Chemotherapy Resistance Testing in Lung Cancer Patients

[gpawelski]

A study led by a lung cancer surgeon at Jefferson Medical College suggests that oncologists should take more advantage of laboratory tests that have the potential to help determine a lung cancer patient's resistance to chemotherapy drugs. All too often, patients with non-small-cell lung cancer (NSCLC) are given standard chemotherapy drugs after surgery in a "hit or miss" fashion, without doctors knowing which drugs might have better chances than others to help treat the tumor. Steps should be taken to validate such resistance tests in clinical trials.

Reporting recently in the Journal of Thoracic and Cardiovascular Surgery, Thomas d'Amato, M.D., Ph.D., assistant professor of surgery at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and his colleagues analyzed data on 4,571 non-small cell lung cancer tumors' resistance to four pairs of chemotherapy agents, each of which included a standard platinum-based drug: carboplatin and paclitaxel (taxol), cisplatin and navelbine, cisplatin and docetaxel and cisplatin and gemcitabine.

Using the "extreme drug resistance" test to monitor cancer resistance in a test tube, they found resistance in 30 percent of tumors to carboplatin-paclitaxel, 24 percent to cisplatin-navelbine, 42 percent to cisplatin-gemcitabine and 27 percent to cisplatin-docetaxel.

"Clinical unresponsiveness for most patients with lung cancer to standard chemotherapy may be explained and measured accurately with an assay that measures a specific patient's tumor resistance to a given cytotoxic drug," Dr. d'Amato says. "This assay has the potential to guide therapy and can be used to tailor a patient's therapy by avoiding chemotherapeutic agents that will likely be ineffective."

Lung cancer is the leading cause of cancer death around the world. According to the American Cancer Society, an estimated 213,380 new cases of lung cancer (both small cell and non-small cell) will occur this year in the United States. About 160,390 people will die of this disease.

Chemoresistance testing isn't new. Dr. d'Amato says that it has been applied successfully in ovarian and recurrent ovarian cancer and has helped many oncologists rule out chemotherapy agents because of toxicity and a low probability of clinical response. While the prevalence of drug resistance to common chemotherapy drugs in non-small cell lung cancer is alarmingly high, he says, the assay's usefulness in tailoring appropriate therapies that help patients has yet to be proven.

"I believe the resistance assay is terribly underused," he says. "Having this assay available for a number of years, it is surprising that it has not been integrated into any clinical trials. In this age of targeted agents, it is time to avoid empiric therapy if possible, particularly in cancer. We don't cure many with lung cancer with chemotherapy."

Dr. d'Amato's group also used the resistance assay to attempt to find markers - specific genes - that may be associated with resistance to chemotherapy, based on patient tumor resistance and individual gene expression profiles.

"In this era of empiric therapy, particularly with novel agents that are expensive, molecular testing needs to be paired to these studies," he says. "Clinical trial data is needed proving an agent's usefulness before clinical oncologists will use it."

d’Amato, Thomas A. Adjuvant Chemotherapy and the Role of Chemoresistance Testing for Stage I Non-Small Cell Lung Cancer. Thorac Surg Clin 17 (2007) 287–299.

Dr. d'Amato's paper discusses the drug resistance in lung cancer (particularly Taxol-resistance). Dr. Christos Kosmas, consultant medical oncologist, Department of Medicine and Medical Oncology Unit at Helena-Venizelou Hospital, Athens, Greece entitled, "Carcinomatous Meningitis: Taxane-Induced," has published a paper about Carcinomatous Meningitis: Taxane Induced? Which found what is called "dissemination after taxane-based (Taxol) chemotherapy.

http://cancerfocus.net/forum/showthread ... b1e5&t=648

[RandyW]

This makes a lot of sense. If I read it right I think, (Its early here this morning), this says that you should get a test to make sure the chemo will work on the tumour befoer etaking the chemo regiment, Right???? Great idea, and would save money in long run and help more people with treatments available to the patients. Thanks for the info, good to hear from you!

[gpawelski]

The "extreme drug resistance" test (EDR) is a soft agarose tritiated thymidine assay, which is a direct descendent of the original Salmon/Von Hoff Human Tumor Stem Cell or Clonogenic assay of the late '70s/early '80s. The assay is excellent at identifying drugs most likely not to work.

All available cell-based assays (cell-death and cell-growth) are able to report drug "resistance" information. Resistance implies that when a patient's cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow.

The goal of all cell-based tests is to determine the response of a patient's cancer cells to proposed chemotherapy agents. Knowing which chemotherapy agents the patient's cancer cells are "resistant" to is important. Then these options can be eliminated, thereby avoiding the toxicity of ineffective agents.

Some cell-based assays (cell-death) also are able to report drug "sensitivity" information. Sensitivity implies that when a patient's cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.

Cell-death assays can predict tumor cell sensitivity, or which agent would be most effective. Choosing the most effective agent can help patients to avoid the physical, emotional, and financial costs of failed therapy and experience an increased quality of life.

The EDR cell-growth assay is much less useful than are the various cell-death assays for the purpose of identifying effective treatment regimens. It doesn't mean that the information provided by the EDR assay is not helpful, it's that there are better ways of getting more useful information like higher evaluability rates, more drugs tested per specimens, multiple drug concentrations tested, and more extensive clinical validation of assay results.

