[Rich66]

GDPawel's related points on Taxol:

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-ins***utional 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 en***led, "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 Ins***ute, Harvard Medical School, Boston, in the September, 2002 issue of The American Journal of Oncology Review, describes the complete lack of progress in the chemothe****utic treatment of metastatic breast cancer since 1970. Dr. Shulman noted that a retrospective com*****ion 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 Ins***ute 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, appe***e 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 Ins***ute
(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 ****ysis
(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


The original article about Pachmann's findings(mentioned above), a follow up by Fehm et al which makes the distinction regarding what type of cells are released and relevance, and further commentary on the distinctions by Pachmann:



CH321 • 03/29/05 • Scheduled for MAY 2005
Neoadjuvant Chemotherapy for Breast Cancer Can Cause Release of Tumor Cells

SAN ANTONIO—Using a technique that quantifies circulating tumor cells, German investigators have shown that neoadjuvant chemotherapy with paclitaxel causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor.
Reporting her findings at the 27th Annual San Antonio Breast Cancer Symposium (abstract 6014), Katharina Pachmann, MD, professor of experimental oncology and hematology, Friedrich-Schiller University, Jena, Germany, said that the impact of these released cells on relapse is not clear. The finding could help explain the fact that complete pathologic responses do not correlate well with improvements in survival.
“During the applied combination therapy, three different phases could be observed,” she said. “An initial decline in the number of circulating cells during the epirubicin (Ellence)-containing part of the regimen, followed by a steep increase during paclitaxel treatment, and a subsequent re-decrease if a third segment with CMF cyclophosphamide/methotrexate/fluorouracil) was administered before surgery.”

Ironically, she said, paclitaxel produces the greatest degree of tumor shrinkage but also the greatest release of circulating tumor cells. In three different paclitaxel containing regimens, with five to eight patients in each group, circulating cell numbers massively increased whereas tumor size decreased. These cells remained in the circulation for at least 5 months after surgery, Dr. Pachmann reported.
“The tumor collapses, but we find more cells 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,” she said. “These cells are alive in the circulation, and they would be accessible to an additional treatment, such as tamoxifen. We have shown that tamoxifen treatment will reduce circulating tumor cells in some patients but not all. In this study, the patients received no further treatment after surgery.”

She noted that the initial decrease in circulating tumor cells correctly predicted final tumor reduction in patients with HER2-negative tumors, but this correlation was less pronounced in HER2-positive patients who additionally received trastuzumab (Herceptin).



Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer

Tanja Fehm¹ , Sven Becker¹, Graziella Becker-Pergola¹, Karl Sotlar², Gerhard Gebauer³, Silke Dürr-Störzer¹, Hans Neubauer¹, Diethelm Wallwiener¹ and Erich-Franz Solomayer^1
1Department of Obstetrics and Gynecology, University of Tuebingen, Calwerstrasse 7, D-72076 Tuebingen, Germany
²Department of Pathology, University of Tuebingen, Calwerstrasse 7, D-72076 Tuebingen, Germany
³Department of Gynecology and Obstetrics, University of Heidelberg, Vossstrasse 9, 69115 Heidelberg, Germany


Breast Cancer Research 2006, 8:R60doi:10.1186/bcr1611
The electronic version of this article is the complete one and can be found online at: http://breast-cancer-research.com/content/8/5/R60

............

Patients with complete remission of the primary tumor have a better clinical outcome compared with those with partial remission or compared with nonresponders [5,6]. Local therapy response is normally assessed by palpation and imaging techniques including ultrasound and mammography. The efficacy of neoadjuvant treatment on disseminated tumor cells (DTC) is assumed to be correlated to local therapy response. Complete remission is considered a surrogate marker for complete eradication of micrometastatic disease. However, 13–25% of patients with pathological complete response develop metastatic disease over 5 years [1,5-8].
Eradication of a minimal residual disease may be monitored by serial bone marrow analysis during NST, offering new insights into the effects of systemic therapy on minimal residual disease. DTC can be detected in 30–40% of untreated primary breast cancer patients prior to surgery [9-12]. Tumor cell persistence after removal of the primary tumor and adjuvant chemotherapy has been suggested to indicate chemotherapy resistance and poor clinical outcome [13-15]. The efficacy of neoadjuvant chemotherapy may therefore be indicated by bone marrow negativity or by the presence of disseminated apoptotic cells that were susceptible to cytotoxic agents.


