Chemosensitivity Testing

gdpawel

Chemo resistance may be the one reason many ovarian cancer patients are only receiving very short remissions (not cures). The effectiveness of taxol/carboplatin combination is limited because of the late stages of recurrent ovarian cancer and most patients develop resistance. Most cancer patients have the drug bounce off their tumors, doing little if any good. Because of the "dose-intense" nature of the treatment, it also suppresses the immune system, making it possible new tumors to grow because the patient has been rendered unable to resist them.

The body's immune system attacks and eliminates not only bacteria and other foreign substances but also cancer cells. Cancer cells are not foreign to the body but their biological function has been altered in that it doesn't respond to the body's normal mechanisms for controlling cell growth and reproduction. The abnormal cells can continue to grow, resulting in cancer. Much of the body's protection against cancer is carried out directly by cells of the immune system rather than by antibodies circulating in the bloodstream. A malfunctioning immune system can fail to stop the growth of cancer cells.

It has not been shown that platinum-based combination therapy is superior to single agent alkylator therapy. No substantial benefit has been found in giving ovarian cancer patients this therapy. Clinicians have found that the toxic effects of this treatment can cause a lower quality of life for these patients.

Taxol does not improve standard first-line ovarian cancer treatment. Studies (Lancet - August 17, 2002 edition) suggest that for initial treatment of women with ovarian cancer, widely used standard drugs are equally as effective as treatments that include Taxol and Carboplatin and may be considered the preferred treatment as they have fewer side effects. The results of these studies doesn't mean that Taxol has not role in the treatment of ovarian cancer, but they allow doctors and ovarian cancer patients to have choices according to each individual's needs.

Also of note, some combination chemotherapy drugs do permeate (pass through) the blood brain barrier (the system that protects the brain from foreign substances by blocking their passage from the blood). A group of platinum based drugs like Cisplatin and Carboplatin are such drugs and natural substances such as Taxol, also cross the barrier (there are others).

In recent years, the incidence of central nervous system (CNS) metastasis has increased. Unfortunately, some these chemotherapeutic agents weaken the blood-brain barrier (BBB) transiently and allow CNS seeding. Taxol with Carboplatin are two of the drugs that violate the blood-brain barrier (dose dependent). In essence, it breaks down, damages the blood-brain barrier to invite microscopic cancer cells into the Central Nervous System. A NCI observational study in 1995 reported experience in their clinic where recurrent systemic disease occurred in all patients for which they received dose intense Paclitaxel (Taxol) therapy. Brain metastasis was the only site of disease recurrence. I've had numerous cancer patients and loved ones of cancer patients who have written to me (because of my extensive postings and articles on the internet) with their experience with brain mets after dose intense taxol/carboplatin regimens. These patients had either ovarian, breast or lung cancers.

The jury is out on how ovarian cancer spreads. As less is known about this disease than other cancers, this has not been definatively answered and there is controversy amoung the ranks of researchers and clinicians. Many believe it does not spread via the lymph and spreads through cells shedding into ascites in the absominal cavity and then seeding in distant sites. It may spread this way but is probably not the only way as it is found in lymph nodes as well. It has long been believed that it does not metastasize to the brain. However, in recent years, women living longer are developing brain mets. One school of thought believes that platinum drugs (Carboplatin) maybe weakening the blood brain barrier (but that does not explain "every" instance).

If you understand the politics of the Chemotherapy Drug Concession, oncologists have the financial incentive to select certain forms of chemotherapy over others because they receive higher reimbursement. Typically, doctors give patients prescriptions for drugs that are then filled at pharmacies. But medical oncologists buy the chemotherapy drugs themselves, often at prices discounted by drug manufacturers trying to sell more of their products and then administer them intravenously to patients in their offices. the practice creates a potential conflict of interest for these doctors, who must help cancer patients decide whether to undergo chemotherapy or not or to continue if it is not proving to be effective and which drugs to use.

Chemosensitivity Testing

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, expecially 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.

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. In instances of severe drug hypersensitivity, failed therapy, recurrent disease and metastatic disease, it can provide assistance in selecting optimal chemotherapy regimens. Today, chemosensitivity testing has progressed to the point where it is 85% - 90% effective.

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 assyas are also 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.

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

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 http://www.rational-t.com/

Weisenthal Cancer Group, Huntington Beach, CA. Larry M. Weisenthal, MD, PhD. Solid Tumors and Hematologics. 1-714-894-0011 / FAX 1-714-893-3659 / e-mail: 72203,2235@compuserve.com

TealRibbon

Greg,

Thanks for the cheery info on OVCA. You certainly get around on the internet, I have seen your postings on this subject many times. I am so sorry for the loss of your wife. This disease leaves so many wounded in its wake. Gods blessings on you.

gdpawel

TealRibbon said:

Greg,

Thanks for the cheery info on OVCA. You certainly get around on the internet, I have seen your postings on this subject many times. I am so sorry for the loss of your wife. This disease leaves so many wounded in its wake. Gods blessings on you.