The cell-death assays are not growing anything. They are testing a drug or combinations of drugs (cytotoxic and/or targeted) with cells that are in their natural state (live/fresh), three dimensional tumor cell clusters. Clusters maintain natural cell-cell interactions.

A personal treatment plan would be cheaper than the conventional (empiric) treatment protocol. Treating a patient with a drug or combinations of drugs that is most beneficial (sensitive), the first time around, eliminating most or all of the medication to manage side effects, and eliminating drugs that would be "resistant" to the cancer cells.

This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free and overall survival.

Literature Citation:

Eur J Clin Invest 37 (suppl. 1):60, 2007

Thorac Surg Clin 17 (2007) 287–299.

[gpawelski]

Ann Surg Oncol. 2009 Oct;16(10):2848-55. Epub 2009 Jul 16.

Survival among patients with platinum resistant, locally advanced non-small cell lung cancer treated with platinum-based systemic therapy.

d'Amato TA, Pettiford BL, Schuchert MJ, Parker R, Ricketts WA, Luketich JD, Landreneau RJ.

Forum Health-Western Reserve Health System, Youngstown, OH, USA.

Adjuvant chemotherapy following resection of locally advanced non-small cell lung cancer has become the standard of care. Clinical application of in vitro chemotherapy resistance assays may identify patients who are more or less apt to respond to platinum-based adjuvant chemotherapy. Tumor specimens obtained from patients with resected non-small cell lung cancer (NSCLC) were submitted for the Extreme Drug Resistant (EDR) assay. In vitro chemotherapy resistance to platinum agents correlated with a decreased survival, as did resistance to platinum-based doublet therapy. Patients with tumor low drug resistance to platinum-doublets had a 78% survival at 36 months. This retrospective study supports selective use of the EDR assay in clinical practice and merits continued evaluation of the EDR assay in future NSCLC clinical trials.

BACKGROUND: Recent adjuvant chemotherapy trials after resection of stage II and III non-small cell lung cancer (NSCLC) have identified important survival differences among patients with immunohistochemical evidence suggesting platinum resistance. No clinical information exists regarding the impact upon survival of patients treated with platinum agents who exhibit cellular evidence of their tumors' resistance to platinum. We evaluated the utility of the extreme drug resistance (EDR) assay to predict mortality among a consecutive group of stage II through IV NSCLC patients receiving adjuvant or definitive platinum-based chemotherapy after resection or surgical biopsy.

METHODS: The Extreme Drug Resistance (EDR) Assay is a clinically validated cellular proliferation assay used to test tumors for chemotherapy drug resistance. Based on response in the EDR assay, tumor specimens from stage II through IV NSCLC patients were segregated into three groups: extreme drug resistant (EDR), intermediate drug resistant (IDR), and low drug resistant (LDR). Patient survival was evaluated after platinum-based chemotherapy.

RESULTS: Platinum IDR/EDR was statistically significant in predicting shorter overall survival (29.8 months vs. 15.6 months) among platinum IDR/EDR-resistant patients compared with LDR patients (P = 0.047). Median survival was 16.6 months for patients with IDR/EDR to platinum and any other second agent of doublet therapy compared with patients with LDR to any platinum-based doublet where median survival was not achieved (P = 0.0268).

CONCLUSIONS: This is the first study to demonstrate the utility of the EDR assay to predict poor clinical outcome when platinum-based therapy is used to treat patients with biological evidence of tumor resistance to platinum. These data corroborate the finding of recent studies evaluating possible molecular correlates to poor response to specific chemotherapeutic agents.

PMID: 19609620 [PubMed - indexed for MEDLINE]

[jaminkw]

Not having an identified tumor, I'm guessing I wouldn't be a candidate for this. But if I did, I know I would certainly welcome it. I've responded to the chemo treatments I've had thus far but dread any new ones. You never know what or how bad the side effects will be OR if it will work. Interesting. Thanks.

Judy

[gpawelski]

A published study in ovarian cancer raised the question of the distinction between "chemosensitivity" and "chemoresistance" (drug resistance). The 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.

The Matsuo, et al study (Int J Cancer. 2009 Dec 1;125(11):2721-7) and another study presented at the 2009 ASCO meeting (J Clin Oncol 27:15s, 2009 suppl; abstr 5504) showed no useful correlation between the "extreme drug resistance" (cell-growth assay) endpoint and any clinical outcome in ovarian cancer. While the Matsuo, et al study showed highly significant correlations between the chemosensitive (cell-death assay) endpoint and both progression-free and overall survival.

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" higher 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.”

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” (“low resistance”) group and away from agents in the “resistant” (“low sensitivity” group).

When clinically relevant and accepted drugs may have the same efficicay, and a tumor is "resistant" to one of them, it is within the standard of care to give the drug with the least "resistance" and/or the drug with the most "sensitivity."

My personal belief is in having additional support of drug patient-specific activity as determined by extensive laboratory pre-tests to bolster the clinical justification of the drug(s) chosen, with no economic ties to outside healthcare organizations; recommendations made without financial or scientific prejudice.

http://www.ncbi.nlm.nih.gov/pubmed/1953 ... d_RVDocSum

http://www.asco.org/ASCOv2/Meetings/Abs ... ctID=32065