Prostate cancer medical therapy: Difference between revisions

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{{CMG}}
 
{{CMG}} {{AE}} {{sali}}
{{Prostate cancer}}
{{Prostate cancer}}


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===Radiation therapy===
===Radiation therapy===
* [[Radiotherapy]] uses [[ionizing radiation]] to kill prostate cancer cells. When absorbed in tissue, [[ionizing radiation]] such as [[Gamma]] and [[x-rays]] damage the [[DNA]] in cells, which increases the probability of [[apoptosis]].
* [[Radiotherapy]] uses [[ionizing radiation]] to kill [[prostate]] [[cancer]] cells. When absorbed in tissue, [[ionizing radiation]] such as [[Gamma]] and [[x-rays]] damage the [[DNA]] in cells, which increases the probability of [[apoptosis]].
* Radiation therapy is commonly used in prostate cancer treatment
* Radiation therapy is commonly used in prostate cancer treatment.
* It may be used instead of [[surgery]] or after surgery in early stage prostate cancer. [[Radiation therapy]] appears to cure small [[tumors]] that are confined to the prostate just about as well as surgery.<ref name=”cancergov”>National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq</ref>
* It may be used instead of [[surgery]] or after surgery in early stage prostate cancer. [[Radiation therapy]] appears to cure small [[tumors]] that are confined to the prostate just about as well as surgery.<ref name="”cancergov”">National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq</ref>
* In advanced stages of prostate cancer, radiation is used to treat painful [[bone metastases]].
* In advanced stages of prostate cancer, radiation is used to treat painful [[bone metastases]].
* Radiation therapy is often offered to men whose medical problems make [[surgery]] more risky.
* Radiation therapy is often offered to men whose medical problems make [[surgery]] more risky.
* Two different kinds of radiation therapy are used in prostate cancer treatment:<ref name=”cancergov”>National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq</ref>  
* Two different kinds of radiation therapy are used in prostate cancer treatment:<ref name="”cancergov”">National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq</ref>
* Rising PSA on ADT, if testosterone level is not completely suppressed, luteinizing hormone (LH) can be measured.
* If its non-suppressed LH, correct administration of the GnRH analogue can be verified.<ref name="pmid26041764">{{cite journal |vauthors=Gillessen S, Omlin A, Attard G, de Bono JS, Efstathiou E, Fizazi K, Halabi S, Nelson PS, Sartor O, Smith MR, Soule HR, Akaza H, Beer TM, Beltran H, Chinnaiyan AM, Daugaard G, Davis ID, De Santis M, Drake CG, Eeles RA, Fanti S, Gleave ME, Heidenreich A, Hussain M, James ND, Lecouvet FE, Logothetis CJ, Mastris K, Nilsson S, Oh WK, Olmos D, Padhani AR, Parker C, Rubin MA, Schalken JA, Scher HI, Sella A, Shore ND, Small EJ, Sternberg CN, Suzuki H, Sweeney CJ, Tannock IF, Tombal B |title=Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015 |journal=Ann Oncol |volume=26 |issue=8 |pages=1589–604 |date=August 2015 |pmid=26041764 |pmc=4511225 |doi=10.1093/annonc/mdv257 |url=}}</ref>
:* [[External beam radiotherapy|External beam radiation therapy]]
:* [[External beam radiotherapy|External beam radiation therapy]]
:* [[Brachytherapy]]
:* [[Brachytherapy]]


