Taxol Doesn't Treat Common Breast Cancer

[dee]

Taxol Doesn't Treat Common Breast Cancer

By MARILYNN MARCHIONE, AP Medical Writer

Wed Oct 10, 6:37 PM
The widely used chemotherapy drug Taxol does not work for the most common form of breast cancer and helps far fewer patients than has been believed, surprising new research suggests.
If further study bears this out, more than 20,000 women each year in the United States alone might be spared the side effects of this drug or similar ones without significantly raising the risk their cancer will return. That would be roughly half of all breast cancer patients who get chemo now.
"We want to make sure these data are correct before withholding it (Taxol) from some patients ... the stakes are high," said the lead researcher, Dr. Daniel Hayes of the University of Michigan. "On the other hand, we don't want to keep a therapy that doesn't work."
In the study, Taxol did the most good for women who had overactive HER-2 genes _ the target of the newer breast cancer drug Herceptin. These women were about 40 percent less likely to have a recurrence if they received Taxol.
Conversely, Taxol did not significantly help women whose tumors were HER-2 negative and were being helped to grow by estrogen. This is the most common form of the disease.
The differences were revealed by a new analysis of a study done in the 1990s, using modern genetic tools that were not available at that time.
"The days of 'one size fits all' therapy for patients with breast cancer are coming to an end," Dr. Anne Moore of Weill Cornell Medical College wrote in an editorial accompanying the study in Thursday's New England Journal of Medicine.
"Oncologists have a responsibility to their patients to be aware of this report."
The original study involved more than 3,000 women whose cancer had spread to nearby lymph nodes but not widely throughout the body. This is the situation of about one-fourth of the 175,000 women diagnosed with breast cancer in the U.S. each year.
Researchers tested adding paclitaxel, sold as Taxol by New York-based Bristol-Myers Squibb Co. and now also in generic form. They gave it after surgery to remove the cancer and treatment with the chemo drugs Adriamycin and Cytoxan.
Taxol improved survival and became a new standard of care. But the drug frequently causes neurological side effects including numbness and tingling in the hands and feet. In the original study, 18 percent of women had this problem months and even years after taking Taxol.
Even more worrisome has been the growing evidence that some women do not benefit as much from chemo as others. Hayes and other researchers wondered whether that was true in their Taxol study.
They retrieved frozen tissue samples from 1,500 of the original participants, did genetic tests to better identify their types of cancer, and discovered big differences in who had responded to the drug.
The study was paid for by grants from the federal government and a breast cancer foundation. Several researchers consult for Bristol-Myers Squibb.
"We should have done this a long time ago," but the tools were lacking and researchers now have the advantage of longer follow-up of these women, said another senior author, Donald Berry. He is biostatistics chief at the University of Texas M.D. Anderson Cancer Center.
Berry is reanalyzing another earlier Taxol study, and Moore urged other scientists to do the same.
With more evidence, "we can begin to use the biology of the cancer to decide whether the chemotherapy will work" before subjecting women to it, Hayes said.
The typical four-cycle treatment with generic paclitaxel costs $7,000 or more, including infusion fees that doctors charge. Insurance typically pays most of this.
For now, many doctors will be reluctant to skip Taxol or other chemo, said Dr. Julie Gralow, a cancer specialist at the University of Washington School of Medicine. Some may fear lawsuits if the cancer recurs and the chemo wasn't given, she said.
"It's just so much easier to give the chemotherapy and know you've been super-aggressive."
However, Kris Miller, a 54-year-old former nurse from Chelsea, Mich., said patients should be given the choice. She has had problems since taking Taxol two years ago for a type of breast cancer that the new research suggests would not respond to the drug.
"Most people recover from it, and I guess I'm one of those unfortunate ones that did not," she said of the side effects. "I have severe numbness and tingling, mostly in my feet. It becomes painful by the end of the day. It never goes away."
"I hope they give people that option," to weigh the risks and benefits and possibly skip Taxol, she said. "If I was going through it now, I would like to have that information."
___
On the Net:
New England Journal: http://www.nejm.org

[Lani]

for the sake of Alaska Angel and others node negative
This study was only done in node positive patients (interestingly because chemotherapy was recommended in the US to all invasive bc patients whether node negative or node positive)

I think that is why they are quoting 20,000 as the number of women who might avoid chemo--had they done the study includiing node negative patients and IF they got the same result, there would probably be four to five times as many women angry this morning.

Was that purposeful? Or did they just assume that the node negatives would be covered by the TAILOR RX study out in a few years (which really does not answer the same question as it uses a methodology/algorith derived on tamoxifen treated patients who received chemotherapy regimens which I don't believe are required to be identical).