...........


Response of the primary tumor is reflected by bone marrow status

DTC were detected in 53% of patients after completion of neoadjuvant therapy. The highest positivity rate was observed in patients with progressive disease (80%), followed by patients with stable disease (68%) and those with partial remission (48%). Only 10 of 24 (42%) patients with pathological complete remission were DTC positive. The response of the primary tumor was therefore reflected by the presence of DTC. Interestingly, the overall incidence was higher compared with the preoperative positivity rates reported in primary breast cancer patients prior to surgery and not treated by chemotherapy, ranging from 30% to 50% [9-12]. Most of the patients, however, had initially advanced stages with nodal involvement. In general, these patients tend to have higher positivity rates in the bone marrow. In addition, most of the patients still have tumor left despite neoadjuvant chemotherapy. It has been shown that regressing tumors still shed tumor cells into the blood circulation to the same extent as progressing tumors [21]. Therefore, even if patients respond to chemotherapy, cells may be still shed into the bone marrow until removal of the primary tumor. Most of these cells may have no relevance and undergo apoptosis induced by cytotoxic agents.

Presence of apoptotic cells in bone marrow after systemic treatment

Apoptosis is programmed cell death, which represents a signaling pathway that leads to cellular suicide in an organized manner. Apoptosis is fundamentally different from the necrotic mode of cell death, in which the cells suffer a major insult, resulting in a loss of membrane integrity, swelling and disrupture of the cell. The gold standard for detection of apoptosis has been morphological assessment either with electronic microscopy or with light microscopy [22-28]. Cells are characterized by specific morphologic signs of celllular shrinkage, membrane blebbing (cleavage of cytoskeletal proteins leading to blebbing), nuclear condensation and fragmentation [26]. The alteration of the cytoskeleton takes place first [42] and the intact intermediate filament network is then replaced by cytokeratin inclusions (Figure 1c). The final stages are apoptotic bodies (Figure 1c,d) [28].
Given that apoptosis is the principle mechanism of chemotherapy-induced regression [29], we analyzed the bone marrow aspirates for the presence of apoptotic DTC by immunocytochemical staining with M30 antibody. This antibody reacts with a caspase cleaved epitope of cytokeratin 18 expressed during early apoptosis [18].
No apoptotic DTC could be detected in the bone marrow of patients with progressive disease, whereas the positivity rate of only apoptotic DTC was 4% in patients with stable disease versus 14% in patients with partial remission or complete remission. The presence of only apoptotic DTC was therefore reflected by the therapy response. A subset of patients with stable disease, partial remission or complete remission had both apoptotic cells and nonapoptotic cells, reflecting heterogeneity in terms of therapy responsiveness also observed in the primary tumor [30].

Clinical relevance of disseminated tumor cells in patients with complete remission