====Side effects of radiation therapy====
====Side effects of radiation therapy====
* Both types of [[radiation therapy]]
* Both types of [[radiation therapy]] have following adverse effects:<ref>{{cite journal| last=Lawton| first=CA| coauthors=Won M, Pilepich MV, Asbell SO, Shipley WU, Hanks GE, Cox JD, Perez CA, Sause WT, Doggett SR, et al| title=Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706| journal=Int J Radiat Oncol Biol Phys| year=1991| month=September| volume=21| issue=4| pages=935–9| pmid=1917622}}</ref><ref>{{cite journal| last=Lawton| first=CA| coauthors=Won M, Pilepich MV, Asbell SO, Shipley WU, Hanks GE, Cox JD, Perez CA, Sause WT, Doggett SR, et al| title=Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706| journal=Int J Radiat Oncol Biol Phys| year=1991| month=September| volume=21| issue=4| pages=935–9| pmid=1917622}}</ref>
:* [[Diarrhea]]
:* [[Diarrhea]]
:* Mild [[Gastrointestinal bleeding|rectal bleeding]]<ref>{{cite journal| last=Lawton| first=CA| coauthors=Won M, Pilepich MV, Asbell SO, Shipley WU, Hanks GE, Cox JD, Perez CA, Sause WT, Doggett SR, et al| title=Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706| journal=Int J Radiat Oncol Biol Phys| year=1991| month=September| volume=21| issue=4| pages=935–9| pmid=1917622}}</ref>
:* Mild [[Gastrointestinal bleeding|rectal bleeding]]
* [[External beam radiotherapy|External beam radiation therapy]]
* [[External beam radiotherapy|External beam radiation therapy]] has following adverse effects:<ref>{{cite journal| last=Brenner| first=DJ| coauthors=Curtis RE, Hall EJ, Ron E| title=Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery| journal=Cancer| year=2000| month=January 15| volume=88| issue=2| pages=398–406| pmid=10640974| doi=10.1002/(SICI)1097-0142(20000115)88:2<398::AID-CNCR22>3.0.CO;2-V}}</ref>
:* [[Colon cancer]]  
:* [[Colon cancer]]  
:* [[Bladder cancer]]<ref>{{cite journal| last=Brenner| first=DJ| coauthors=Curtis RE, Hall EJ, Ron E| title=Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery| journal=Cancer| year=2000| month=January 15| volume=88| issue=2| pages=398–406| pmid=10640974| doi=10.1002/(SICI)1097-0142(20000115)88:2<398::AID-CNCR22>3.0.CO;2-V}}</ref>
:* [[Bladder cancer]]


===Hormonal therapy===
===Hormonal therapy===
* [[Hormonal therapy (oncology)|Hormonal therapy]] uses medications or surgery to block prostate cancer cells from getting [[dihydrotestosterone]] (DHT), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate cancer to stop growing and even shrink.<ref>{{cite journal| last=Robson| first=M|author2=Dawson N| title=How is androgen-dependent metastatic prostate cancer best treated?| journal=Hematol Oncol Clin North Am|date=June 1996| volume=10| issue=3| pages=727–47| pmid=8773508|doi=10.1016/S0889-8588(05)70364-6}} Review.</ref>
* [[Hormonal therapy (oncology)|Hormonal therapy]] uses medications or surgery to block prostate cancer cells from getting [[dihydrotestosterone]] ([[Dihydrotestosterone|DHT]]), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking [[Dihydrotestosterone|DHT]] often causes prostate cancer to stop growing and even shrink.<ref>{{cite journal| last=Robson| first=M|author2=Dawson N| title=How is androgen-dependent metastatic prostate cancer best treated?| journal=Hematol Oncol Clin North Am|date=June 1996| volume=10| issue=3| pages=727–47| pmid=8773508|doi=10.1016/S0889-8588(05)70364-6}} Review.</ref>
:* Hormonal therapy for prostate cancer targets the pathways the body uses to produce DHT. A [[feedback loop]] involving the [[testicles]], the [[hypothalamus]], and the [[pituitary]], [[adrenal]], and prostate glands controls the blood levels of DHT. First, low blood levels of DHT stimulate the [[hypothalamus]] to produce [[gonadotropin releasing hormone]] (GnRH). GnRH then stimulates the [[pituitary gland]] to produce [[luteinizing hormone]] (LH), and LH stimulates the [[testicles]] to produce testosterone. Finally, [[testosterone]] from the [[testicles]] and [[dehydroepiandrosterone]] from the [[adrenal gland]]s stimulate the prostate to produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting this pathway at any point.
* Hormonal therapy for prostate cancer targets the pathways the body uses to produce [[DHT]]. A [[feedback loop]] involving [[testicles]], [[hypothalamus]], [[pituitary]], [[adrenal]], and prostate glands to control the blood levels of [[DHT]]. First, low blood levels of [[DHT]] stimulate the [[hypothalamus]] to produce [[gonadotropin releasing hormone]] (GnRH). GnRH then stimulates the [[pituitary gland]] to produce [[luteinizing hormone]] (LH), and LH stimulates the [[testicles]] to produce testosterone. Finally, [[testosterone]] from the [[testicles]] and [[dehydroepiandrosterone]] from the [[adrenal gland]]s stimulate the prostate to produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting this pathway at any point.
* However, hormonal therapy rarely cures prostate cancer because cancers which initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is therefore usually used when cancer has spread from the prostate.<ref>{{cite journal| last=Robson| first=M|author2=Dawson N| title=How is androgen-dependent metastatic prostate cancer best treated?| journal=Hematol Oncol Clin North Am|date=June 1996| volume=10| issue=3| pages=727–47| pmid=8773508|doi=10.1016/S0889-8588(05)70364-6}} Review.</ref>
* Hormonal therapy rarely cures prostate cancer because cancers which initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is therefore usually used when cancer has spread from the prostate.<ref>{{cite journal| last=Robson| first=M|author2=Dawson N| title=How is androgen-dependent metastatic prostate cancer best treated?| journal=Hematol Oncol Clin North Am|date=June 1996| volume=10| issue=3| pages=727–47| pmid=8773508|doi=10.1016/S0889-8588(05)70364-6}} Review.</ref>
* It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.<ref>{{cite journal| last=Robson| first=M| coauthors=Dawson N| title=How is androgen-dependent metastatic prostate cancer best treated?| journal=Hematol Oncol Clin North Am| year=1996| month=June| volume=10| issue=3| pages=727–47| pmid=8773508| doi=10.1016/S0889-8588(05)70364-6}} Review.</ref>
* It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.<ref>{{cite journal| last=Robson| first=M| coauthors=Dawson N| title=How is androgen-dependent metastatic prostate cancer best treated?| journal=Hematol Oncol Clin North Am| year=1996| month=June| volume=10| issue=3| pages=727–47| pmid=8773508| doi=10.1016/S0889-8588(05)70364-6}} Review.</ref>


