Chemosensitivity Testing

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, 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.

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 assays 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/

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 / e-mail: mail@weisenthal.org

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.

I read this message a couple of days ago, right after my oncologist said I should be on Taxol Carboplatin. I sent your message to him with a letter saying I was not going to do that regimen because of the blood brain barrier issue. I also had never heard of chemosensitivity testing. How do you know about it and is it routine? I'm afraid they didn't do it with my tumor but I'm going to ask.

Thanks for this wealth of info. I'm not sure that my questions were actually answered. Is it routine to do this testing and should I be able to find out the results?

Also - what information do you have that indicates Taxol crosses the blood brain barrier? I found a monograph on it that said it didn't.

I seriously doubt that your doctors have any understanding whatsoever of the "current" technologies of chemosensitivity testing, which are based on "cell-death" and not "cell-growth." In 1983, publications introduced assays based not on cell-growth, but on cell-death. This was a good five years before dissemination of understanding of the concept of apoptosis. Because clinical oncologists did not understand about apoptosis, these pioneering publications with cell-death (instead of cell-growth) endpoints were ignored, and neither clinical trials nor the application of cell-death drug resistance assays were supported by academic and private practice clinical oncologists.

This testing has been available since 1993. In fact, Dr. William Grace, a practicing oncologist and director of cancer research and chief of medical oncology at St. Vincent's Hospital and Medical Center (NYC) has been utilizing assay-testing since 1995. He believes it is unethical not to use chemosensitivity testing in his practice. The problem with standard empiric chemotherapy is that it's like taking a machine gun and shooting everything in the way and hoping you get the cancer cells along with it. If you target the therapy, meaning you're only treating patients who will benefit from the treatments, you'll eliminate patients from having undue chemotherapy side-effects without any benefit.

The fact that some doctors may not agree or do not understand isn't stopping many cancer patients from taking this matter into their own hands, and sending their live path specimens off to one of the fifthteen private labs for assay-testing to be done. There is approximately 10,000 individual patient specimens currently being submitted for testing by more than 1,000 clinical oncologists, surgeons and pathologists annually in the United States. It seems probable that a self-educated oncologist, genuinely on the cuttin-edge would tend to be aggressive in actual treatment beyond mere rhetoric and make use of running tests on the biopsy before selecting a chemotherapy option.

Both fluid and solid tumor (200mg in size) specimens may be sent out via Federal Express or another overnight courier service for testing at one of more than a dozen labs around the country. Note that the choice of a lab is not a geographical consideration, but a technical consideration. All of the labs that are listed are experienced and capable of providing very useful information. However, the labs vary considerably with regard to technologies, approach to testing, what they try to achieve with the testing, and cost. These private laboratories have been offering these assays as a non-investigational, paid service to cancer patients, the average cost being about $2,000, in a situation where 20 different drugs and combinations are tested, at two drug concentrations in three different assay systems.

Assay-tests could be performed from ovarian cancer cells in pleural fluid (fluid from the cavity that surrounds the lungs) which is evidence of Stage IV ovarian cancer, or from Ascites (an abnormal accumulation of fluid in the abdomen), and of course lymph nodes. A worse case scenario is the spinal fluid (spinal tap) but only to diagnose Leptomeningeal Carcinomatous (ovarian). The labs will provide you and your physician with in depth information and research on the testing they provide, and results.

As in the Lancet studies, widely used standard drugs could be 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 no role in the treatment of ovarian cancer, but they allow doctors and ovarian cancer patients to have choices according to each individual's needs. And the way to know each individual's needs is where chemosensitivity testing comes into play. Ovarian cancer assays show results which do not support treatment with standard Taxol/Platinum as first line therapy.

Tissue specimens sent in for assay-testing could show synergy to combination Taxol and Carboplatin or tests could show resistance to combination Taxol and Carboplatin. In case of resistance, the test could show (as an example) that a novel combination of Vinorelbine, Gemcitabin and high-dose Tamoxifen may be very synergistic and test sensitivie. Patients treated with this three drug combination can have only minimal nausea and with no other toxicity.

It was thought that the protection provided by the blood-brain barrier (BBB) may isolate the nervous system tissue from the anti-tumor effects of chemotherapy. Until the 90's, chemotherapeutic drugs were meant for the vascular system. They never could penetrate the blood-brain barrier. Scientists developed drugs that could permeate the blood-brain barrier. It was thought that this would greatly increase the effectiveness of the drug. However, it can invites other substances into the central nervous system, like resistant microscopic cancer cells.