The most interesting group of patients to elucidate the biology of chemoresistance and metastatic disease are those with complete remission of the primary tumor and persisting tumor cells in the bone marrow. The aim of (neo)adjuvant chemotherapy is to eradicate micrometastatic disease to improve disease-free survival and overall survival. Theoretically, if complete remission indicates complete eradication of metastatic disease, no patients with complete remission should have disseminated DTC or should develop metastatic disease during the course of disease. Several studies have shown, in fact, that patients without DTC have the best outcome. However, 13–25% of these patients suffer from systemic relapse. Since no primary tumor is left, one of the sources of metastatic cells is likely to be in the bone marrow. In our study, nonapoptotic DTC could be detected in 10 out of 24 (42%) patients with complete remission. Similar positive rates of tumor cell persistence have also been observed in breast cancer patients after surgery and completion of adjuvant therapy [13-15]. These DTC have the capability to survive in the blood circulation despite cell-matrix loss and are apparently resistant to systemic therapy. Two important steps of the metastatic cascade are therefore fulfilled [21]. Since it has already been demonstrated that patients with persistent DTC have a poor prognosis [13-15], determination of the bone marrow status after neoadjuvant chemotherapy might identify those patients at a high risk for metastatic disease and identify patients who may need secondary therapy.
Clearly not all disseminated cells may necessarily be cells with metastatic potential, however, since the positivity rate of 42% is higher than the expected relapse rate for patients with complete remission, ranging from 13 to 25%. Meng and colleagues [31] have shown that circulating tumor cells can be detected in the blood of breast cancer patients more than 20 years after primary diagnosis without evidence for recurrence, supporting the theory of (lifelong) tumor cell dormancy. An important task will therefore be the identification of those persistent and temporarily dormant cells that will cause a metastatic disease. As a very provocative theory it has been suggested that this subpopulation of persistent DTC may also be seen as cancer stem cells since they are dormant but have the ability to regrow following treatment [32,33]. Identification and further characterization of this subset will offer the chance to understand the mechanism of tumor cell growth and metastatic disease. Furthermore, development of new drugs based on these results will optimize treatment strategies since these disseminated cells are directly linked to metastatic spread.

Conclusion

The presence of apoptotic tumor cells in bone marrow is reflected by therapy response of the primary tumor to systemic therapy. Patients with complete response, however, still may have nonapoptotic DTC, indicating that the response of the primary tumor does not necessarily reflect the therapeutic effect on DTC. Even patients with complete remission but positive bone marrow status after primary systemic therapy may therefore need secondary adjuvant therapy, which may be based on bisphosphonates or antibody-based strategies, to completely eradicate minimal residual disease.




Comments(1)

Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer Tanja Fehm, Sven Becker, Graziella Becker-Pergola, Karl Sotlar, Gerhard Gebauer, Silke Dürr-Störzer, Hans Neubauer, Diethelm Wallwiener and Erich-Franz Solomayer Breast Cancer Research 2006, 8:R60doi:10.1186/bcr1611

Release of tumor cells during neoadjuvant therapy

Katharina Pachmann (01 November 2006) Friedrich Schiller University of Jena, Germany
The present report by Dr. Fehm confirms our previous results about dissemination of tumor cells during the course of neoadjuvant therapy presented already at the 2004 San Antonio Breast cancer symposium (Pachmann K., Camara O., Pachmann UA. Influence of primary tumor chemotherapy in breast cancer on circulating tumor cells. Indications for massive cell release into circulations concurrent with tumor size reduction. (2004) Breast Cancer Research and Treatment 88: S224), which was commented in several publications: "An article in the May 2005 issue of Oncology News International (Vol. 14, No. 5) reports that neoadjuvant chemotherapy* may cause the release of cancer cells into the blood. Katharina Pachmann, MD, of Friedrich-Schiller University in Germany said that "ironically, paclitaxel produces the greatest degree of tumor shrinkage but also the greatest release of circulating tumor cells." The cells remained in the circulation for at least 5 months after subsequent surgery. Dr. Pachmann said that this observation corresponds with results found in patients, that is, tumor response does not mean increased survival". In accordance with our results Dr. Fehm shows that after neoadjuvant therapy disseminated cells are found at a higher frequency than before. We would like to emphasize in addition, that most of these cells are not apoptotic but even of these non-apoptotic cells not all are necessarily metastatic cells. Rather, a minimal fraction of them (perhaps less than 0.01% as shown by the group of Dr. Chambers) is expected to form metastases, but release of such cells is the first step and should be avoided or the released cells be destroyed by additional chemotherapy after surgery, as suggested by us.
With best regards
Katharina Pachmann




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 tumor
Full Text PDF: http://www.biomedcentral.com/content/pdf/bcr1516.pdf

John Souglakos; Lambros Vamvakas; Stella Apostolaki; Maria Perraki; Zacharenia Saridaki; Irine Kazakou; Athanasios Pallis; Charalambos Kouroussis; Nikos Androulakis; Kostas Kalbakis; Georgia Millaki; Dimitris Mavroudis; Vassilis Georgoulias

Abstract

Introduction: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse.

