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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/24 01:33:55」(JST)

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Oxaliplatin, marketed as Eloxatin by Sanofi, is a platinum-based antineoplastic agent used in cancer chemotherapy.^[2]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.^[3]

Medical uses

Oxaliplatin is used for treatment of colorectal cancer, typically along with folinic acid and 5-fluorouracil in a combination known as FOLFOX. Oxaliplatin has been compared with other platinum compounds used for advanced cancers, such as cisplatin and carboplatin.

Advanced colorectal cancer

In clinical studies, oxaliplatin by itself has modest activity against advanced colorectal cancer.^[4] When compared with just 5-fluorouracil and folinic acid administered according to the de Gramont regimen, a FOLFOX4 regime produced no significant increase in overall survival, but did produce an improvement in progression-free survival, the primary end-point of the phase III randomized trial.^[5]

Adjuvant treatment of colorectal cancer

After and/or before^[6] the curative resection of colorectal cancer, chemotherapy based on 5-fluorouracil and folinic acid reduces the risk of relapse. The benefit is clinically relevant when cancer has spread to locoregional lymph nodes or penetrated through the wall of the rectum or colon (stage III, Dukes C). The addition of oxaliplatin improves relapse-free survival, but data on overall survival have not yet been published in extenso.

When cancer has not spread to the locoregional lymph nodes, nor penetrated through the wall of the rectum or colon (stage II, Dukes B) the benefit of chemotherapy is marginal and the decision on whether to give adjuvant chemotherapy should be carefully evaluated by discussing with the patient the realistic benefits and the possible toxic side effects of treatment. This is even more relevant when the oncologist proposes treatment with oxaliplatin.

Adverse effects

Side-effects of oxaliplatin treatment can potentially include:

Neurotoxicity leading to chemotherapy-induced peripheral neuropathy, a progressive, enduring and often irreversible tingling numbness, intense pain and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs, often with deficits in proprioception.^[7]
Fatigue
Nausea, vomiting, or diarrhea
Neutropenia (low number of a type of white blood cells)
Ototoxicity (hearing loss)
Extravasation if oxaliplatin leaks from the infusion vein it may cause severe damage to the connective tissues.
Hypokalemia (low blood potassium), which is more common in women than men^[8]
Persistent hiccups^[9]

In addition, some patients may experience an allergic reaction to platinum-containing drugs. This is more common in women.^[8]

Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.^[7]

Structure and mechanism

The compound features a square planar platinum(II) center. In contrast to cisplatin and carboplatin, oxaliplatin features the bidentate ligand 1,2-diaminocyclohexane in place of the two monodentate ammine ligands. It also features a bidentate oxalate group.^[10]

According to in vivo studies, oxaliplatin fights carcinoma of the colon through non-targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA,^[11] which prevent DNA replication and transcription, causing cell death.

History

Oxaliplatin was discovered in 1976 at Nagoya City University by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 in 1979. Oxaliplatin was subsequently in-licensed by Debiopharm and developed as an advanced colorectal cancer treatment. Debio licensed the drug to Sanofi-Aventis in 1994. It gained European approval in 1996 (initially in France) and approval by the U.S. Food and Drug Administration in 2002. Generic oxaliplatin was first approved in the United States in August 2009.^[12] Patent disputes caused generic production to stop in 2010, but it restarted in 2012.^[13]^[14]

Patent information

Eloxatin is covered by patent numbers 5338874 (Expiry Apr 07,2013), 5420319 (Expiry Aug 08,2016), 5716988 (Expiry Aug 07,2015) and 5290961 (Expiry Jan 12, 2013) (see Electronic Orange Book patent info for Eloxatin).^[15] Exclusivity code I-441, which expired on Nov 04, 2007, is for use combination with infusional 5-FU/LV for adjuvant treatment stage III colon cancer patients who have undergone complete resection primary tumor-based on improvement in disease free survival with no demonstrated benefit overall survival after 4 years. Exclusivity code NCE, New Chemical Entity, expired on Aug 09, 2007.^[15]

