High Dose Tamoxifen For Brain Tumors
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High Dose Tamoxifen For Brain Tumors



Update 6/8/2004


There was a report on using Tamoxifen at the same time as radiation for brain tumors. Click here for the details!

Update 4/9/02


There was a report on increasing the efficacy of Tamoxifen by inducing a hypothyroid state. Click here for the details!


Andrew James Parker
Dept. Biomedical Science,
University of Sheffield,
Sheffield, England

Updated May 25, 2000

Generic Name :   Tamoxifen

USA Brand Name:   Nolvadex (Zeneca Pharmaceuticals)

Other Proprietary Names:   Dignatomoxi, Emblon, Fentamox, Istubol, Kessar, Mamofen, Noltam, Novofen, Oestrifen, Tamaxin, Tamifen, Tamoplex, Tamoxen, Valodex, Zitazonium

Classification:   Antineoplastic; Antiestrogen

BT Dosage:   200mg/day (f) 240mg/day (m) [Adult] 60 -100mg/day [Children] Dosage depends on weight, tolerance and toxicity and varies according to individual circumstances. Always take in consultation with a physician.

Delivery:  Oral tablet

Potential Side Effects:   Hot flushes; Vaginal bleeding; Early onset menopause; GI distress; Vomiting; cataracts; Visual disturbances; Dizziness; thrombosis

Availability:   This drug is routinely prescribed, inexpensive and should be readily available.

Abstract:   The drug tamoxifen is most commonly associated with chemotherapy of breast cancer but has been used recently to treat other cancers including brain tumors. The mechanism of its action is complex involving several sites in and on cells. Current opinion suggests that its key role in malignant glioma is to inhibit a cell signaling enzyme called protein kinase C. It does this in a dose-dependent manner and consequently is administered at a much higher dose for brain tumor sufferers than is given to breast cancer patients. It has a low toxicity and its side effects are minimal. There is evidence to suggest that it should not be used in conjunction with the anti-epileptic (anticonvulsant) phenytoin. It has been used on its own and in conjunction with other drugs (adjuvant chemotherapy). Although tamoxifen does not improve all instances of brain tumor, there is considerable evidence that it is of benefit to many.A new non-invasive procedure may be able to detect those patients who will respond to tamoxifen.

TAMOXIFEN MINIREVIEW


The drug tamoxifen was synthesised in 1962 by scientists at ICI working on a contraceptive pill. Since it blocks the natural hormone estrogen (a steroid), it was classified as a nonsteroidal estrogen antagonist (8) . It has been used in the treatment of breast cancer for over 20 years (16) , although its efficacy has often been controversial (63) . Articles in the Lancet in the spring (3) and summer (61, 79) of 1998 respectively supported then refuted the value of tamoxifen with breast cancer. Later that year, the FDA approved tamoxifen citrate for reducing the incidence of breast cancer in women at high risk for developing the disease. In May 2000, an extensive study reported by Professor Sir Richard Peto has found convincingly in favor of tamoxifen, with the death rate falling by a third over ten years (54) . In addition to breast cancer, tamoxifen has been used to treat other cancers such as melanoma (30, 65) , hepatocellular carcinoma (73) , ovarian cancer (81) and prostate cancer (10) . This short review considers its application to cancer of the brain.

The action of tamoxifen is now known to operate at several sites in the cell (e.g. as a channel blocker : 2, 36, 74) and to affect numerous genes (40) but early studies concentrated on its action as an antihormone, specifically an antiestrogen (33, 67, 83) . Antiestrogenic mechanisms have been studied for around 40 years 83) but are still not fully understood. One known mechanism is that the tamoxifen molecule competes with the natural female hormone (estrogen) for binding sites on the surface of cells (46) . Estrogens are known to promote the growth of breast cancer cells, so if an antiestrogen such as tamoxifen blocks those sites, the effect of estrogen is diminished. Experiments have shown that tamoxifen blocks the effect of estradiol in cultures of astrocytes (31) , but are related to the type of estrogen receptor (ER) present (41) . Although tamoxifen has been found to be effective in decreasing brain tumor proliferation, whether this is mediated via the ER remains controversial, despite evidence of such mechanisms with a glioblastoma cell line (43) and in meningiomas (25) . Other studies have shown a specific cell cycle action of tamoxifen, mediated by mechanisms other than estrogen inhibition (66). There is also an important interaction between the ER and an enzyme called protein kinase C (35) .