* There are several forms of hormonal therapy:<ref name=”cancergov”>National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq</ref>  
* There are several forms of hormonal therapy:<ref name="”cancergov”">National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq</ref><ref>{{cite journal| last=Loblaw| first=DA| coauthors=Mendelson DS, Talcott JA, Virgo KS, Somerfield MR, Ben-Josef E, Middleton R, Porterfield H, Sharp SA, Smith TJ, Taplin ME, Vogelzang NJ, Wade JL Jr, Bennett CL, Scher HI; American Society of Clinical Oncology| title=American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer| journal=J Clin Oncol| year=2004| month=July 15| volume=22| issue=14| pages=2927–41| pmid=15184404| doi=10.1200/JCO.2004.04.579}} Erratum in: J Clin Oncol. 2004 November 1;22(21):4435.</ref>  
*[[Antiandrogens]]
:* [[Antiandrogens]]
:* [[Flutamide]]
::* [[Flutamide]]
:* [[Bicalutamide]]
::* [[Bicalutamide]]
:* [[Nilutamide]]
::* [[Nilutamide]]
:* [[Cyproterone acetate]] 
::* [[Cyproterone acetate]] 
:* [[Aminoglutethimide]]
:* [[Gonadotropin-releasing hormone analog|GnRH antagonists]]
* [[Gonadotropin-releasing hormone analog|GnRH antagonists]]<ref>{{cite journal| last=Loblaw| first=DA| coauthors=Mendelson DS, Talcott JA, Virgo KS, Somerfield MR, Ben-Josef E, Middleton R, Porterfield H, Sharp SA, Smith TJ, Taplin ME, Vogelzang NJ, Wade JL Jr, Bennett CL, Scher HI; American Society of Clinical Oncology| title=American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer| journal=J Clin Oncol| year=2004| month=July 15| volume=22| issue=14| pages=2927–41| pmid=15184404| doi=10.1200/JCO.2004.04.579}} Erratum in: J Clin Oncol. 2004 November 1;22(21):4435.</ref>
:* [[Estrogen ]]
* [[Estrogen ]]
:* Antiadrenal therapy
* [[Antiadrenal]] therapy
::* [[Ketoconazole]]
:* [[Ketoconazole]]
::* [[Aminoglutethimide]]
:* [[Aminoglutethimide]]