References

^ Ehrsson H, Wallin I, Yachnin J (2002). "Pharmacokinetics of oxaliplatin in humans". Medical Oncology 19 (4): 261–265. doi:10.1385/MO:19:4:261. PMID 12512920.
^ Apps, M. G., Choi, E. H. Y., Wheate, N. J. (2015). "The state-of-play and future of platinum drugs". Endocrine-related Cancer 22 (4): 219–233. doi:10.1530/ERC-15-0237. PMID 26113607.
^ "www.who.int" (PDF).
^ Becouarn Y, Ychou M, Ducreux M, et al. (1998). "Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers". J Clin Oncol 16 (8): 2739–44. PMID 9704726.
^ De Gramont A, Figer A, Seymour M, et al. (2000). "Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer". J Clin Oncol 18 (16): 2938–47. PMID 10944126.
^ National Cancer Institute, Rectal Cancer Treatment (PDQ®)
^ ^a ^b Pasetto LM, D'Andrea MR, Rossi E, Monfardini S (August 2006). "Oxaliplatin-related neurotoxicity: how and why?". Crit. Rev. Oncol. Hematol. 59 (2): 159–68. doi:10.1016/j.critrevonc.2006.01.001. PMID 16806962.
^ ^a ^b Chay WY, Chew L, Yeoh TT, Tan MH (May 2010). "An association between transient hypokalemia and severe acute oxaliplatin-related toxicity predominantly in women". Acta Oncol 49 (4): 515–7. doi:10.3109/02841860903464015. PMID 20092386.
^ http://www.drugs.com/sfx/oxaliplatin-side-effects.html
^ Apps, M. G., Choi, E. H. Y., Wheate, N. J. (2015). "The state-of-play and future of platinum drugs". Endocrine-related Cancer 22 (4): 219–233. doi:10.1530/ERC-15-0237. PMID 26113607.
^ Graham, Joanne; Mushin, Mohamed; Kirkpatrick, Peter (January 2004). "Oxaliplatin". Nature Reviews Drug Discovery 3 (1): 11–2. doi:10.1038/nrd1287. PMID 14756144.
^ "Generic Eloxatin availability". Drugs.com. Retrieved 19 April 2014.
^ http://www.prnewswire.com/news-releases/hospira-announces-us-re-launch-of-generic-oxaliplatin-injection-165568176.html
^ "Top 10 best-selling cancer drugs: Eloxatin–$1.2 billion". FiercePharma. 15 May 2012. Retrieved 20 April 2014.
^ ^a ^b Orange Book. accessdata.fda.gov. URL: http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021759&Product_No=001&table1=OB_Rx. Accessed on: July 22, 2007.

External links

Oxaliplatin - Official web site of manufacturer.
Oxaliplatin Prescribing Information - Official prescribing information.
NCI Drug Information Summary on Oxaliplatin

Additional sources

Graham J, Mushin M, Kirkpatrick P (2004). "Oxaliplatin" (PDF). Nat Rev Drug Discov 3 (1): 11–2. doi:10.1038/nrd1287. PMID 14756144.

UpToDate Contents

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1. 成人における抗癌剤の投与 dosing of anticancer agents in adults
2. 転移性大腸癌に対する全身化学療法：終了した臨床試験 systemic chemotherapy for metastatic colorectal cancer completed clinical trials
3. プラチナベースの化学療法の神経学的合併症の概要 overview of neurologic complications of platinum based chemotherapy
4. 手術不能な転移性大腸癌に対する全身化学療法：治療に関する推奨 systemic chemotherapy for nonoperable metastatic colorectal cancer treatment recommendations
5. 緩和ケアの最新情報 whats new in palliative care

English Journal

A preclinical and clinical review of aflibercept for the management of cancer.

Gaya A, Tse V.SourceGuy's and St. Thomas' Hospital, NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, United Kingdom.
Cancer treatment reviews.Cancer Treat Rev.2012 Aug;38(5):484-93. Epub 2012 Jan 20.
Aflibercept, also known as vascular endothelial growth factor (VEGF)-Trap, is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting not only all forms of VEGF-A, but also VEGF-B and placental growth factor. It inhibits VEGF-induced angiogenesis in precl
PMID 22264850

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis.

Modest DP, Reinacher-Schick A, Stintzing S, Giessen C, Tannapfel A, Laubender RP, Brodowicz T, Knittelfelder R, Vrbanec D, Schmiegel W, Heinemann V, Zielinski CC.SourceaDepartment of Medicine III, Klinikum Grosshadern bInstitute of Medical Informatics, Biometry, and Epidemiology, University of Munich, Munich, Germany cDepartment of Internal Medicine, Knappschaftskrankenhaus dCenter for Clinical Studies in Oncology eInstitute of Pathology, Ruhr-University fDepartment of Gastroenterology and Hepatology, Berufsgenossenschaftliche Kliniken Bergmannsheil Bochum, Germany gCECOG, Central European Cooperative Oncology Group hDepartment of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria iKBC Rebro, Oncology Department, Zagreb, Croatia.
Anti-cancer drugs.Anticancer Drugs.2012 Jul;23(6):666-673.
KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.
PMID 22441566

Japanese Journal

Repeated Administration of Amitriptyline Reduces Oxaliplatin-Induced Mechanical Allodynia in Rats

Sada Hikaru,Egashira Nobuaki,Ushio Soichiro [他]
Journal of pharmacological sciences 118(4), 547-551, 2012-04
NAID 40019232647

Oxaliplatin-induced neurotoxicity involves TRPM8 in the mechanism of acute hypersensitivity to cold sensation.