Cancer that progresses during treatment or recur within six months of treatment is considered "refractory." After treatment is completed, the surviving drug-resistant cells often proliferate rapidly and metastasize. Numerous cancer patients have the drug(s) bounce off their tumors, doing little if any good. The chemo drug that the cancerous tumor is resistant to can actually spread the cancerous cells, rather than the cancer itself spreading.

For more information about assays showing results which do not support treatment with Taxol and Platinum as first-line therapy, go to the below web url and visit the other urls posted previously.

http://www.weisenthal.org/ovataxol.htm

I just spoke with the gynecologic oncologist who did the cancer removal as part of they surgery I went through in February. He said they don't do the testing with the first cancer surgery but he really had no explanation of why not. He said they only do it when the cancer rercurs. He also had no response about the blood brain barrier issue w/ Taxol-Carboplatin. Do you have any statistics (I did read the link you sent) regarding whether either or both of those ALWAYS permeate the blood brain barrier or if it's only in certain higher doses? Also, do you work at the Simon Weisenthal lab?

Interesting that your gyn-onc had no response?? Other than the 1995 NCI observational study and a prospective evaluation study (AJCO 2002;63:6-15), I have not seen any one else caring to reseach the associations.

I am a retired individual. Because of my personal experiences, I've been an advocate for a number of cancer subjects over the last five years. HBO Therapy for radiation-induced necrosis, abolition of the Chemotherapy Drug Concession, as well as encouraging the technologies of Individualized Therapy.

A group of leading chemotherapy experts have been working to promote research and clinical application of cancer therapies tailored for each individual patient. Their approach is in stark contrast to standard or empiric therapy, in which chemotherapy for a specific patient is based on results from prior clinical studies.

They advocate use of scientifically-proven class of chemosensitivity and resistance assays (CSRAs) that measure drug-induced cancer cell-death (apoptosis). I believe that patients should be afforded access to such technology as an alternative to the off-the-shelf "best guess" therapy typically administered.

Gregory,

Thanks for the latest info. I'm going back to the oncologist tomorrow afternoon to discuss both of the issues that you've raised, the effectiveness of Taxol and the affect platinum drugs have on the BBB. In your first posting you said that Taxol crosses the BBB but I pulled down a monograph on the subject (pdf downloadable from this URL
http://www.cancercare.ns.ca/inside.asp?cmPageID=202&action=d ) that flatly says it doesn't cross.
I know that the Carboplatin is always given after the Taxol. What info do you have that indicates that Taxol also permeatest the BBB?
Does it permanently leave holes or can the BBB recover itself? I've been trying to research this but have not found anything that talks about this issue. Also, do you know if the permeation is dose dependent or not?

Thanks in advance,

Delia

PS:Have you any experience/knowledge about Topotecan? The monograph for it says it does so 30% of the time, whatever that means.

Taxol permeates blood brain barrier:

http://clincancerres.aacrjournals.org/cgi/content/full/5/3/4

http://www.brain-tumour.net/neurosurgery/chemotherapy/index.

Taxol plus Carboplatin versus Standard Chemotherapy

http://www.weisenthal.org/icon_3.htm

Thank you for the links. I'm finding some too.
I hope you are getting some sleep there in PA unless you moved back to San Diego (I'm in San Francisco).

Delia

Ideally, it should be on the basis of currently available, fresh tumor cell culture drug resistance testing (CCDRT). In the absence of CCDRT, previously-untreated patients with poorly-differentiated tumors should be treated with single agent carboplatin, while patients with moderate (or moderate-well) differentiated tumors should be treated with a regimen which includes one or more non-platinum drugs.

There is a clear relationship between platinum resistance and tumor differentiation. Poorly-differentiated tumors are, on average, significantly more sensitive to platinums than are well-differentiated tumors. In contrast, Taxol resistance is not related to tumor differentiation. In the absence of CCDRT, single agent platinum may be the most appropriate first line chemotherapy for poorly-differentiated tumors, while platinum/Taxol may be more appropriate for well-differentiated tumors.

It should be recalled that the original American cooperative group trials of platinum versus non-platinum combination therapy showed that the main group of patients who benefited from platinum were patients with poorly-differentiated tumors.

Sources:

August 17 2002 edition of The Lancet

January 2004 Annual Meeting of ASCO