ADDITIONAL INFORMATION REGARDING OVARIAN CANCER & RADIATION/CHEMOTHERAPHY BY GREG PAWELSKI
When a patient has an infection, doctors often send a sample of infected blood or tissue to a lab where they can grow the bacteria and see which antibiotics are most effective. Chemosensitivity testing is an attempt to do something similar for cancer; fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. It is highly desirable to know what drugs are effective against your particular cancer cells before highly-toxic agents are systemically administered to your body.
One approach to individualizing patient therapy is chemosensitivity testing. Chemosensitivity assay is a laboratory test that determines how effective specific chemotherapy agents are against an individual patient's cancer cells. Often, results are obtained before the patient begins treatment. This kind of testing can assist in individualizing cancer therapy by providing information about the likely response of an individual patient's tumor to proposed therapy. Chemosensitivity testing may have utility at the time of initial therapy, and in instances of severe drug hypersensitivity, failed therapy, recurrent disease, and metastatic disease, by providing assistance in selecting optimal chemotherapy regimens.
All available chemosensitivity assays 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. Some chemosensitivity assays 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.
The goal of all chemosensitivity 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. In addition, some chemosensitivity assays 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.
Fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. Chemosensitivity testing does have predictive value, especially in predicting what "won't" work. Patients who have been through several chemotherapy regimens and are running out of options might want to consider chemosensitivity testing. It might help you find the best option or save you from fruitless additional treatment. Today, chemosensitivity testing has progressed to the point where it is 85% - 90% effective.
Chemosensitivity testing might help you find the best option, or save you from fruitless additional treatment. Another situation where chemosensitivity testing might make particularly good sense is in rare cancers where there may not be enough experience or previous ideas of which drugs might be most effective.
Finally, there has been a veritable deluge of new approvals of cytotoxic drugs in recent years as the tortuous FDA process has been speeded and liberalized. In many cases a new drug has been approved on the basis of a single very very narrow indication. But these drugs may have many useful applications - and it's going to take years to find out. Chemosensitivity testing offers a way of seeing if any of these new drugs might apply to your specific cancer.
Cell Culture Drug Resistance Testing refers to laboratory testing of a patient's own cancer cells with drugs that may be used to treat the patient's cancer. A group of lab tests known as human tumor assay systems (HTAS) can aid oncologists in deciding which chemotherapies work best in battling an individual patient's form of cancer. The assay is a lab test performed on a biopsy specimen containing living cancer cells. It's used to determine the sensitivity or resistance of malignant cells to individual chemotherapy agents. Depending on how well the tumor cells respond to each chemotherapy agent, they are rated as sensitive, resistant or intermediate to chemotherapy. The concept is that you are better off using a chemotherapy drug that your tumor reacts to strongly than one your tumor resists.
There have been over 40 publications in peer-reviewed medical literature showing correlations between cell-death assay test results and the results of clinical chemotherapy in more than 2,000 patients. In every single study, patients treated with drugs active in the assays had a higher response rate than the entire group of patients as a whole. In every single study, patients treated with drugs inactive in the assays had lower response rates than the entire group of patients. In every single study, patients treated with active drugs were much more likely to respond than patients treated with inactive drugs, with assay-active drugs being 7 to 9 times more likely to work than assay-inactive drugs. A large number of peer-review publications also reported that patients treated with assay-tested "active" drugs enjoyed significantly longer survival of cancer than patients with assay-tested "negative" drugs.
Listing of "Reputable" Labs USA:
These labs will provide you and your physician with in depth information and research on the testing they provide.