So when repeating the study, be sure you know it counts only for node positive patients...but as node negative patients are considered less likely to recur than node positive patients (at least when looking at breast cancer as a whole vs subsets of it) it would seem that the absolute (vs relative) benefits/of lack of benefits of taxanes would be even smaller

How about now adding serum her2neu testing, bone marrow biopsies and/or Circulating tumor cell testing to the ER and her2 testing(and hopefully eventually gene expression profiling) to even better delineate who is most likely to recur/metastasize, thus treating those most likely to benefit and avoiding over treatment of those not likely to benefit (and more likely to have lifelong problems from the treatment)

Getting off my soapbox...

Hope this helped

[gdpawel]

The most widely used chemo drug for breast cancer and it does not work for the most common form of breast cancer, and helps far fewer patients than has been believed? This would be roughly half of all breast cancer patients who get chemotherapy now.

MD Anderson's Donald Berry says that "we should have done this [study] a long time ago." He says that "tools" were lacking to do this, so they gave virtually every breast cancer patient Taxol, just in case? I'm sorry, the "tools" were there. They've kept them under a breadbox for the last fifteen years.

Taxol is an extremely potent drug, often producing a number of side effects in patients. Side effects can include severe allergic reactions, cardiovascular problems, infections developing from white blood cell deficiencies, apolecia, joint and muscle pain, irritation at the drugs injection site, low red blood cell count, mouth or lip sore, and numbness or burning in the hands and feet.

They say that for now, many doctors will be reluctant to skip Taxol for fear of lawsuits if the cancer recurs and Taxol wasn't given. It's just so much easier (and more money to be made) to give the Taxol and know you've been "super-aggressive."

Oncologists have the responsibility to their patients to be aware of this report and patients should be given the choice not to receive Taxol.

According to the National Cancer Institute's official cancer information website on "state of the art" chemotherapy, no data support the superiority of any particular regimen. It would appear that published reports of clinical trials provide precious little in the way of guidance.

I agree with University of Michigan's Dr. Hayes, we should use the biology of the cancer to decide whether the chemotherapy will work before subjecting women to it. The problem is that few drugs work the way oncologists think and few of them take the time to think through what it is they are using them for. More emphasis should be put on matching treatment to the patient (personalized medicine), through the use of individualized pre-testing.

http://content.nejm.org:80/cgi/conte...rt/357/15/1496

Is Taxol the Vioxx of Cancer Drugs?

In the last decade, the incidence of central nervous system (CNS) metastasis has increased. The very first reference I found of this was a NCI observational study in 1995 that 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. The cerebellum was involved in two out of three patients, presenting with headache, dizziness, unsteady gait, nausea and vomiting (all the things that happened to my wife in 1998, after her adjunct Taxol treatment in 1997).

This is what led me to research this further and found out about the rarity of ovarian cancer cells metastasizing to the brain. Ovarian cancer uncommonly involves the nervous system. Brain metastasis was a "rare" complication of ovarian cancer with only 67 well-documented cases in medical literature, until 1994. A multi-institutional study of 4027 ovarian cancer patients over 30 years identified only 32 cases while an autopsy study of ovarian cancer reported an incidence of 0.9%. Even more "rare" is the occurrance of Carcinomatous Meningitis. Until 1994, there have been only 14 cases reported. This presentation is similar to metastases from other solid tumors (breast, lung). (1)

In 2002, I came across a study by Christos Kosmas, M.D., consultant medical oncologist, Department of Medicine and Medical Oncology Unit at Helena-Venizelou Hospital, Athens, Greece entitled, "Carcinomatous Meningitis: Taxane-Induced," which found what is called "dissemination after taxane-based (Taxol) chemotherapy." The study conclusions stated that Carcinomatous Meningitis (a CNS metastasis) after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared retrospectively to non-taxane-treated patients. (2)

A commentary by Dr. Lawrence N. Shulman, Vice Chair for Clinical Services and Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, in the September, 2002 issue of The American Journal of Oncology Review, describes the complete lack of progress in the chemotherapeutic treatment of metastatic breast cancer since 1970. Dr. Shulman noted that a retrospective comparision of a well-characterized "standard-dose" database with a less well-characterized "high-dose" database suggested that there was increased early mortality for "high-dose" therapy. (3)

An editorial by Drs. V. Valero and G.N. Hortobagyi in the March 15, 2003 issue of the Journal of Clinical Oncology, reviewed all of the large, prospective, randomized trials published comparing taxane-based chemotherapy regimens. They conclude that none of these regimens have increased either complete response rates or overall survival, with median survivals remaining at two years or less, or precisely the same results which were being obtained over thirty years ago. (4)

In 2004, as reported at the 27th Annual San Antonio Breast Cancer Symposium, using a technique that quantifies circulating tumor cells, German investigators from Friedrich-Schiller University in Jena, have shown that neoadjuvant chemotherapy with paclitaxel (taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding could help explain the fact that complete pathologic responses do not correlate well with improvements in survival.

