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Old 02-19-2012, 09:32 AM
gdpawel gdpawel is offline
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Default Taxanes (Taxol)

Researchers have identified a genetic biomarker that can predict a patient's likelihood of experiencing taxane-induced peripheral neuropathy, which is characterized by a pain and numbness in fingers and toes and can keep patients from receiving the intended amount of their therapy, complicating treatment.

The marker in the RWDD3 gene. The findings came from a large genome-wide association study of 2,204 early-stage breast cancer patients enrolled in a clinical trial that used weekly paclitaxel for 12 weeks in all arms. This marked the first time a genetic biomarker has been reported for taxane-induced neuropathy.

Dr. Bryan P. Schneider of the Simon Cancer Center at Indiana University, Indianapolis, and his colleagues, looked for variations in DNA called single nucleotide polymorphisms (SNPs) in each patient. During the study and follow-up period, 613 of the patients reported experiencing grade 2-4 neuropathy.

By looking at more than 1.2 million SNPs in each patient, Dr. Schneider and his colleagues were able to identify genetic subgroups most likely to develop neuropathy.

Those who carried two normal nucleotides in a specific regulatory gene had a 27% chance of experiencing neuropathy. But those who carried one normal nucleotide and one SNP had a 40% chance and those who carried two SNPs had a 60% chance.

The researchers also found that older patients and blacks were much more likely to have peripheral neuropathy. The likelihood of neuropathy increased 12.9% with every decade of age. Blacks saw a two-fold increase in the likelihood of developing neuropathy.

The study was funded by the Eastern Cooperative Oncology Group under the National Cancer Institute.

There is another novel agent for ovarian cancer. It's a new target in the ErbB family. Epidermal growth factor is an important target in many cancers, including human epidermal growth factor receptor 2 (HER-2) in breast cancer. These have not made much of an impact in ovarian cancer, but there are other members of the ErbB family, including ErbB-3, a target that is commonly present in ovarian cancer. More than half of all cases have increased expression with amplification. It provides a rather interesting target because of an autocrine growth loop. Ovarian cancer cells secrete a compound molecule called "neuregulin," which actually binds to this target and turns on pathways that lead to increased growth and drug resistance. So, it is an important pathway to try to block. MM-121 is an antibody that very selectively blocks HER-3 and dimerizes with HER-2 to turn on a pathway that essentially leads to increased growth and drug resistance. It is a target that makes sense in ovarian cancer, and may be used in combination with weekly paclitaxel. This may be sensible because weekly paclitaxel is a very good treatment for relapsed ovarian cancer, but it needs to get better at reversing resistance to it.

One of the mechanisms for resistance actually involves a pathway downstream of HER-3 -- the MAP kinase (AKT) pathway. If they can block that, they might be able to enhance the activity of weekly paclitaxel. The results of a feasibility study showed that MM-121 (which is an intravenous antibody given as a loading dose and then weekly) adds very little toxicity to weekly paclitaxel. It is probably not any different. They saw that the efficacy is promising, but this was not a randomized trial; it was a fairly small feasibility study that led to a randomized study, which has already half completed recruitment. So we may see the results of the first randomized trial of weekly paclitaxel with MM-121, the first anti-HER-3 targeted agent in ovarian cancer.

Liu J, Patel R, Kato G, et al. A phase 1 study of the anti-ERBB3 antibody MM-121 in combination with weekly paclitaxel in patients with advanced gynecological and breast cancers. Program and abstracts of the 2012 Annual Congress of the European Society for Medical Oncology; September 28-October 2, 2012; Vienna, Austria. Abstract 974.
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Last edited by gdpawel : 10-12-2012 at 03:56 PM. Reason: additional info
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Old 02-19-2012, 09:33 AM
gdpawel gdpawel is offline
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Default Residual neurotoxicity in ovarian cancer patients

Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study

Sandro Pignata, Sabino De Placido, Rosalbino Biamonte, Giovanni Scambia, Giovanni Di Vagno, Giuseppe Colucci, Antonio Febbraro, Marco Marinaccio, Alessandra Vernaglia Lombardi, Luigi Manzione, Giacomo Carteně, Mario Nardi, Saverio Danese13, Maria Rosaria Valerio, Andrea de Matteis, Bruno Massidda, Giampietro Gasparini, Massimo Di Maio, Carmela Pisano1 and Francesco Perrone

Abstract

Background:

Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for
advanced ovarian cancer.