Analytical Biosystems, Inc., Providence, Rhode Island. Ken Blackman, PhD. Solid Tumors Only. 1-800-262-6520
Anticancer, Inc., San Diego, CA. Robert Hoffman, PhD. Solid Tumors Only. 1-619-654-2555
Impath, Inc., New York, NY. David Kern, MD Solid Tumors and Hematologics. 1-800-447-8881
Oncotech, Inc., Irvine, CA. John Fruehauf, MD. Solid Tumors and Hematologics. 1-714-474-9262 / FAX 1-714-474-8147
Sylvester Cancer Institute, Miami, FL. Bernd-Uwe Sevin, MD. Solid Tumors Only. (especially GYN). 1-305-547-6875
Human Tumor Cloning Laboratory, San Antonio, TX. Daniel D. Von Hoff, MD. Solid Tumors Only. 1-210-677-3827
Rational Therapeutics Institute, Long Beach, CA. Robert A. Nagourney, MD Solid Tumors and Hematologics. 562-989-6455
DiaTech Oncology, Brentwood, TN. Vladimir D. Kravtsov, MD, PhD Medical Director 1-615-294-9033
Weisenthal Cancer Group, Huntington Beach, CA. Larry M. Weisenthal, MD, PhD. Solid Tumors and Hematologics. 1-714-894-0011 / FAX 1-714-893-3659
David Hanbidge is one of many who attribute being alive today to the individualized cancer treatments developed from assays conducted on his cancer. Five years ago, David was diagnosed with small cell lung cancer, a highly lethal form of the disease. "I was 54 and wanted to beat this thing," he says. His surgeon sent tumor tissue to Dr. Robert Nagourney, Medical Director of the Todd Cancer Institute at Long Beach Memorial Medical Center, for chemosensitivity testing. The
results showed that Hanbidge's cancer was sensitive to several novel chemotherapy combinations. Hanbidge underwent assay-directed therapy five years ago and remains free of disease today. "I believe I am cured," he says. Hanbidge is surprised to find that most people believe that this is already standard practice. "Not the case," he tells them. Patients need to know that these assays exist and to insist they be used. "I would do the tests again. Why would you not want to improve your odds?" he asks.
Elizabeth Panke, a Cincinnati pathologist was diagnosed with an aggressive form of ovarian cancer five years ago. The standard treatment, a course of the drugs carboplatin and taxol, failed to stop the cancer. Although doctors advised her against CSRA testing, Dr. Panke, who was dying, sent samples of her tumor cells to two labs. The lab that used the cell-growth method recommended the same drugs that had already failed. The other lab, run by Dr. Nagourney, used the cell-death method, and suggested that the drugs cisplatin and Gemzar worked best on her tumor. Dr. Panke underwent treatment, and three weeks later, her cancer had disappeared. "I was told by all the oncologists I went to not to do this test, that it was a waste of money and time,'' says Dr. Panke. "I'm an anecdotal case but I know a lot of other anecdotal cases who wouldn't be alive if it wasn't for this assay."
When 43-year-old Philadelphia pharmaceutical consultant Mark Fisher was diagnosed with late-stage lung cancer a year ago, he insisted his cancer be tested with a CSRA. In the lab, his tumor didn't respond to standard drugs, and instead the test showed an odd combination of five different drugs had the biggest impact. The drugs eliminated cancer from his body and he is undergoing further radiation therapy for a brain metastasis. "The thing that has surprised me since my chemo is the number of people I've met who haven't even heard of it," says Dr. Fisher.
Studies of Assay-Directed Chemotherapy in Ovarian Cancer
Kurbacher and colleagues (Kurbacher, CM, et al. Anticancer Drugs 9:51-57, '98) treated 25 previously treated patients with ovarian cancer with assay-directed chemotherapy and compared outcomes with 30 non-randomized but clinically well-matched controls. In the control group, there was a response rate of 37%, in the assay-directed group, there was a response rate of 64%. Assay-directed therapy also produced a greater benefit with respect to both response rate and progression-free survival in the subgroup of patients with platinum-resistant disease. A current multi-institutional, international trial is currently in progress to further determine whether assay-directed therapy is superior to empiric therapy.
Loizzi and colleagues (Loizzi, V, et al. Am J Obstet Gynecol. 2003 Nov;189(5):1301-7) treated 50 ovarian cancer patients in their first recurrence following platinum-based therapy with assay-directed therapy and compared clinical outcomes with 50 additional non-radnomized but well-matched patients who received chemotherapy without assay information. In the group with initial platinum-sensitive disease, response rates were 65% for assay-directed chemotherapy versus 35% for empiric chemotherapy. However, in the platinum-resistant group, there was no improvement for assay-directed therapy. Response rates were 21% versus 16% (not significant).
Weisenthal and colleagues (Weisenthal, et al.) recently completed an analysis of the overall survival of 549 ovarian cancer patients with tumors submitted to their laboratory for testing between January, 1993 and January, 2001. Kaplan-Meier survival curve analysis showed median survivals of 44 months for first-line chemotherapy of previously untreated patients and 41 months for second-line chemotherapy of patients meeting the clinical definition of initially platinum-sensitive disease.
In addition, recently performed analysis of long-term survival of ovarian cancer patients who had tumor biopsy specimens referred to their laboratory for cell culture drug resistance testing (CCDRT or chemosensitivity testing), with the data analyzed as a function of whether or not the attempted chemosensitivity testing was evaluable or in-evaluable. Approximately 95% of specimens submitted for testing yielded an evaluable result, while approximately 5% were in-evaluable for reasons relating to poor viability of the specimen, insufficient yield of tumor cells in the specimen.
