What are Chemosensitivity and Chemoresistance Testing? |
An ESUN Article
Treatment of patients with unresectable or metastatic sarcoma is based upon selection of active chemotherapy agents identified in phase II clinical trial studies. The approach to treatment in the palliative setting and the sequence of regimens is not standardized. Generally, the first line regimens involve single agents, e.g., adriamycin, ifosfamide or gemcitabine or a combination of two or more agents. Clinical trials with novel agents are ongoing and are generally proposed following lack of response or progression upon treatment with the above mentioned chemotherapies.
The diversity and heterogeneity of these tumors will continue to challenge those faced with developing effective treatments. Given the palliative nature of the treatment, a key question is repeatedly asked which begs an appropriate answer, "Which chemotherapy agent is mostly likely to impact the course of disease and spare the patient of side effects?" This leads to the question, "Is there a series of tests (assays) which could be performed on a portion of the tumor which would predict a response and thereby guide the doctor in selecting a cytotoxic agent?" In my experience, patients are often willing to trade the risk of side effects with the hope of securing a better result.
The observation by Erlich and Pasteur in 1877 of the effects of antimicrobial agents on cultured bacteria is the first description of an in vitro drug response assay.
In a recently published article, Dr. Schrag and her colleagues (Ref. 1) state, "A chemotherapy sensitivity assay refers to any in vitro laboratory analysis that is performed specifically to evaluate whether tumor growth is inhibited by a known chemotherapy drug or, more commonly, a panel of drugs. Sometimes these assays are referred to as chemoresistance assays because they identify agents that do not influence in vitro tumor cell growth. In this technology assessment, we refer to both types of analyses as CSRAs. They are contrasted with empiric therapy, which refers to [a] choice of chemotherapy based on the clinical literature describing outcomes achieved when patients receive particular chemotherapy agents."
Strategies to individualize chemotherapy treatment based upon in vitro drug response assays have been in development yet have met with frustration as the overall positive predictive accuracy is too low to be useful for routine practice. The chemosensitivity assays are most accurate for chemoresponsive diseases (e.g., testicular and Hodgkin’s Disease) where, paradoxically, there is no need for such an assay given the curative first-line regimens.
In a recently published article, Dr. Schrag and her colleagues (Ref. 1) conclude, "The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority."
Often confused, sensitivity and resistance assays are not mirror opposites. The chemosensitivity assays are hampered by a number of systems. The in-vitro predictions of clinical response are influenced by restrictions of drug delivery to sanctuary sites such as the brain or areas poorly perfused. The drugs may be inactivated by circumstances creating areas of hypoxia or acidosis.
Tera Parker-Pope, in her recent analysis of the Schrag report (Ref. 2), she gives examples of people who have been helped by CSRAs in treating their cancer. She goes on in her article to state, "The ASCO panel says the cell-death tests weren't included in the review simply because there weren't any reliable studies assessing them. But even the cell-growth assays appear to be better than nothing. In many studies cited in the ASCO report, twice as many patients who were given assay-guided therapy responded to treatment, compared to patients who were given standard therapies. Even so, the researchers concluded that the studies didn't show that using the tests helped people live longer than those prescribed a standard treatment."
The chemoresistance assay of Kern and Weisenthal (Ref. 3), known as the Extreme Drug Resistance Assay, has been shown to have a greater than 99% accuracy in predicting what drugs will not effect a clinical response. Additional studies have confirmed these findings which are independent of disease type. While the knowledge of drug resistance status may serve as a guide in planning treatment, it is incorrect to assume that this method will avoid ineffective treatment and related toxicities.
In a retrospective analysis of treatment outcomes of women with recurrent ovarian cancer with platinum resistant tumors there was no improvement in outcomes with EDR guided therapy (Ref. 5). At present, research strategies are focused on characterizing the potential mechanisms for drug resistance and sensitivity. Molecular characterization of gene expression in untreated and treated specimens will serve as a model to further characterize pathways for targeted therapeutics.
Additional CSRA Resources:
The Human Tumor Assay Journal is an online compilation of CSRA-related material edited by Dr. Larry Weisenthal.
Among the firms that undertake CSRA testing are (in alphabetical order):
Anticancer Inc.
Genzyme Genetics
Oncotech
Precision Therapeutics, Inc.
Rational Therapeutics Inc.
References
1. Schrag, Garewal, Burstein, Samson, Von Hoff, and Somerfield, American Society of Clinical Oncology Technology Assessment: Chemotherapy Sensitivity and Resistance Assays, J. of Clinical Oncology, Vol. 22, No. 17, September 1, 2004, pp 3631-3638.
2. Parker-Pope T., Custom Chemo: Some Doctors Want It, But Key Panel Says Tests Aren't Ready, Wall Street Journal, September 14, 2004; D1.
3. Kern, D. H. and Weisenthal, L. M., Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures, J. of the National Cancer Institute, Vol. 82, pp 582-588.
4. Loizzi V., et al, Treatment based on EDR drug resistance testing leads to improved outcomes in patients with recurrent ovarian cancer, ASCO 2003 Abstract 189, Oncology News International Vol. 12, No. 4.
V1N5 ESUN Copyright © 2004 Liddy Shriver Sarcoma Initiative.