Bicalutamide

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Bicalutamide (INN, USAN, BAN)
Bicalutamide.svg
Bicalutamide ball-and-stick.png
Systematic (IUPAC) name
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
Clinical data
Trade names Casodex
AHFS/Drugs.com monograph
MedlinePlus a697047
Pregnancy
category
  • US: X (Contraindicated)
Legal status
  • ℞ (Prescription only)
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability Well-absorbed
Protein binding 96%
Metabolism Hepatic (CYP3A4)
Biological half-life 6 days (acute),[1]
7–10 days (chronic)[2]
Identifiers
CAS Number 90357-06-5 YesY
ATC code L02BB03 (WHO)
PubChem CID: 2375
IUPHAR/BPS 2863
DrugBank DB01128 YesY
ChemSpider 2284 YesY
UNII A0Z3NAU9DP YesY
KEGG D00961 N
ChEMBL CHEMBL63560 N
Synonyms ICI-176334[3]
PDB ligand ID 198 (PDBe, RCSB PDB)
Chemical data
Formula C18H14F4N2O4S
Molecular mass 430.373 g/mol
  • O=C(Nc1cc(c(C#N)cc1)C(F)(F)F)C(O)(C)CS(=O)(=O)c2ccc(F)cc2
  • InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25) YesY
  • Key:LKJPYSCBVHEWIU-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

Bicalutamide (brand names Casodex, Cosudex, Calutide, Kalumid) is a synthetic, non-steroidal, pure antiandrogen used in the treatment of prostate cancer,[4][5][6] hirsutism,[7][8] and other androgen-dependent conditions.[3][9][10] Developed and marketed by AstraZeneca,[11] bicalutamide was approved in 1995 as a combination treatment (with a gonadotropin-releasing hormone (GnRH) analogue (e.g., leuprorelin) or surgical castration)[12][13] for stage D2 metastatic prostate cancer, and has since also been approved and used, for instance in Germany, as a monotherapy for the treatment of an earlier stage of the disease, stage C or D1 locally advanced prostate cancer.[14] Prior to the approval of enzalutamide, a recently introduced, newer non-steroidal antiandrogen with improved effectiveness, bicalutamide was regarded as the standard-of-care antiandrogen for the treatment of prostate cancer.[15]

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[16]

Medical uses

Prostate cancer

Bicalutamide is indicated for the treatment of stage D2 metastatic prostate cancer in combination with castration (pharmacological with a GnRH analogue or surgical with an orchiectomy)[17] or as a monotherapy.[18] However, while effective, most advanced prostate cancer patients eventually become resistant to antiandrogen including bicalutamide therapy, due to progressive mutations in the androgen receptor (AR) resulting in the transformation of these drugs from antagonists into agonists of the AR.[19]

Other/off-label uses

Bicalutamide, along with other non-steroidal antiandrogens including flutamide and nilutamide, is used as a component of hormone replacement therapy for trans women.[20][21] However, relative to flutamide and nilutamide, bicalutamide is, in general, clinically preferred due to its superior safety, tolerability, and pharmacokinetic profiles (see below).[22][23]

Low-dose (25 mg/day) bicalutamide has been found to be effective in the treatment of hirsutism in women.[7][8][24]

Bicalutamide is useful in combination with the aromatase inhibitor anastrozole as a puberty blocker in the treatment of precocious puberty in boys.[25][26] This is a cost-effective alternative to GnRH analogues for the treatment of this condition. Moreover, the combination is effective in gonadotropin-independent precocious puberty in boys, such as in familial male-limited precocious puberty (a.k.a. testotoxicosis), where GnRH analogues are not effective.[25][26]

Side effects

Known potential side effects of bicalutamide, many of which may be exclusive to males, include breast pain/tenderness, gynecomastia, hot flashes, depression, fatigue, sexual dysfunction (including loss of libido and erectile dysfunction),[27] diarrhea, nausea, pruritus (itching), and, rarely, hepatic changes (e.g., transiently elevated levels of transaminases, jaundice[28]).[29][30][31][32]