This data represented the survival of patients for whom tumor biopsy specimens were submitted to the laboratory for cell culture drug resistance testing (chemosensitivity testing). There was no information regarding what forms of chemotherapy was actually administered to these patients. The Kurbacher study and Weisenthal series employed assays using cell death endpoints, while the Loizzi study employed a cell proliferation endpoint.
It is important to note what has been known for more than 40 years, that ovarian and other forms of cancer represent heterogenous diseases where the tumors of different patients have different responses to chemotherapy, and where important treatment advances will require individualizing treatment based on testing the individual properties of each patient's cancer. This is far superior to empiric analaysis which which results in a one-size-fits-all treatment paradigm. Cell culture drug resistance testing improves patient survival in chemotherapy for ovarian cancer.
Cell Culture Drug Resistance Testing (Chemosensitivity Testing) Predicts for Patient Survival in Ovarian Cancer
Konecny, et al. (Gynecol Oncology 77:258-73,'00) tested the tumors of 38 previously untreated FIGO stage III patients who received treatment (independent of assay results) with one of serveral platinum-based regimens. Drugs were tested as combinations: cicplatin + cyclophosphamide, cisplatin + Taxol, etc. Twenty nine assay-sensitive patients had a significantly longer progression-free survival (median 28.5 vs 12.6 months, P=0.033) and overall survival (median 46 vs 18 months, P=0.03), compared with nine patients classified as assay-resistant. The ATP endpoint was used in this study.
Taylor, et al. (Eur J Gynaecol Oncol 22:278-82,'01) tested the tumors of 93 previously untreated FIGO stage III and IV patients who received treatment (independent of assay results) with either a platinum-based regimen (71 patients) or with a single agent alkylator (22 patients). Drugs were tested as single agents, with the tumor classified as sensitive, if at least one drug used in subsequent treatment was active in cell culture drug resistance testing and as resistant, if all drugs were inactive in cell culture drug resistance testing. Fifty-one assay-sensitive patients had a median survival of 23 months, while fourty-two assay-resistant patients had a median survival of 19 months. The three year survival of the sensitive group was 36% compared to 16% in the resistant group, while five year survivals for the sensitive group were 24% versus 12% for the resistant group (P=0.033). The MTT endpoint was used in this study.
Holloway, et al. (Gynecol Oncology 87:8-16,'02) tested the tumors of 79 previously untreated patients with optimally debulked stage III/IIc disease (63 cases) and suboptimally debulked stage III or stage IV disease (16 cases). Patients were treated with platinum/taxol if cell culture drug resistance testing did not show resistance to Taxol or else cyclophosphamide/platinum, cyclophosphamide/doxorubicin/platinum or platinum alone if cell culture drug resistance testing showed resistance to Taxol. Median progression-free survival was 6 months in 17 cases with platinum resistance in the assay, compared to 24 months for 62 cases exhibiting sensitivity to platinum. Median overall survial for the resistant group was 24 months, but was not reached in the sensitive group. Estimated 5 year survival was 19% in the resistant group, compared to 68% in the sensitive group. The tritiated thymidine endpoint was used in
Nagourney, et al. (Gynecol Oncology 88:35-39,'02) tested the tumors of 17 previously treated ovarian cancer patients with the combination of gemcitabine + cisplatin. Assay results were cut at the median IC50 value for the drug combination. Patients with sensitive tumors had an 85% progression-free survival probability at 6 months, compared to approximately 28% for assay-resistant tumors, and Kaplan-Meier progression-free survival curves were superior in the assay-sensitive group (P2=0.012). Overall survival was also superior in the assay-sensitive group (P2=0.05). The DISC assay endpoint (delayed loss of cell membrane integrity) was used in this study.
Weisenthal, et al correlated the results of cell culture drug resistance testing to both cisplatin and carboplatin with long-term, overall patient survival in ovarian cancer. Specimens from previously treated patients were significantly more resistant to platinums than were specimens from untreated patients, and this difference was most pronounced in the case of poorly-differentiated tumors. Well-differentiated tumors had significantly greater platinum resistance than poorly-differentiated tumors. In untreated patients, resistance to cisplatin and (separately) to carboplatin correlated significantly with long-term survival, as reported prospectively. This relationship was strongest in the case of poorly-differentiated tumors. There was also a significant relationship between platinum resistance and patient survival in previously treated patients who relapsed greater than 6 months following the most recent chemotherapy with the primary, platinum-based regimen.
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Last Updated On: 02/08/2006
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