Methods: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR.

Results: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007-0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51-101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97-12.84; P = 0.001) were independent predictive factors for CNS relapse.

Conclusion: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs.

Breast Cancer Res. 2006;8(4) ©2006 BioMed Central, Ltd.

The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement are not clear. Although taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration [12,13]. Moreover, preclinical data suggest that taxanes are unable to penetrate the intact blood–brain barrier; in these models, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid was found to be significantly lower than in other organs, and thus was undetectable in the brain, in the spinal cord or in any other site of the CNS [14]. It has more recently been proposed that 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 [15].
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 was correlated with increased incidence of relapse in several studies [16,17]. The possible correlation of this finding with an increased incidence of CNS relapse was not reported in any of these studies.

.......

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. Nevertheless, this parameter did not emerge as an independent predictive factor in the multivariate analysis. It is important to note, however, that a similar difference was not observed in patients with other types of solid tumor treated or not with a taxanecontaining chemotherapy regimen.
Taxanes are highly effective in breast cancer and they prolong the survival of patients with advanced disease. It is also well known that CNS involvement is more frequent in the late stages of the disease. A possible explanation could therefore be that the increase in survival and the prolonged period of advanced disease is correlated with the increased frequency of CNS relapse. It is important to note that such a correlation
could represent a confounding factor, in a retrospective analysis. For example, someone can hypothesize that physicians may have chosen more aggressive treatment for patients with aggressive tumors. These patients also showed increased incidence for CNS relapse. Although this observation could be explained with the 'sanctuary site' hypothesis, experimental studies in mice have demonstrated that the blood–brain barrier is intact inside and around brain metastases smaller than 0.2 mm2 but not in larger lesions [29]. This finding implies that the barrier should not be a major obstacle to using chemotherapy in the treatment of brain metastases, at least in the advanced stages of the disease. In addition, more recent studies have shown that paclitaxel is exported by the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries [15]

We have previously reported that the use of Transtuzumab could decrease or eradicate CK-19 mRNA-positive CTCs [30]. Based on these results we have initiated a randomized clinical trial to evaluate the effect of Transtuzumab administration on the disease-free survival of patients with early breast cancer and CK-19 and HER-2 mRNA-positive CTCs. The incidence of CNS relapse in correlation with the detection of CK-19 mRNA-positive CTCs will be prospectively evaluated in this ongoing study.

PDF of full text attached

Advanced Breast Cancer: Treatment
with Docetaxel/Epirubicin

An interesting observation regarding a higher incidence of central nervous system
(CNS) involvement in patients treated with docetaxel/epirubicin was reported by an
Italian group, based on a pooled analysis of their phase I and II studies (Pagani et
al., 1999, 2000). A total of 92 patients were included in these two studies and
the authors reported that 28 (30%) of the 92 patients treated with this combination
developed CNS metastases; 25 patients developed cerebral metastasis, two leptomeningeal, and one both (Crivellari et al., 2001). Median time for the development
of CNS metastases from the start of chemotherapy was 15 months (range 5–42), when the six patients presenting CNS progression within 3 months from start of treatment were excluded. It is noteworthy that 11 patients (39%) had disease progression
only in the CNS. Although, this observation could be easily explained by the sanctuary site ‘hypothesis’, as a consequence of an intact blood-brain barrier, this is not proven and the exact explanation remains to be elucidated. The authors conclude that as anthracycline- and taxanecontaining regimens are increasingly used both in the metastatic and in the adjuvant setting, a careful monitoring of any neurological
symptoms should be advisable.