Methods:

120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria.

Results:

55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy.

Conclusion:

A significant proportion of patients with advanced ovarian cancer treated with firstline carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.

BMC Cancer 2006, 6:5 doi:10.1186/1471-2407-6-5

[url]http://www.biomedcentral.com/content/pdf/1471-2407-6-5.pdf
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Old 02-19-2012, 09:35 AM
gdpawel gdpawel is offline
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Default Side Effects of Taxol Use

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.

Some other common Taxol side effects can trigger hypertension or problems with the heart, such as arrhythmias, congestive heart failure, or bradycardia. Many patients on chemotherapy become anemic, and that can trigger further cardiac complications.

Chemotherapy in general can have a deadly side effect: heart trouble. However, the "antimicrotubules" class of chemotherapy drugs, of which Taxol is a member, is supposed to be relatively rare (they really don't know). The Platins (Carboplatin and Cisplatin) may be much different. Heart problems are more common than people think, affecting up to 25% of cancer patients. According to MD Anderson cardiologists, many doctors do not adequately monitor their patients or manage their care to minimize the health risk. Chemotherapy can help achieve a clinical response (remission), but treatments can also hurt heart muscle by reducing the hearts ability to pump.

Problems can range from insignificant to so severe that a patient can die from the heart damage rather than the cancer itself. In many cases, cancer treatment heart damage isn't detected until it is advanced because traditional heart imaging tools often miss heart muscle damage.

There are problems that traditional heart imaging tests, like nuclear scans (Pet Scan or PET/CT Scan) or ultrasound, often miss until the damage is serious. Wake Forest University Medical Center is testing Magnetic Resonance Imaging as a better way to detect heart trouble in cancer patients. The Center says it is a very promising technology because to date there has not been a method to precisely monitor the heart function or blood flowing through blood vessel.

In patients who are showing heart trouble, the hope is that doctors can tweak therapy and avoid serious damage to the heart. It is hoped to get a two-fold win, detection of cancer and treatment and a nice working heart and cardiovascular system. A high-tech heart check may one day help to wipe out a potentially deadly side effect of cancer treatments. The MRI heart check is still under study, early results show the technology is more effective at detecting early heart muscle damage than the traditional methods.

Ironically, this is what it says on the Warning Label for Taxol (30, 100, 300)

Taxol (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Severe hypersensitivity reactions characterised by dyspnoea, flushing, chest pain and tachycardia and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in patients receiving Taxol. Patients receiving Taxol should be pre-treated with corticosteroids, promethazine, and H2 antagonists to prevent these reactions. (See "DOSAGE AND ADMINISTRATION" section). Patients who experience severe hypersensitivity reactions to Taxol should not be rechallenged with the drug.

Taxol therapy should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Taxol.

The polyoxyethylated castor oil in Taxol can result in phthalate leaching from polyvinyl chloride (PVC) containers, at levels which increase with time and concentration. Consequently, the preparation, storage and administration of diluted TAXOL should be carried out by using non-plasticized PVC-containing equipment.
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Old 02-19-2012, 09:36 AM
gdpawel gdpawel is offline
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Default Common chemotherapy drug triggers fatal allergic reactions

A chemotherapy drug that is supposed to help save cancer patients' lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA's Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent - a derivative of castor oil -- that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern's Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

"The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them," Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

"The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment," said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication," Bennett said. "Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor."

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

"The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent," said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

Source: Northwestern University Feinberg School of Medicine
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Old 02-19-2012, 09:38 AM
gdpawel gdpawel is offline
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Default Who Needs Taxol?

In the last fifteen years, 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.
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Old 02-19-2012, 09:38 AM
gdpawel gdpawel is offline
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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)

Taxol actually causes cancer cell microtentacles to grow longer and allows tumor cells to reattach faster, which may have important treatment implications for breast cancer patients. Researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center have discovered that microtentacles, or extensions of the plasma membrane of breast cancer cells, appear to play a key role in how cancers spread to distant locations in the body.

Microtentacles are microtubule-based protrusions that occur in detached cells. These protrusions are unusual in that they are not actin-based. The function of microtentacles may be to aid in metastasis. Breast cancer cells that have microtentacles travel more slowly in blood vessels than breast cancer cells that do not have microtentacles. The microtentacles may allow these cells to latch on to blood vessel walls and invade other tissues.