Some of the above-listed side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when bicalutamide is combined with a GnRH analogue (due to suppression of estrogen levels),[33] and others, including hot flashes, depression, fatigue, and loss of libido,[34] may occur much more often when bicalutamide is combined with a GnRH analogue.[35][36][37] It has been hypothesized that this is due to the suppression of both androgen and estrogen levels by GnRH analogues, as estrogen may be able to compensate for various negative central effects of androgen deprivation, while bicalutamide monotherapy, contrarily, increases estrogen levels.[35]

Tamoxifen, a selective estrogen receptor modulator, has been found to be highly effective in preventing and reversing bicalutamide-induced gynecomastia in men with prostate cancer.[38][39] For reasons that are unclear, anastrozole, an aromatase inhibitor, has been found to be much less effective in comparison to tamoxifen for this indication.[38][39] A systematic review of non-steroidal antiandrogen-induced gynecomastia and mastodynia concluded that tamoxifen, 10–20 mg/day, and radiotherapy could effectively manage the condition without relevant side effects, with tamoxifen showing superior effectiveness.[40]

In accordance with its antiandrogen properties, bicalutamide reduces the weight of the prostate gland and seminal vesicles,[41] though not the testes.[42] As such, it may produce hypospermia or aspermia (reduced or absent semen/ejaculate production),[43] an often-observed effect of antiandrogen therapy for prostate cancer.[44] However, in spite of this, bicalutamide, conversely, does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish fertility.[42]

From a theoretical standpoint, flutamide, nilutamide, and bicalutamide are all thought to be capable of causing hepatotoxicity,[45][46] However, relative to flutamide (which has an estimated incidence rate of 3 in every 10,000, or 0.0003%), hepatotoxicity is much rarer in nilutamide and bicalutamide, and the risk is thought to be significantly less with nilutamide and even further less with bicalutamide.[2][46][47] A total of four cases of bicalutamide-associated hepatotoxicity have been reported in the medical literature.[28]

A few cases of interstitial pneumonitis in association with bicalutamide treatment have been reported in the medical literature[48][49][50] Incidence is very rare, and the risk of interstitial pneumonitis is far less relative to that seen with nilutamide.[49]

All of the approved non-steroidal antiandrogens, flutamide, nilutamide, bicalutamide, and enzalutamide, have been found to possess an off-target action of inhibiting GABAA receptor currents in vitro to varying extents.[51] In addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficient doses.[51] Bicalutamide was not found to do this, but this may have simply been due to the limited brain penetration of bicalutamide in rodents.[51] In any case, regardless of animal findings, enzalutamide is the only non-steroidal antiandrogen that has been found to be associated with a significantly increased incidence of seizures clinically, so the relevance of aforementioned findings with regard to the other agents is unclear.[51]

Contraindications

Due to its actions as an antiandrogen, bicalutamide is a teratogen and should not be taken or handled by women who are or who may become pregnant.[52][53] It is known to have the potential to cause fetal defects, such as ambiguous genitalia.[52][53]

In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, it should be used cautiously in these patients.[54][55]

Comparison with other antiandrogens

Relative to the non-steroidal antiandrogens flutamide and nilutamide, bicalutamide has the highest affinity for the AR (e.g., 4-fold greater than flutamide),[27] as well as the longest half-life (~6 days for bicalutamide versus 5–6 hours for flutamide and ~2 days for nilutamide).[22] Bicalutamide is described as the most potent of the non-steroidal antiandrogens as well as the most well-tolerated (not including/considering enzalutamide).[1] It is for these reasons, as well as a better safety profile, that bicalutamide has largely replaced flutamide and nilutamide in the treatment of prostate cancer.[45]