One interesting note about Dr. Larry Weisenthal (Weisenthal Cancer Group). Someone very close to him had advanced ovarian cancer a few years ago. She underwent heroic debulking surgery (from pelvic floor to diaphragm) and tissue specimens were sent for chemosensitivity testing which showed resistance to single agent cisplatin and carboplatin and resistance to taxol. The three drug combination of vinorelbine, gemcitabin and high dose tamoxifen was very synergistic and tested sensitive. She was treated with 6 cycles of gemcitabine, carboplatin, vinorelbine and high dose tamoxifen with only minimal nausea and with no other toxicity. Her CA-125 normalized, her bowel symptomatology normalized and she gained back all of the 25 or so pounds which she had lost. She stated that she now feels better than she has in years and will undergo a second laparotomy sometime soon. This person "never" would have benefited with taxol/carboplatin.

gdpawel

There are few more imprecise and drastic measures than chemotherapy as a treatment for cancer. The process involves poisoning a patient's system with toxic chemicals in an effort to kill malignant cancer cells. As one who has personnally seen a loved one suffer, I can attest to its destructive and debilitating side effects. Patients generally need steroid pre-treatment and many have a severe reduction in white blood cells.

There has been no real progess in the treatment of most common forms of cncer. Recent NCI data showed that U.S. cancer mortality rates have increased and age-adjusted cancer mortality rates in response to treatment have not imporved in several decades, despite the introduction of many new drugs. There is a mind-set of cancer culture that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that rewards academic achievement and publication over all else.

Investigators rely on models that are grossly deficient at predicting success. Hundreds of cancer drugs are pushed into the pipeline and many are approved by the FDA, even though their proven activity has little to do with curing cancer. Hundreds of clinical trials of one-size-fits-all therapy in tens of thousands of patients having results that have trivial hypotheses and produce no progress.

Proof of efficacy of a cancer treatment such as chemotherapy requires a randomized trial in which it has been shown that the group treated with chemotherapy experienced significantly increased survival when compared to that of an untreated group. This has never been done. Most claims for the efficacy of a chemotherapeutic agent comes from trials showing shrinkage of tumors or from comparison of survival rates of unmatched groups over time. Unless tumor shrinkage is accompanied by evidence of increased survival, the treatment cannot be claimed to be effective.

Additionally, in clinical trials, many patients are excluded because they could not complete the rather arduous treatment. So randomized comparisons are of healthier treated patients against all the controls, rendering a lot a trials flawed.

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 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 this study.

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.

gdpawel

gdpawel said:

There are few more imprecise and drastic measures than chemotherapy as a treatment for cancer. The process involves poisoning a patient's system with toxic chemicals in an effort to kill malignant cancer cells. As one who has personnally seen a loved one suffer, I can attest to its destructive and debilitating side effects. Patients generally need steroid pre-treatment and many have a severe reduction in white blood cells.

There has been no real progess in the treatment of most common forms of cncer. Recent NCI data showed that U.S. cancer mortality rates have increased and age-adjusted cancer mortality rates in response to treatment have not imporved in several decades, despite the introduction of many new drugs. There is a mind-set of cancer culture that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that rewards academic achievement and publication over all else.

Investigators rely on models that are grossly deficient at predicting success. Hundreds of cancer drugs are pushed into the pipeline and many are approved by the FDA, even though their proven activity has little to do with curing cancer. Hundreds of clinical trials of one-size-fits-all therapy in tens of thousands of patients having results that have trivial hypotheses and produce no progress.

Proof of efficacy of a cancer treatment such as chemotherapy requires a randomized trial in which it has been shown that the group treated with chemotherapy experienced significantly increased survival when compared to that of an untreated group. This has never been done. Most claims for the efficacy of a chemotherapeutic agent comes from trials showing shrinkage of tumors or from comparison of survival rates of unmatched groups over time. Unless tumor shrinkage is accompanied by evidence of increased survival, the treatment cannot be claimed to be effective.

Additionally, in clinical trials, many patients are excluded because they could not complete the rather arduous treatment. So randomized comparisons are of healthier treated patients against all the controls, rendering a lot a trials flawed.

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 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 this study.

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.

The clinical utility and clinical accuracy of cell culture drug resistance testing (chemosensitivity testing) with cell-death endpoints has now been proven beyond doubt.

Data on it may be reviewed at http://www.htaj.com/chemosensitivity_and_resistance_testing.wmv (a 27 minute video on .wmv format)

and http://weisenthal.org/faqw.htm

The cost of drugs is enormous. Patients are followed with serial CT scans, MRIs and even Pet Scans, just to see if a tumor is growing or shrinking. Not to mention the hospitalizations for toxicity, bone marrow transfusions, etc. The point is, the cost of ineffective therapy is truly enormous and assay-testing is particulary good at identifying ineffective therapy.