assay reports (chosen from CCDRT performed on patients with ovarian cancer). In the future, examples of other forms of cancer will be added. Shown additionally are explanations of (1) how the assay distinctions between "sensitive," "intermediate," resistant," and "EDR" are made and (2) what is the relationship between "clinically expected" probability of response and "assay-predicted" probability of response, given the different categories of CCDRT results ("S," "I," "R," and "EDR").
Example #1(PDF file): Previously-treated ovarian cancer. Progressive disease following carboplatin/Taxol, topotecan, and Doxil. "Clinically-expected" (or Pre-Test) response rate to a wide variety of reasonable treatment options ranged from 5 to 20%. After CCDRT, all drugs and regimens were found to test in either the "EDR," "Resistant," or "Intermediate" ranges, with corresponding assay-predicted probabilities of clinical response ranging from 2 to 25%. These results indicate that the most promising of the tested treatment options were pentamethylmelamine (surrogate for the clinical drug hexamethylmelamine), single agent gemcitabine, or the gemcitabine/cisplatin combination. These potential treatments offered probabilities of clinical benefit ranging from 12 to 25% (as opposed to 2 to 4% for the drugs testing in the "EDR" and "resistant" ranges). Which, if any, of these potential treatments to choose versus choosing a form of hormonal therapy versus choosing participation in a clinical trial of investigational therapy was a matter of clinical judgement and patient wishes.
Example #2(PDF File): Previously-treated ovarian cancer. Progressive disease while on primary treatment with carboplatin/Taxol, followed by progressive disease while receiving tandem autologous stem cell transplants for tandem high dose chemotherapy treatments (costing more than $200,000). CCDRT results showed resistance to most agents tested, including platinums. Single agent gemcitabine had intermediate activity, as did single agent topotecan. The gemcitabine + carboplatin combination was highly synergistic and showed good activity (i.e. tested in the "sensitive" range). Prior to CCDRT, the clinically-expected response probabilities ranged from 10 to 20%. Following CCDRT, these treatment options were assigned to categories of below-average, average, and above-average response probabilities, ranging from 2% to 38%. The gynecologic oncologist and patient elected to treat with the carboplatin + gemcitabine combination, and the patient, who had never responded to any prior therapy, had a complete disappearance of previous massive, unresectable, abdomen and pelvis-filling disease, with the patient remaining in remission for four years.
Example #3(PDF File): Previously-untreated ovarian cancer. The patient's tumor tested in the "sensitive" range to cisplatin and carboplatin, but in the "resistant" range to taxanes (Taxol and Taxotere). In view of two large, multi-institutional prospective, randomized trials showing no advantage to treatment with Taxol/platinum over single agent platinum when given to patients in the absence of CCDRT, these results support treatment with single agent carboplatin, or perhaps to treatment with the gemcitabine/platinum or platinum/etoposide combinations. At a bare minimum, owing to poor activity of Taxol in the assay, the absence of synergy between platinum and Taxol, and to the lack of clear-cut benefit in unselected patients of platinum/Taxol over single agent platinum in prospective, randomized clinical trials, this patient should have selective dose reduction of Taxol, with maintenance of full dose platinum, in the event that dose attenuation is required to manage toxicity as repeated treatment cycles are given.
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