Chemotherapy designed to kill dividing cancer cells seems to make the tentacles grow further and faster. If you take a cell that doesn't have very many tentacles and actually treat it with the tubulin stabilizer, Paclitaxel (Taxol), that causes this cell to generate more tentacles. So, at the same time you're actually reducing the ability of the tumor cell to divide, you can be increasing its ability to reattach in a distant site. This research will also play a role in other major cancers: lung, colon, ovarian, and prostate.

They feel that more research is needed into how chemotherapies that slow down cell division affect metastasis. The timing of giving these drugs can be particularly important. If you treat people with taxol before surgery to shrink the primary tumor, levels of circulating tumor cells go up 1,000 to 10,000 fold, potentially increasing metastasis. (12)

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
(12) Oncogene (2010) 29, 3217–3227; doi:10.1038/onc.2010.68

The Human ATP-Binding Cassette (ABC) Transporter Superfamily [url]http://www.ncbi.nlm.nih.gov/books/NBK31/
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Old 02-19-2012, 09:39 AM
gdpawel gdpawel is offline
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Default Unpublished Clinical Trials

One of the researchers listed in the foot notes of my paper had told me that the study he finally published in the journal Oncology, was rejected by all other American & Europen cancer journals (Journal of Clinical Oncology, Cancer, Annals of Oncology, European Journal of Cancer, International Journal of Cancer) where it had been submitted. The journals were reluctant to publish such a scientific report, simply because taxanes (both taxol and taxotere) were at the time very intensively advertized in these journals.

Less than 20 percent of registered clinical trials of cancer drugs are eventually published in medical journals, according to a review published online by the The Oncologist medical journal.

A search of the National Institutes of Health's ClinicalTrials.gov web site identified 2,028 registered research studies of cancer treatments. Major medical journals require all studies considered for publication be registered at ClinicalTrials.gov or another publicly accessible database.

And a subsequent search of the National Library of Medicine's PubMed database showed that just 17.6 percent of the trials were eventually published in peer-reviewed medical journals.

The publication rate was particularly low for industry-sponsored studies, such as those funded by drugmakers (just 5.9% compared to 59% for studies sponsored by collaborative research networks. Of published studies, nearly two-thirds had positive results in that the treatment worked as hoped. The remaining one-third had negative results like the outcome was disappointing or did not merit further consideration of the tested treatment, they report.

The finding raises concern about publication bias in cancer treatment trials, according to the researchers, Scott Ramsey and John Scoggins of University of Washington and Fred Hutchinson Cancer Research Center in Seattle.

The researchers suspect the rate of negative results is much higher in the studies that have gone unpublished. "It is likely that many unpublished studies contain important information that could influence future research and present practice policy," they wrote.

Of course, we know why a registered trial may not be published, some fail and a researcher may decide the result doesn't enhance knowledge or one's reputation. And some sponsors don't want negative results out there. Same goes for some journal editors.

But "unpublished trials may have special importance in oncology, due to the toxicity and/or expense of many therapies," they wrote. In other words, the knowledge base is incomplete. And who does that help?
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Old 02-22-2012, 05:24 PM
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Default Assay Results Do Not Support Treatment with Taxol + Platinum as First Line Therapy

History of Randomized Clinical Trials in Ovarian Cancer: Pre-Taxol Era

For many years (from the early 60s to late 70s), the "standard" ovarian cancer chemotherapy was single agent melphalan (or chemotherapy with a related "alkylating agent," such as cyclophosphamide). These "alkylators" were inexpensive and usually well tolerated oral drugs. In the late 70s, the NCI reported the results of a randomized clinical trial in the New England Journal of Medicine in which a complex and toxic combination ("HEXA-CAF") ostensibly produced superior results, compared to single agent melphalan. But this study was not confirmed. By the early 80s, some data appeared initially to support the concept that cisplatin-based combinations might produce superior outcomes. The new standard became cisplatin + cyclophosphamide (CTX). Later on, carboplatin was introduced, and the combination of carboplatin + CTX was found to produce results equivalent to cisplatin + CTX, but the former combination was better tolerated. This became the new standard. However, a landmark meta-analysis published in the early 90s, analyzing studies including 8,000 patients and 6,000 deaths to determine what had been learned about optimum first line chemotherapy concluded that "no conclusions could be made." The study authors concluded that previous studies (often involving hundreds of patients) had been much too small to provide statistical power, and the authors announced that their cooperative group was initiating a prospective trial to compare single agent carboplatin versus the combination of cisplatin + doxorubicin + CTX which was to accrue 2,500 patients.