In comparison to bicaclutamide, the newer non-steroidal antiandrogen enzalutamide has 5- to 8-fold higher affinity for the AR,[56][57] possesses mechanistic differences resulting in improved AR deactivation,[56][58] shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity,[56][59] and has a slightly longer half-life (8–9 days versus ~6 days).[60] In accordance, enzalutamide appears to be a much more potent antiandrogen relative to bicalutamide (for instance, producing substantially greater increases in testosterone levels relative to bicalutamide at similar dosages (114% for enzalutamide 160 mg/day relative to 66% for bicalutamide 150 mg/day), and similar increases (with the 160 mg/day dosage) in testosterone, estradiol, and luteinizing hormone (LH) levels relative to high-dosage bicalutamide (300–600 mg/day)),[61][62] and the drug has demonstrated superior effectiveness in comparison to bicalutamide in the treatment of prostate cancer.[63] In terms of tolerability, enzalutamide and bicalutamide appear overall to be similar,[citation needed] with a similar moderate negative effect on sexual function and activity, for instance.[62] However, enzalutamide has a risk of seizures and other side effects such as anxiety and insomnia related to off-target GABAA receptor inhibition that bicalutamide does not appear to have.[51][60] Also, unlike bicalutamide, enzalutamide is still on-patent, and for this reason, is extremely expensive ($7,450 USD for a 30-day supply as of 2015).[64] Contrarily, the cost of bicalutamide is very low in comparison (from $15.44 for a 30-day supply of once-daily 50 mg tablets).[65]

In clinical studies, flutamide has been found to be more effective than both spironolactone and cyproterone acetate in the treatment of androgen-dependent conditions such as acne and hirsutism in women.[66][67][68] Bicalutamide has similarly been tried and found to be effective in the treatment of hirsutism in women.[7][8][24] However, although it has not been compared head-to-head with other antiandrogens in any trials for such conditions, relative to flutamide, as mentioned above, bicalutamide is several times more potent and has a much longer half-life, and hence would be expected to be at least equivalent or perhaps even more effective in comparison.[22][27] In accordance with this notion, the efficacy of bicalutamide has been found to be at least equivalent to flutamide in the treatment of prostate cancer in a direct head-to-head comparison, and indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen (PSA) and testosterone, respectively, were observed.[69][70]

It is noteworthy that monotherapy with non-steroidal, pure antiandrogens including flutamide and bicalutamide significantly increases androgen and estrogen levels in men, but that this does not occur in women.[71][72][73] As such, bicalutamide on its own may be significantly more effective as an antiandrogen in women relative to men. However, monotherapy with higher dosages of bicalutamide (150 mg/day) has still been found to be clinically effective in the treatment of prostate cancer in men, and thus as an antiandrogen.[14]

Pharmacology

Antiandrogen

Bicalutamide acts as a potent and highly selective competitive silent antagonist of the androgen receptor (AR). This prevents the activation of the AR and subsequent upregulation of androgen-responsive genes by androgens such as testosterone and dihydrotestosterone (DHT).[41][74] Bicalutamide has also notably been found to accelerate the degradation of the AR.[75] Owing to its selectivity, unlike steroidal antiandrogens such as cyproterone acetate and megestrol acetate,[76] bicalutamide does not additionally inhibit or suppress androgen production in the body – instead, it exclusively blocks androgen binding and subsequent receptor activation at the level of the AR.[77]

Based on animal research, it was initially thought that bicalutamide was unable to cross the blood-brain-barrier and hence was a peripherally-selective antiandrogen.[41][69] This conclusion was drawn from the finding that bicalutamide does not increase luteinizing hormone (LH) or testosterone levels in animals (including in rats and dogs),[41][69][78][79] as antiandrogens like flutamide normally do this by blocking ARs in the hypothalamus and pituitary gland and thereby disinhibiting the hypothalamic-pituitary-gonadal (HPG) axis.[35] In humans however, bicalutamide has been found to increase LH and testosterone levels, and to a comparative extent relative to flutamide and nilutamide.[35][54][69][80][81] As such, it appears that bicalutamide does indeed cross the blood-brain-barrier in humans and affect central function, as supported by potential side effects such as diminished sexual interest, fatigue, and depression.[34] It has since been hypothesized that this difference of bicalutamide in animals and humans may be due to species-related differences in drug tissue distribution.[54][81]