Protein kinase C (PKC) denotes a group of enzymes that regulate functions such as cell growth and differentiation. It is known to be involved in a process called signal transduction. This is a messenger system, which transfers a signal arriving at the cell surface (e.g. hormone or neurotransmitter) into a cellular response. Protein kinase C has been implicated in glioma invasion (18, 77) and its role in malignant glioma growth and proliferation has been reviewed (5, 12, 27, 60) . Tamoxifen has been shown to block cell growth in brain tumor cell lines (26, 49, 68) and inhibits PKC (10, 47) . Proliferative signal transduction in glioma cells has been shown to occur through a predominantly PKC-dependent pathway (6, 7) . One isoform of PKC (isoform A) may be of particular importance (6, 18) . In addition to tamoxifen's action against PKC in adult high-grade gliomas, it has been shown to inhibit proliferation of cell lines derived from both low- and high-grade pediatric glial tumor (56) . A model cell system has been constructed for the screening and identification of PKC inhibitors potentially active against astrocytoma cells in culture (69, 70) .

As well as tamoxifen, a number of other PKC inhibitors have been shown to be effective in glioma inhibition. These include calphostin C (38, 59) and UCN-01 (57) .Another PKC inhibitor, hypericin (derived from the herb St John's Wort) has been used with tamoxifen for adjuvant chemotherapy of malignant glioma. In a study of seven human malignant glioma cell lines it was found that hypericin and tamoxifen induce apoptosis in a concentration and time-dependent manner (80) . In one patient, hypericin was able to replace tamoxifen's growth inhibition after loss of sensitivity to tamoxifen after a 22-month period (34, 55, 85) . One study on the action of tamoxifen on PKC activity in glioblastoma tissue found the inhibitory effect arrested the cell in the G (1) phase of the cell cycle. However, this action was observed to occur in a dose-dependent manner (22) and it is apparent that to be effective against gliomas tamoxifen has to be administered in a high dose.

The dose of tamoxifen used in the treatment of breast cancer is in the range 20-40 mg/day. However, since it has been shown that tamoxifen inhibits PKC in a dose dependent manner (22, 39, 80) , investigators have used higher doses to treat brain tumors. A key worker in this area is William Couldwell who, in a pioneering study (21) , first gave tamoxifen in antiestrogen doses (40mg/day) to monitor possible side effects in a cohort of malignant glioma patients. Provided no adverse reactions were observed dosage was then increased to 160mg (female) and 200mg/day (male). A positive response was obtained with a minority of patients (3 out of 11). A later study using the same dosage also found a subgroup of patients responding or stabilizing with high-dose tamoxifen. (23) .

In a study using doses graded between 40, 80 and 120mg/day, it was found that the patients receiving the higher doses demonstrated a longer median survival (51) . One study using 240mg/m (2) observed a variation in tamoxifen metabolic profile (29) . If there is a variation in how individuals metabolize this drug this may partially explain the variation in response to tamoxifen. However at that same dosage [240mg/m (2) ] another group found that symptoms of neurotoxicity occurred when tamoxifen was given in conjunction with interferon alpha-2a (17) .

In childhood glioma (45) , tamoxifen has been shown to produce tumor reduction and halting of tumor progression (9) . Pollack et al (58) found stabilization in 4 of 14 patients previously exhibiting progressive disease. One group had received 60mg/m (2) and a second group 100mg/m (2) daily. This study concluded that tamoxifen's low toxicity and easy administration; its proven effectiveness with some patients merited further study. Furthermore it was suggested that in patients with malignant gliomas, tamoxifen could potentate the effects of conventional chemothrapeutic agents.

A drug is said to have a synergistic effect when its action in combination with another drug is greater than the action of the two drugs administered separately - a "gestalt" pharmacology. There is considerable support for this effect with tamoxifen. Experiments on a human glioblastoma cell line (39) found that tamoxifen or tumor necrosis factor alpha could each inhibit proliferation in a dose-dependent manner. However, when given together the inhibitory action was greater than either agent alone. It has also been shown to improve quality of life when used in conjunction with procarbazine (11) and hypericin (86) . Similarly, the antiestrogenic action of tamoxifen is potentiated by bepridil - a sodium-calcium exchange blocker - in experiments on human astrocytoma and neuroblastoma cells (42) . Synergism has also been reported with radiotherapy (13, 26, 28, 50) .