It is very important to note that it is widely accepted that platinum-based combination chemotherapy has been proven to be superior to single agent alkylating agent therapy (used in ovarian cancer since the 1960s). However, this is not true, as clearly shown in the landmark meta-analysis. A re-analysis of the original meta-analysis still did not show any advantage, 10 years out, for platinum-based therapy over single agent alkylator therapy. In other words it has NOT been shown that platinum-based combination therapy is superior to single agent alkylator therapy. Yet many would maintain that not to treat an ovarian cancer patient with platinum is tantamount to malpractice. This position cannot be supported (and is, in fact, refuted) by prospective, randomized clinical trials.

Taxol Bursts Upon the Ovarian Cancer Scene

Midway into the above 2,500 patient study, the glamour drug of the 1990s, paclitaxel (Taxol), came along. A prospective, randomized trial showed the superiority of cisplatin/Taxol over carboplatin/cyclophosphamide, and the former combination quickly became the new standard, which ostensibly made the ongoing, long-term, expensive study of cisplatin + doxorubicin + CTX instantly irrelevant and obsolete. The new cisplatin/Taxol combination is, parenthetically, vastly more expensive and toxic than was the oral melphalan "standard" of the 1970s (>$25,000 per patient, as opposed to <$1,000 per patient). And does Taxol add anything to cisplatin (or carboplatin) alone? Of the drugs introduced in the 1990s, probably no drug was more highly touted than Taxol, and in no disease was it more highly touted than in ovarian cancer. Indeed, it would be accurate to state that most clinical oncologists probably feel that it would be tantamount to malpractice not to use either Taxol/cisplatin or Taxol/carboplatin as first line therapy in ovarian cancer. This point of view is, in fact, given the imprimatur of the NCI's authoritative PDQ description of state of the art therapy.

Flies in the Taxol Ointment

A recent, large, multi-institutional trial (Gynecologic Oncology Group # 132) randomized ovarian cancer patients to (1) Taxol/cisplatin, (2) Taxol alone, and (3) cisplatin alone. Patients could be crossed over to the other drugs in the event of disease progression. The result? Taxol alone was inferior to the other two regimens, while cisplatin alone was, if anything, superior to the Taxol/cisplatin combination in complete remission rate and duration of response and most certainly was no worse than the combination. So what is the level of evidence supporting the use of Taxol/cisplatin over cisplatin alone? And given that carboplatin has been shown (in combination trials) to be therapeutically equivalent to cisplatin, but less toxic, is it not reasonable to consider using single agent carboplatin alone, as first line chemotherapy?

In a very recent editorial (JNCI 92:674-5,2000), Dr. William McGuire succinctly summarized the status of clinical trials in ovarian cancer and presented his own view of the future, stating "thus, even though more than 5400 patients with advanced ovarian cancer have been accrued to randomized trials in the last decade to "fine tune" the regimen with the best therapeutic index, what is best is still unclear." McGuire further maintained that randomized clinical trials must now be international in scope, as single institutions do not have the capability to carry out studies of sufficient statistical power, nor even do individual cooperative groups, nor do intergroup studies combining several cooperative groups; rather only a truly global effort is up to the task of methodically testing all of the myriad potential combinations to define the next 2 month improvement in median survival, based on the paradigm of one size fits all chemotherapy.

By coincidence, in a perfect example of just such a global effort, the results of a very important large international study were presented at the American Society of Clinical Oncology annual meeting in New Orleans, May 20, 2000. The Third International Collaborative Ovarian Neoplasm Study (ICON3) included 2074 patients from 132 hospitals in 8 countries. At the time of this second planned analysis, median follow up was 29 months, 925 patients remained alive without progressive disease and 1293 had either died or developed progressive disease. Two year survival was 64% in the group treated with carboplatin/Taxol (now considered "mandatory" standard therapy in the USA) and an identical 64% in patients treated either with single agent carboplatin or with the very old regimen cyclophosphamide + doxorubicin + cisplatin. Subgroup analysis revealed no group for which treatment assignment caused significant differences in either progression-free survival or overall survival. The study chairman reported that "even if there is (ultimately) a difference in survival, it will probably be only about 2%." Though there had been an initial suggestion (reported in the printed abstract) that patients with bulky disease benefited more from Taxol, this difference was not sustained in the longer-term data which was reported at the meeting.

