A just-published study in ovarian cancer raises the question of the distinction, if any, between “chemosensitivity” and “chemoresistance” (or “drug resistance”). It has been my position, for a long time, that these distinctions are largely semantic and not of useful clinical relevance. Resistance is the relative absence of sensitivity and sensitivity is the relative absence of resistance.
A number of authors have tried to claim superiority for one type of assay over another, when, in reality, both assays are attempting to make the same distinction — which drugs are the more promising and which are the less promising for a given clinical application? One good example of this attempt to claim the semantic high ground is the very complicated argument made by John Fruehauf and Dave Alberts in a letter published in the Journal of Clinical Oncology. (In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins, DOI: 10.1200/JCO.2005.05.281).
The letter by Fruehauf and Alberts is ironic in the context of the just-published paper by Matsuo, K. et al. (Low drug resistance to both platinum and taxane chemotherapy on an in-vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian, and peritoneal cancer. Int. J Cancer, 2009 DOI: 10.1002/ijc.24654). Fruehauf and Alberts extol the virtues of the drug resistance side of the coin, specifically referring to the soft agarose, tritiated thymidine assay of Kern, with statistical definitions of drug resistance originated by me (Kern and Weisenthal, JNCI, 1990). Yet both the Matsuo study (above) and another recent study (just presented at the June, 2009 ASCO meeting) show no useful correlation between the “extreme drug resistance” endpoint and any clinical outcome in ovarian cancer, while the Matsuo study shows highly (and independently) significant correlations between the “low drug resistance” (which could just as easily be called “chemosensitive”) endpoint with both progression-free and overall survival.
Correlations between “Sensitive” vs “Resistant” cell death assay results and clinical response to chemotherapy in published studies
Several things are evident:
1. In all individual studies, patients treated with drugs classified as “sensitive” had a higher response rate than that for all the patients in each individual study.
2. In all individual studies, patients treated with drugs classified as “resistant” had a lower response rate than that for all the patients in each individual study.
3. In all individual studies, patients treated with drugs classified as “sensitive” had a MUCH high response rate than for patients treated with drugs classified as “resistant.”
4. Averaging up all of the studies, patients treated with drugs classified as “sensitive” had an 8-fold higher response rate than patients treated with drugs classified as “resistant.”
I think that all of the above data point to the fact that differences between “chemosensitivity” and “chemoresistance” are entirely semantic and that the proper role for these assays is to direct attention towards agents in the “sensitive” (or “low resistance”) group and away from agents in the “resistant” (or “low sensitivity” group).
- Larry Weisenthal/Huntington Beach, CA USA
Tags: CCDRT, cell culture assays, ITRT
It amazes me not only that some private insurance carriers don’t like to pay for Oncologic In Vitro Chemoresponse Assays, but that they don’t emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments.
The validation standard that private insurance companies is accepting from molecular profiling tests is accuracy and not efficacy. The “bar” has been instantly lowered. No longer will it be essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these molecular profiling tests is prove that the test has a useful degree of accuracy. However, when it comes to the validation standard they want for cell-based profiling tests, it is efficacy.
The cell-based profiling tests have the same entitlement to be judged by the same validation standard as molecular profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the “profile” at the whole cell level.
However, profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the test, which is to identify efficacious therapies irrespective of drug mark-up rates.
The evidence in support of these assays is more than sufficient to justify the funding of comparative effectiveness research (CER) – validation trials, if any are truly needed, as claimed – speciously and self-servingly – by the medical establishment.
Everyone is scared to death – and rightly so – at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.
Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.
The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.
It explains the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies. The pressure, in fact, is so great that the companion diagnostics they’ve approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.
I think that in both of these areas – private insurance carriers and the FDA – there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately.
Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments – everybody wants that – but also, in the “here and now,” using currently-available cell-based assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.