As touched on above, blockade of the AR by bicalutamide in the hypothalamus and pituitary gland suppresses the negative feedback of androgens on the release of LH.[35] This, in turn, leads to a significant increase in androgen and estrogen levels.[82] Bicalutamide will more than block the effects of the increased androgen levels (in demonstration, monotherapy is still clinically effective in the treatment of prostate cancer),[14] but the effect of the elevated estrogen levels will remain unopposed and lead to feminizing effects, most notably gynecomastia.[83]

If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels will be prevented and the risks of excessive estrogens, such as gynecomastia, will be reduced.[33] However, since both androgens and estrogens are essential for normal bone metabolism, reducing the anabolic bone effects of both androgens (which increase bone formation by stimulating osteoblasts)[84] and estrogens (which reduce bone resorption by inhibiting osteoclasts)[85] will increase bone loss and promote osteoporosis.[86] In addition, hot flashes, depression, fatigue, and loss of libido are much more likely to occur when bicalutamide is combined with a GnRH analogue.[36][37] It has been proposed that this, including maintenance of mood and sexual interest, may be due to estrogen compensating for the decreased androgen activity in the brain.

Non-steroidal antiandrogens including bicalutamide, flutamide, nilutamide, and enzalutamide show a significantly lower risk of certain side effects, including hot flashes, depression, fatigue, loss of libido, and decreased sexual activity, relative to treatment with GnRH analogues, maximal androgen blockade (MAB), cyproterone acetate, or surgical castration in prostate cancer.[5][35][87][88] For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for MAB and 69% reported complete loss of erectile function relative to 93% for MAB.[5] Another large study reported a rate of impotence of only 9.3% with bicalutamide relative to 6.5% for standard care (the controls), a rate of decreased libido of only 3.6% with bicalutamide relative to 1.2% for standard care, and a rate of 9.2% with bicalutamide for hot flashes relative to 5.4% for standard care.[89] One other study reported decreased libido, impotence, and hot flashes in only 3.8%, 16.9%, and 3.1% of bicalutamide-treated patients, respectively, relative to 1.3%, 7.1%, and 3.6% for placebo.[90]

It has been proposed that the increase in estrogen levels caused by non-steroidal antiandrogens compensates for the androgen blockade in the brain, which may explain the above-described difference (as GnRH analogues, MAB, and cyproterone acetate, contrarily, decrease both androgen and estrogen levels).[87][88][91] In regards to sexual interest and function, this idea is supported by a variety of findings, including animal studies showing that estrogen deficiency results in impaired sexual behavior, that treatment with tamoxifen results in significantly lowered libido in 30% of men being treated with it for male breast cancer, and that in men with congenital estrogen deficiency, estrogen administration restores libido and the frequency of sexual intercourse, among others.[87][88][91] It has been proposed that due to the lower relative effect of non-steroidal antiandrogens including bicalutamide and flutamide on sexual interest and activity, with two-thirds of advanced or metastatic prostate cancer patients treated with non-steroidal antiandrogens retaining sexual interest, these agents may be preferable and result in improved quality of life for those who wish to retain sexual interest and function relative to other antiandrogen therapies in prostate cancer.[35]

Several metabolites of testosterone and DHT, including estradiol, 3α-androstanediol, and 3β-androstanediol, are potent estrogens, and 3β-androstanediol is also a potent GABAA receptor-potentiating neurosteroid.[92][93] Due to the fact that bicalutamide does not lower androgen levels, the levels of these androgen metabolites are likely not lowered either, unlike with therapies such as GnRH analogues. These steroids have been found to have AR-independent positive effects on sexual motivation,[92][93][94] and may explain the preservation of sexual interest and function by bicalutamide and other non-steroidal antiandrogens. They also have antidepressant and anxiolytic effects,[95][96][97] and may account for the lower incidence of depression with bicalutamide and other non-steroidal antiandrogens relative to other therapies.