Not all of tamoxifen's interactions are beneficial. There is evidence to support an adverse reaction with phenytoin (32, 64) and care should be exercised if tamoxifen is being considered for patients receiving this anti-convulsant. One report suggests that it may protect glioma cells from the action of cytotoxins (72) . A study reporting risk of thrombosis with tamoxifen (71) requires examination. Out of 4095 patients, 21 incidences of thrombosis were observed (0.5%), only one of these cases occurred with a brain cancer sufferer. The age range was 29 - 75 years and no evidence is presented as to whether the reported incidence exceeds that of a normal population not receiving chemotherapy.

Tamoxifen is generally considered to be of low toxicity (14, 82) but some workers have expressed doubts as to whether tamoxifen may be carcinogenic (4, 75) . However, such evidence is less substantial than that for its beneficial effects and indeed many malignant brain tumor sufferers would consider a "long term " risk in a positive way. In terms of proven carcinogenicity, tamoxifen is considerably less harmful than many other chemothrapeutic agents (15) .

As the number of trials and treatments of brain tumors with tamoxifen increases, so do the analyses and statistical analyses of such protocols (20, 37, 48, 84) . A review of treatment of high-grade astrocytomas by all treatments (37) found in favor of the nitrosoureas and platinums in the treatment of this type of tumor but also highlights the many problems associated with such group comparisons. How are patients selected for treatment and inclusion in the study? Do they receive the same dose - for the same period, and are they stratified by histology? Because these surveys are derived from individual patients and each patient will have received the physician's best treatment it is impossible to determine a standard treatment, only overall trends. If there is a subset of patients who are particularly susceptible to one chemotherapy, their positive response may be diluted by many that are not. The laws of statistics forbid a researcher from subjective selection of sample.

Long term survival with tamoxifen has been reported with a woman who developed a solitary brain metastasis following cancer of the breast. Following surgery and radiotherapy, this patient received tamoxifen and is generally well 10 years after brain metastases (53) . A positive response to tamoxifen has been observed with other metastatic brain tumors (44, 78) . Indeed the point is made that tamoxifen offers the benefit of treating both the primary (extracranial) and secondary (intracranial) tumors (44) . A detailed report of long term survival with primary brain tumor and tamoxifen awaits collation and analysis (52)

In summary, the evidence for tamoxifen in chemotherapy of brain tumor, although by no means proven, is more than encouraging. As with many experimental chemotherapies, there is often more promise shown with in vitro tissue culture studies than are delivered in clinical trials. There are many reasons for such a difference in response (76) . It would seem that this drug is effective with a minority of malignant glioma sufferers (21, 23) . The reason for this may be attributable to individual variations in tamoxifen metabolism (29) or it may point to variations in brain tumor pathology or metabolism yet to be clarified. Use of screening assays to predict the action of tamoxifen (1, 69, 70) may give insights into variations amongst gliomas and their susceptibility to this agent. Even more promising is the use of proton magnetic resonance spectroscopic imaging to predict how malignant gliomas will react to tamoxifen chemotherapy (62) . This paper suggests that it is possible to accurately predict the response of the tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. Certainly tamoxifen's low toxicity (71, 82) and minimal side effects coupled with its ready availability and low cost, present strong arguments for its application. It may be given alone (53, 69) or in combination with other agents (39, 42, 80) which enhances its action. It has also shown promise in conjunction with other techniques such as stereotactic radiosurgery (24) and radiotherapy (26, 28)

The potential benefits of tamoxifen clearly outweigh possible deleterious effects in brain tumor patients. It may only achieve a positive effect in a minority of patients but that fortunate group should not be denied the benefit simply because the drug does not improve survival for all brain tumor sufferers. The very fact that its action may take a considerable time to be manifest (19) will be good news to many. Indeed, the reasons underlying tamoxifen's variability may well indicate further avenues of research and treatment and broaden our understanding of this pernicious disease.





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