Conclusions

I doubt that objective reviewers outside of the academic clinical oncology establishment would conclude that the paradigm of performing huge randomized studies to identify the best treatment to give to the average patient has done anything other than waste money and waste patient clinical trials resources (i.e. patient lives), although it has generously supported the careers of its proponents, who are the thought leaders in clinical oncology today. At the end of the day, the only clear conclusion possible after more than 20 years of these cooperative group trials of empiric chemotherapy in ovarian cancer is that there is no clear and meaningful advantage associated with any form of therapy ever examined in these trials. This emperor truly has no clothes. Why is it justifiable to defend (and even insist on) treating all patients with Taxol combinations (which, for the average patient, probably cost $15,000 more than non-Taxol combinations, such as single agent carboplatin or cisplatin-doxorubicin-cyclophosphamide)?

What makes more sense?

1. Treat all patients with carboplatin/Taxol?

2. Choose between reasonable treatment regimens (e.g. single agent carboplatin, carboplatin/Taxol, cisplatin/doxorubicin/cyclophosphamide, gemcitabine/cisplatin, cisplatin/topotecan, cisplatin/vinorelbine, cisplatin/Doxil, cisplatin/etoposide, vinorelbine/Taxol, vinorelbine/docetaxel, gemcitabine/vinorelbine, vinorelbine/thiotepa, cyclophosphamide/doxorubicin, etc.) with the assistance of information from a well-validated Human Tumor Assay performed by an experienced laboratory?

Larry M. Weisenthal, M.D., Ph.D. Weisenthal Cancer Group
April 14, 2003
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  #9  
Old 02-24-2012, 11:12 AM
gdpawel gdpawel is offline
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Default Cabozantinib (XL184) Taxol's demise?

They were looking for drugs to treat the inflammation seen in Crohn's disease and ulcerative colitis. They tested a compound called a PPAR-gamma modulator. It would never normally have been thought of as a cancer drug, or in fact a drug of any kind. They ran several tests and found the compound killed pretty much every epithelial tumor cell lines they have seen. Epithelial cells line organs such as the colon, and also make up skin.

They reported in the journal International Cancer Research that it killed colon tumors in mice without making the mice sick. The compound worked in much the same way as the taxane drugs, including Taxol, which were originally derived from Pacific yew trees. It targets part of the cell cytoskeleton called tubulin. Tubulin is used to build microtubules, which in turn make up the cell's structure.

Destroying it kills the cell, but cancer cells eventually evolve mechanisms to pump out the drugs that do this, a problem called resistance. Resistance to anti-tubulin therapies, like Taxol, is a huge problem in many cancers. They see this as another way to get to the tubulin. The PPAR-gamma compound does this in a different way from the taxanes, which might mean it could overcome the resistance that tumor cells often develop to chemotherapy.

Most of the drugs like Taxol affect the ability of tubulin to form into microtubules. This doesn't do that -- it causes the tubulin itself to disappear. They do not know why. They planned to do more safety tests in mice. As the compound is already patented, the team will probably have to design something slightly different to be able to patent it as a new drug.

The investigational drug cabozantinib is showing promise against several types of advanced cancer, and may also reduce or eliminate bone metastases (cancer that has spread to the bone) in some patients. These results will be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

Metastatic cancer refers to cancer that has spread to distant sites in the body. Several types of cancer—including cancers of the prostate, lung, and breast—have a tendency to spread to the bone. Bone metastases can lead to serious problems such as fracture and spinal cord compression, and may require treatment with surgery or radiation therapy.

Cabozantinib is an investigational drug that targets two proteins—MET and VEGFR2—that play a role in the development and progression of many types of cancer.

To evaluate cabozantinib in the treatment of advanced cancer, researchers conducted a Phase II clinical trial among 398 patients. The nine types of cancer included in the study were breast, stomach/gastroesophageal junction, non-small cell lung, ovarian, pancreatic, hormone-refractory prostate, small cell lung, liver, and melanoma. At the start of the study, 39% of the patients had bone metastases.