=== Chemotherapy ===
=== Chemotherapy ===
* [[Chemotherapy]] is used in the treatment of castrate resistant prostate cancer (also called hormone-refractory prostate cancer).
* [[Chemotherapy]] is used in the treatment of castrate resistant prostate cancer (also called hormone-refractory prostate cancer).
* The most commonly used regimen combines the chemotherapeutic drug liste below:
* The most commonly used regimen combines the chemotherapeutic drug liste below:
:* [[Docetaxel]] with a
:* [[Docetaxel]]
:* [[Abiraterone]]
:* [[Corticosteroid]]
:* [[Corticosteroid]]
::* [[Prednisone]]<ref>{{cite journal| last=Tannock| first=IF| coauthors=de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators| title=Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer| journal=N Engl J Med| year=2004| month=October 7| volume=351| issue=15| pages=1502–12| pmid=1547021| doi=10.1056/NEJMoa040720}}</ref>
::* [[Prednisone]]<ref>{{cite journal| last=Tannock| first=IF| coauthors=de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators| title=Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer| journal=N Engl J Med| year=2004| month=October 7| volume=351| issue=15| pages=1502–12| pmid=1547021| doi=10.1056/NEJMoa040720}}</ref>
Line 54: Line 57:
===Other Medications===
===Other Medications===
* [[Bisphosphonates]]
* [[Bisphosphonates]]
:* [[Bisphosphonates]] such as [[zoledronic acid]] have been shown to delay skeletal complications such as [[fracture]]s or the need for radiation therapy in patients with hormone-refractory metastatic prostate cancer.<ref>{{cite journal | author=Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B | title=A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma | journal=J Natl Cancer Inst | year=2002 | pages=1458–68 | volume=94 | issue=19  | pmid=12359855}}</ref>   
:* [[Bisphosphonates]] such as [[zoledronic acid]] have been shown to delay [[skeletal]] [[complications]] such as [[fracture]]s or the need for [[radiation therapy]] in patients with hormone-refractory [[metastatic]] prostate cancer.<ref>{{cite journal | author=Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B | title=A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma | journal=J Natl Cancer Inst | year=2002 | pages=1458–68 | volume=94 | issue=19  | pmid=12359855}}</ref>   
* [[Analgesics]]
* [[Analgesics]]
:* [[Bone pain]] due to [[metastatic]] disease is treated with [[opioid]]. [[Analgesic|Pain relievers]] such as [[morphine]] and [[oxycodone]]
:* [[Bone pain]] due to [[metastatic]] disease is treated with [[opioid]]. [[Analgesic|Pain relievers]] such as [[morphine]] and [[oxycodone]].


==References==
==References==
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[[Category:Urology]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]

Latest revision as of 18:54, 8 February 2021


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

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Overview

The predominant therapy for prostate cancer is surgical resection. Adjunctive chemotherapy, radiation, hormonal therapy, bisphosphonates, and analgesics may be required.

Medical Therapy

Radiation therapy

  • Radiotherapy uses ionizing radiation to kill prostate cancer cells. When absorbed in tissue, ionizing radiation such as Gamma and x-rays damage the DNA in cells, which increases the probability of apoptosis.
  • Radiation therapy is commonly used in prostate cancer treatment.
  • It may be used instead of surgery or after surgery in early stage prostate cancer. Radiation therapy appears to cure small tumors that are confined to the prostate just about as well as surgery.[1]
  • In advanced stages of prostate cancer, radiation is used to treat painful bone metastases.
  • Radiation therapy is often offered to men whose medical problems make surgery more risky.
  • Two different kinds of radiation therapy are used in prostate cancer treatment:[1]
  • Rising PSA on ADT, if testosterone level is not completely suppressed, luteinizing hormone (LH) can be measured.
  • If its non-suppressed LH, correct administration of the GnRH analogue can be verified.[2]