In the study, according to Katharina Pachmann, M.D., professor of experimental oncology and hematology, breast cancer patients undergoing neoadjuvant chemotherapy gave blood samples in which epithelial antigen-positive cells were isolated. Such cells are detected in most breast cancer patients but are rarely found in normal subjects. The investigators measured the levels of cirulating tumor cells before and during primary chemotherapy with several different cytotoxic agents.

Paclitaxel (taxol) produces the greatest degree of tumor shrinkage but also the greatest release of circulating tumor cells. In three different paclitaxel-containing regimens, circulating cell numbers massively increased, whereas tumor size decreased. These cells remained in the circulation for at least five months after surgery.

The tumor shrinks, but more cells are found in the circulation. This corresponds with a high pathologic complete response during paclitaxel treatment, but in the end, this is not reflected in improved survival. These cells are alive in the circulation. What this study has shown, so far, that in three different paclitaxel (taxol) containing regimens, as the tumor collapses (a clinical response, not cure), it produces the greatest release of circulating tumor cells. The study has not looked at any other combination regimens. (5)

The results of these kinds of study are coming out slowly and quietly (now that Taxol is off-patent) and indicate that taxol containing regimens didn't prolong survival over other more conventional and less expensive cytotoxic drugs. Even before the advent of the CellSearch technique, it had been observed in various "cell death" assays, that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from taxane therapy, even in cases where the majority of the cells are being killed by taxanes. It may indeed give clincial response (tumor shrinkage), sometimes impressive, however, these are mostly short-lived and relapses after a response to taxanes (Taxol) are often dramatic. (6)

With these cells being alive in the circulation, it may mean that a patient with invasive breast cancer without lymph node involvement (where systemic treatment "may" benefit), or a patient with invasive breast cancer that involves lymph nodes (where systemic treatment is "usually" recommended), would need additional (anti-estrogen) treatment, such as Tamoxifen (it may be given alone or in addition to chemotherapy, if given).

It has been shown that Tamoxifen treatment will reduce circulating tumor cells in some patients, but not all. So they develop a drug called Herceptin. Why? It has been shown that Herceptin treatment will reduce circulating tumor cells in patients with HER2-negative tumors, but less pronounced in HER2-positive tumors.

Does Herceptin really work on these circulating tumor cells? A study from the Dana Farber Cancer Institute identified central nervous system metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. (7)

In 2006, another report that CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen. Central Nervous System Relapse in Patients With Breast Cancer Is Associated With Advanced Stages, With CK-19 mRNA-positive Circulating Occult Tumor Cells and With Her2/neu-positive tumors.

During the past years it has been frequently observed that patients with breast cancer treated with a taxane-containing chemotherapy regimen, either in the adjuvant setting or in the metastatic setting, presenting central nervous system (CNS) involvement as the only evidence of disease progression. More studies were therefore interested to evaluate the incidence of CNS metastases in patients with early and advanced breast cancer treated with a taxane-containing chemotherapy regimen and to identify predictive factors for CNS relapse.

Recent studies reported that breast cancer patients who received a taxane-containing chemotherapy regimen had a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen. There are also data indicating an increased risk for brain metastases in breast cancer patients receiving trastuzumab (Herceptin).

In the present study it was also possible to confirm the initial clinical observation that breast cancer patients who receive a taxane-containing chemotherapy regimen have a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen.

The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement could be that taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration. Taxanes are unable to penetrate the intact blood-brain barrier, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS.

Also, paclitaxel is exported from the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries, as an explanation for the low concentrations of taxanes in the CNS.

Furthermore, the detection of cytokeratin 19 (CK-19) and of mRNA-positive circulating tumor cells (CTCs) in the peripheral blood and the bone marrow of patients with breast cancer is correlated with increased incidence of relapse.

The aforementioned data suggest that taxanes may not penetrate well into the CNS, and therefore the CNS may represent tumor 'sanctuary' sites for taxane-containing chemotherapy regimens. A difference in the incidence of CNS relapses between patients with breast cancer and other solid tumors treated with taxanes was observed. (8)

The percentage of patients that must respond to a drug before it is approved by the FDA varies from as high as 80% to as low as 20%. Thereafter, it is used routinely for all patients with the same form of cancer, though unfortunately a drug that helps one person does not necessarily mean it will help all patients with the same diagnosis. The response rate for Taxol for FDA approval was 30%.