Unlike with antigonadotropic antiandrogens such as cyproterone acetate, spironolactone, and GnRH analogues, it has been reported that bicalutamide monotherapy (at 50 mg/day) has very little effect on the ultrastructure of the testes and on sperm maturation even after long-term therapy (>4 years).[42] This may be explained by the fact that testosterone levels are far higher in the testes than in the rest of the body (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels, to demonstrate),[98] and systemic bicalutamide therapy is likely unable to result in intratesticular concentrations of the drug that are able to significantly block androgen action in this part of the body due to the higher androgen levels that are present.[42] This is especially so considering that bicalutamide increases circulating testosterone levels and by extension gonadal testosterone production by up to two-fold in males.[82] In contrast to bicalutamide and other pure/non-steroidal antiandrogens, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn suppresses testosterone production by the testes as well as other gonadotropin effects on the testes. As such, bicalutamide and other non-steroidal antiandrogens may uniquely preserve testicular function and spermatogenesis and thus male fertility.[42][99]

The activity of bicalutamide lies in the R-isomer, which binds to the AR with an affinity that is about 30-fold higher than that of the S-isomer.[77] The active R-isomer also has a much longer half-life than the S-isomer.[77] At steady-state, serum levels of (R)-bicalutamide are about 100-fold greater than those of (S)-bicalutamide.[100]

Though a pure antagonist of the AR under normal circumstances, bicalutamide, as well as other earlier antiandrogens, have been found to possess partial agonist properties in the setting of AR overexpression or certain mutations in the ligand-binding domain (LBD) of the AR.[101] As both of these circumstances can eventually occur in prostate cancer, resistance to bicalutamide usually develops and the drug has the potential to paradoxically stimulate tumor growth when this happens.[101][102] This is the mechanism of the phenomenon of antiandrogen withdrawal syndrome.[102] The newer drug, enzalutamide, does not have agonistic properties in the context of overexpression of the AR, though certain mutations in the AR can still convert it from an antagonist to agonist.[101]

Other actions

Bicalutamide, as well as enzalutamide, have been found to act as inhibitors of ABCB1 (P-glycoprotein) efflux and ATPase activity.[103][104][105] This action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells.[103][104][105]

Bicalutamide has been identified as a strong CYP27A1 inhibitor in vitro.[106] CYP27A1 converts cholesterol into 27-hydroxycholesterol, an oxysterol that has multiple biological functions, including direct, tissue-specific activation of the estrogen receptor (ER) (it has been characterized as a selective estrogen receptor modulator) and the liver X receptor.[106] 27-Hydroxycholesterol has been found to increase ER-positive breast cancer cell growth via its estrogenic action, and hence, it has been proposed that bicalutamide and other CYP27A1 inhibitors may be effective as adjuvant therapies to aromatase inhibitors in the treatment of ER-positive breast cancer.[106]

Pharmacokinetics

Dosage and absorption

Bicalutamide is used in dosages of 50 mg/day in combination with a GnRH analogue in the treatment of prostate cancer and at a dosage of 150 mg/day as a monotherapy for prostate cancer.[1] Bicalutamide has been found to be ineffective as a monotherapy in prostate cancer at a dosage of 50 mg/day.[63]

Bicalutamide has been used at a dosage of 25 mg/day in the treatment of hirsutism in women.[7][8][24]

Dosages of bicalutamide of 300 mg, 450 mg, and 600 mg per day all give similar plasma levels of the drug, indicating a saturation of absorption.[107] At a 300 mg per day dosage, plasma levels are about 50% higher relative to 150 mg per day, while plasma levels are only about 15% higher relative to 200 mg per day.[107] As such, plasma levels of bicalutamide reach a plateau at 300 mg per day, with higher dosages being ineffective in raising plasma levels further.[107] In accordance, the effectiveness, tolerability, and toxicity of 150 mg, 300 mg, 450 mg, and 600 mg per day dosages of bicalutamide are all similar.[107] However, there is some evidence of greater effectiveness of 300 mg per day (and the equivalent 450 mg and 600 mg dosages) relative to 150 mg per day in the treatment of prostate cancer.[107]