Patients were initially treated with 12 weeks of cabozantinib. After 12 weeks, patients who had a partial response to treatment (a reduction in detectable cancer) remained on cabozantinib, patients with stable disease (no significant change in the cancer) were randomly assigned to either continue with cabozantinib or to take a placebo, and patients with progressive (worsening) cancer were withdrawn from the study.

By week 12, 9% of patients responded to treatment.

For some types of cancer, cabozantinib produced high disease control rates (defined as either a reduction in cancer or stable disease). The disease control rates were 76% for liver cancer, 71% for prostate cancer, and 58% for ovarian cancer.

Among the 68 patients with bone metastases, 59 had partial or complete disappearance of the cancer on bone scans, often accompanied by significant pain relief. A majority of these patients had hormone-refractory prostate cancer, but patients with breast cancer and melanoma also experience a disappearance of bone metastases. The researchers had not expected this result.

The most common side effects were fatigue and hand-foot syndrome (pain, swelling, numbness, tingling, or redness of the hands or feet).

In a prepared statement, the lead author of the study noted “Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia. The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

Reference: Gordon MS, Vogelzang NJ, Schoffski P et al. Cabozantinib (XL184) has activity in both soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) w/ advanced solid tumors. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 3010.
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Old 02-24-2012, 11:16 AM
gdpawel gdpawel is offline
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Default Activity of cabozantinib (XL184) in advanced ovarian cancer patients

Activity of cabozantinib (XL184) in advanced ovarian cancer patients: Results from a phase II randomized discontinuation trial.

Sub-category: Ovarian Cancer

Category: Gynecologic Cancer

Meeting: 2011 ASCO Annual Meeting

Abstract No: 5008

Author(s): R. J. Buckanovich, R. Berger, A. Sella, B. I. Sikic, X. Shen, D. A. Ramies, D. C. Smith, I. B. Vergote; University of Michigan, Ann Arbor, MI; Sheba Medical Center, Tel HaShomer, Israel; Assaf Harofeh Medical Center, Zerifin, Israel; Stanford University School of Medicine, Stanford, CA; Exelixis, South San Francisco, CA; University Hospital Leuven, Leuven, Belgium

Abstract:

Background

Cabozantinib (Cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced ovarian cancer (OC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ OC. Simultaneous targeting of the MET and VEGF signaling pathways with Cabo may therefore be a promising treatment strategy.

Methods

Epithelial OC pts with progressive measurable disease (mRECIST) received Cabo at 100 mg qd PO over a 12 wk Lead-in stage. Up to 2 prior regimens are allowed for platinum-resistant (R), and up to 3 prior regimens for platinum-sensitive (S) pts. Tumor response was assessed every 6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label Cabo, pts with SD were randomized to Cabo vs placebo, and pts with PD discontinued. Primary endpoint was ORR per mRECIST in the Lead-in stage, and progression free survival (PFS) in the randomized period. Accrual in any cohort could be halted for either high rates of ORR or PD.

Results

Accrual was halted at 68 pts based on an observed high rate of clinical activity. The median number of prior systemic treatments was 2. Most common related AEs ≥Grade 3 were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Dose reductions and permanent discontinuations for AEs occurred in 43% and 10% of pts, respectively. Of 51 pts evaluable for mRECIST RR at 12 wks, 28 are R, 17 are S, and 6 have unknown status. mRECIST RR at 12 wks: overall = 12/51(24%), R = 5/28(18%); S= 5/17(29%). Five additional PRs await confirmation. The overall DCR (PR+SD) at wk 12 is 58% (30/51). After a median f/u of 4 mos (range: 1 to 11 mos), the median duration of response and median PFS have not been reached. CA125 responses (assessed by GCIG criteria) in 40 pts with ≥1 post-baseline result: 7/40 (18%). Median maximum increase in hemoglobin (Hb) in anemic pts (Hb < 11 g/dL) was 1.9 g/dL (N=8 in pts w/ ≥ 6 wk f/u; range, 1.1-3.2 g/dL). All maximum Hb changes occurred w/in the first 12 wks. Randomization in this cohort was halted & pts unblinded due to observed efficacy.

Conclusions

Cabo exhibits clinical activity in ovarian cancer pts with advanced disease, regardless of prior platinum status, as reflected by high rates of response.

Citation: J Clin Oncol 29: 2011 (suppl; abstr 5008)
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