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