Taxol (Paclitaxel) is known as a taxane type of chemotherapy drug. Taxol is given into a vein, but in order for the body to absorb the drug, it must first be dissolved in a solution. The compound wouldn't dissolve very much in any solution. It was discovered that something Taxol would dissove in the might work in a reasonably safe intravenous solution in humans. It was an elixir made of castor oil and marketed as Cremophor EL. It was the only answer. However, this castor-oil carrier is suspected as the culprit behind the misery which includes nausea, vomiting, joint pain, appetite loss, brittle hair and tingling sensations in hands and feet (neuropathy). (9)

The American Cancer Society has mentioned that the solution can cause dangerous allergic reactions in many people, so patients "must" first take other drugs like steroids and antihistamines in "hopes" to prevent a bad reaction. The solution can also leach chemicals from regular plastic tubes used to deliver medication, so Taxol must be given through special tubing.

A new drug for breast cancer (Abraxane) is a new form of Taxol (Paclitaxel). Abraxane does not need to be dissolved in the castor oil solution and does not require special equipment to be given to patients. However, more of the women on Abraxane had numbness and tingling in their hands and feet. And more suffered nausea and vomiting, diarrhea, muscle and joint pain and anemia.

Taxol (Paclitaxel) is an extremely potent chemotherapy drug, often producing a number of side effects in patients. Side effects of Taxol (Paclitaxel) include severe allergic reactions, cardiovascular problems (such as changes in blood pressure), infections developing from white blood cell deficiencies, complete hair loss (apolecia), joint and muscle pain, irritation at the Taxol and other chemotherapy drugs injection site, low red blood cell count, mouth or lip sore, numbness or burning in the hands and feet, and stomach upset/diarrhea. (10)

There is a molecular basis for the peripheral pain caused by Taxol. It appears to be caused when the drug binds to a protein and initiates improper calcium signaling, researchers at Yale School of Medicine reported in a study published in the Proceedings of the National Academy of Sciences. This response leads to side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms. These serious side effects limit the drug's effectiveness. Peripheral pain becomes worse with continued use and increased dosages lead to persistent and irreversible pain.

The binding protein is called neuronal calcium sensor (NCS-1). When paclitaxel (taxol) binds to NCS-1, it makes the cell more sensitive to normal signals and increases the magnitude and frequency of changes in calcium. Over time, increased calcium levels activate an enzyme (calpain) that degrades proteins, especially NCS-1. Calcium signals are needed for nerves to be stimulated and to respond and the loss of NCS-1 makes it more difficult to generate any calcium signals. While the loss of NCS-1 stops the protein interaction that is causing the inappropriate calcium signals, it also decreases the ability to have normal responses. (11)

Sources:

(1) National Cancer Institute
(2) American Journal Clinical Oncology 2002;63:6-15
(3) Am J Oncology Rev 1(3):169-170, '02
(4) J Clin Oncol 21(6): 959-962, '03
(5) Oncol News Int'l, Vol 14, #5, May '05
(6) Cell Function Analysis
(7) Cancer 2003 Jun 15;97(12):2972-7
(8) Breast Cancer Res. 2006;8(4)2006 BioMed Central, Ltd.
(9) Office of Research, Florida State University
(10) Bionumerik
(11) PNAS 104: 11103-11108 June 20, 2007

[medicare]

The widely used chemotherapy drug Taxol does not work for the most common form of breast cancer and helps far fewer patients than has been believed, surprising new research suggests.
If further study bears this out, more than 20,000 women each year in the United States alone might be spared the side effects of this drug or similar ones without significantly raising the risk their cancer will return. That would be roughly half of all breast cancer patients who get chemo now.
"We want to make sure these data are correct before withholding it (Taxol) from some patients ... the stakes are high," said the lead researcher, Dr. Daniel Hayes of the University of Michigan. "On the other hand, we don't want to keep a therapy that doesn't work."

[Hopeful]

Taxol is an extremely potent drug, often producing a number of side effects in patients. Side effects can include severe allergic reactions, cardiovascular problems, infections developing from white blood cell deficiencies, apolecia, joint and muscle pain, irritation at the drugs injection site, low red blood cell count, mouth or lip sore, and numbness or burning in the hands and feet.

Let's add to that the disturbing SE that a percentage of patients who lose their hair on this drug will not have it grow back, making it disfiguring, as well.

Hopeful