Side effects of radiation therapy

Hormonal therapy

  • Hormonal therapy uses medications or surgery to block prostate cancer cells from getting dihydrotestosterone (DHT), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate cancer to stop growing and even shrink.[6]
  • Hormonal therapy for prostate cancer targets the pathways the body uses to produce DHT. A feedback loop involving testicles, hypothalamus, pituitary, adrenal, and prostate glands to control the blood levels of DHT. First, low blood levels of DHT stimulate the hypothalamus to produce gonadotropin releasing hormone (GnRH). GnRH then stimulates the pituitary gland to produce luteinizing hormone (LH), and LH stimulates the testicles to produce testosterone. Finally, testosterone from the testicles and dehydroepiandrosterone from the adrenal glands stimulate the prostate to produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting this pathway at any point.
  • Hormonal therapy rarely cures prostate cancer because cancers which initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is therefore usually used when cancer has spread from the prostate.[7]
  • It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.[8]
  • There are several forms of hormonal therapy:[1][9]

Chemotherapy

  • Chemotherapy is used in the treatment of castrate resistant prostate cancer (also called hormone-refractory prostate cancer).
  • The most commonly used regimen combines the chemotherapeutic drug liste below:

Other Medications

References

  1. 1.0 1.1 1.2 National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/publications/pdq
  2. Gillessen S, Omlin A, Attard G, de Bono JS, Efstathiou E, Fizazi K, Halabi S, Nelson PS, Sartor O, Smith MR, Soule HR, Akaza H, Beer TM, Beltran H, Chinnaiyan AM, Daugaard G, Davis ID, De Santis M, Drake CG, Eeles RA, Fanti S, Gleave ME, Heidenreich A, Hussain M, James ND, Lecouvet FE, Logothetis CJ, Mastris K, Nilsson S, Oh WK, Olmos D, Padhani AR, Parker C, Rubin MA, Schalken JA, Scher HI, Sella A, Shore ND, Small EJ, Sternberg CN, Suzuki H, Sweeney CJ, Tannock IF, Tombal B (August 2015). "Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015". Ann Oncol. 26 (8): 1589–604. doi:10.1093/annonc/mdv257. PMC 4511225. PMID 26041764.
  3. Lawton, CA (1991). "Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706". Int J Radiat Oncol Biol Phys. 21 (4): 935–9. PMID 1917622. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help)
  4. Lawton, CA (1991). "Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706". Int J Radiat Oncol Biol Phys. 21 (4): 935–9. PMID 1917622. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help)
  5. Brenner, DJ (2000). "Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery". Cancer. 88 (2): 398–406. doi:10.1002/(SICI)1097-0142(20000115)88:2<398::AID-CNCR22>3.0.CO;2-V. PMID 10640974. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help)
  6. Robson, M; Dawson N (June 1996). "How is androgen-dependent metastatic prostate cancer best treated?". Hematol Oncol Clin North Am. 10 (3): 727–47. doi:10.1016/S0889-8588(05)70364-6. PMID 8773508. Review.
  7. Robson, M; Dawson N (June 1996). "How is androgen-dependent metastatic prostate cancer best treated?". Hematol Oncol Clin North Am. 10 (3): 727–47. doi:10.1016/S0889-8588(05)70364-6. PMID 8773508. Review.
  8. Robson, M (1996). "How is androgen-dependent metastatic prostate cancer best treated?". Hematol Oncol Clin North Am. 10 (3): 727–47. doi:10.1016/S0889-8588(05)70364-6. PMID 8773508. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help) Review.
  9. Loblaw, DA (2004). "American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer". J Clin Oncol. 22 (14): 2927–41. doi:10.1200/JCO.2004.04.579. PMID 15184404. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help) Erratum in: J Clin Oncol. 2004 November 1;22(21):4435.
  10. Tannock, IF (2004). "Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer". N Engl J Med. 351 (15): 1502–12. doi:10.1056/NEJMoa040720. PMID 1547021. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help)
  11. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B (2002). "A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma". J Natl Cancer Inst. 94 (19): 1458–68. PMID 12359855.

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