Dosages of bicalutamide of 10 mg, 30 mg, and 50 mg per day have been found to produce a moderate effect on sex hormone levels in men with prostate cancer, indicating that the drug has clinically-relevant antiandrogen effects at a dosage as low as 10 mg/day in males.[108]

Duration and metabolism

Bicalutamide has a very long serum half-life of about 6 days with a single dose,[1] and a half-life of 7–10 days with repeated administration, allowing for once-daily dosing.[2]

Bicalutamide is almost exclusively metabolized by the enzyme CYP3A4.[54][100]

It has been reported that bicalutamide may have the potential to inhibit the enzymes CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6, based on in vitro research.[54] However, no relevant inhibition of CYP3A4 has been observed in vivo with bicalutamide at a dose of 150 mg (using midazolam as a specific marker of CYP3A4).[54] In animals, bicalutamide has been found to be an inducer of certain cytochrome P450 enzymes.[54] However, dosages of 150 mg/day or less have shown no evidence of this in humans.[54]

Research

Bicalutamide has been tested with good results for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in a phase II study and has been used off-label for this indication.[109][110][111] The newer non-steroidal antiandrogen enzalutamide may also hold some promise for this type of cancer but has been so far tested only in vitro.[citation needed]

Bicalutamide has been researched in clinical trials for ovarian cancer, with effectiveness observed.[112]

See also

References

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External links

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  68. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  69. ↑ 69.0 69.1 69.2 69.3 Lua error in package.lua at line 80: module 'strict' not found.
  70. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  71. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  72. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  73. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  74. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  75. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  76. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  77. ↑ 77.0 77.1 77.2 Lua error in package.lua at line 80: module 'strict' not found.
  78. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  79. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  80. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  81. ↑ 81.0 81.1 Lua error in package.lua at line 80: module 'strict' not found.
  82. ↑ 82.0 82.1 Lua error in package.lua at line 80: module 'strict' not found.
  83. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  84. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  85. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  86. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  87. ↑ 87.0 87.1 87.2 Lua error in package.lua at line 80: module 'strict' not found.
  88. ↑ 88.0 88.1 88.2 Lua error in package.lua at line 80: module 'strict' not found.
  89. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  90. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  91. ↑ 91.0 91.1 Lua error in package.lua at line 80: module 'strict' not found.
  92. ↑ 92.0 92.1 Lua error in package.lua at line 80: module 'strict' not found.
  93. ↑ 93.0 93.1 Lua error in package.lua at line 80: module 'strict' not found.
  94. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  95. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  96. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  97. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  98. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  99. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  100. ↑ 100.0 100.1 Lua error in package.lua at line 80: module 'strict' not found.
  101. ↑ 101.0 101.1 101.2 Lua error in package.lua at line 80: module 'strict' not found.
  102. ↑ 102.0 102.1 Lua error in package.lua at line 80: module 'strict' not found.
  103. ↑ 103.0 103.1 Lua error in package.lua at line 80: module 'strict' not found.
  104. ↑ 104.0 104.1 Lua error in package.lua at line 80: module 'strict' not found.
  105. ↑ 105.0 105.1 Lua error in package.lua at line 80: module 'strict' not found.
  106. ↑ 106.0 106.1 106.2 Lua error in package.lua at line 80: module 'strict' not found.
  107. ↑ 107.0 107.1 107.2 107.3 107.4 Lua error in package.lua at line 80: module 'strict' not found.
  108. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  109. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  110. ↑ Clinical trial number NCT00468715 for "Bicalutamide in Treating Patients With Metastatic Breast Cancer" at ClinicalTrials.gov
  111. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  112. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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