河野　透,Satomi Machiko,Suno Manabu,Kimura Norihisa,Yamazaki Hirotaka,Furukawa Hiroyuki,Matsubara Kazuo
Brain and Behavior 2(1), 68-73, 2012-1
… We hypothesized that the transient receptor potential melastatin 8 (TRPM8), a putative cold and menthol receptor, contributes to oxaliplatin cold hypersensitivity. … To determine whether the TRPM8 is involved in acute OPN, varying concentrations of menthol were topically applied to the tongues of healthy subjects (n = 40) and colorectal cancer patients (n = 36) before and after oxaliplatin administration. …
NAID 120004225238

Related Pictures

★リンクテーブル★

リンク元	「大腸癌」「オキサリプラチン」

「大腸癌」

Oxaliplatin
Systematic (IUPAC) name
	[(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-O,O')platinum(II)
Clinical data
Trade names	Eloxatin
AHFS/Drugs.com	monograph
MedlinePlus	a607035
Pregnancy; category	US: D (Evidence of risk); ;
Legal status	US: ℞-only;
Routes of; administration	Intravenous
Pharmacokinetic data
Bioavailability	Complete
Biological half-life	~10 - 25 minutes
Excretion	Renal
Identifiers
CAS Number	63121-00-6
ATC code	L01XA03
PubChem	CID: 77994
DrugBank	DB00526
ChemSpider	8062727
UNII	04ZR38536J
KEGG	D01790
ChEMBL	CHEMBL414804
PDB ligand ID	1PT (PDBe, RCSB PDB)
Chemical data
Formula	C8H14N2O4Pt
Molecular mass	397.2858 g/mol
(what is this?) (verify)

　　[★]

英: large bowel cancer
同: 結腸直腸癌, colorectal cancer, CRC, colorectal carcinoma、直腸結腸癌
関: 結腸癌 colon cancer colonic cancer。大腸

first aid step1 2006 p.277

概念

大腸に発生した悪性腫瘍の総称
結腸癌、直腸S状部癌、直腸癌を含む。

疫学

死亡率

日本

男性：第４位(肺＞胃＞肝＞大腸)
女性：第１位(大腸＞胃＞肺＞肝＞乳房＞子宮)

米

3rd most common cancer

リスクファクター(first aid step1 2006 p.277)

colorectal villous adenomas
chronic inflammatory bowel disease (especially ulcerative colitis)
high-fat and low-fiber diets
↑ age
家族性大腸腺腫症 familial adenomatous polyposis (FAP)
遺伝性非ポリポーシス大腸癌 hereditary nonpolyposis colorectal cancer (HNPCC)
DCC gene deletion
personal and family history of colon cancer

×Peutz-Jeghers syndromeはリスクファクターではない

好発部位

直腸・S状結腸　＞　上行結腸・盲腸　＞　横行結腸　＞　下行結腸

直腸が50%、S状結腸25% (出典不明)

頻度

肉眼分類

ボールマンの分類に基づく

早期癌

0型(表在型)

0-I型(隆起型)：Ip(隆起型)、Isp(亜有茎型)、Is(無茎型)

0-II型(表面型)：IIa(表面隆起型), IIc(表面陥凹型)

進行癌

1型(腫瘤型)
2型(潰瘍限局型)
3型(潰瘍浸潤型)
4型(びまん浸潤型)

頻度

進行癌：2型(潰瘍限局型) ＞ 3型(潰瘍浸潤型) ＞ 1型(腫瘤型) > 4型(びまん浸潤型)

早期癌を含めると、2型(潰瘍限局型)(80%)に次いで0型(表在型)が多い。

2型で外周の2/3週以上となると、注腸造影でapple core sign として認められる。

病期分類

Dukes分類

A. 癌腫が腸管壁内に限局するもの　←　固有筋層まで(MP。つまりT2)
B. 癌腫が腸壁を貫いて浸潤するが、リンパ節転移のないもの
C. リンパ節転移があるもの

進行病期分類

stage	定義	治療
0	癌が粘膜にとどまっている。(M)	内視鏡
I	癌が大腸壁にとどまっている。(SM,MP)	SM軽度浸潤(＜2cm)では内視鏡、それ以外は手術療法
II	癌が大腸壁の外まで浸潤している。(SS,SE)	手術療法
III	リンパ節転移がある。	手術療法＋補助化学療法
IV	肝転移、肺転移または腹膜播種がある。	手術療法 and/or 化学療法 and/or 放射療法

大腸癌取り扱い規約第7版(2009年)

壁深達度

M：粘膜内まで
SM：粘膜下層まで
MP：固有筋層まで

漿膜を有する部位

SS：MP越えているが漿膜下にとどまる
SE：漿膜表面に露出
SI：他臓器に直接浸潤

漿膜を有しない部位

A：固有筋層を越えて浸潤
AI：他臓器に直接浸潤

進行度

	N0	N1	N2	H1,H2,H3,M1 P1,P2,P3
M	0
SM MP	I	IIIa	IIIb	IV
SS,A SE SI,AI	II	IIIa	IIIb	IV

リンパ節郭清

1群リンパ節郭清：D1：腫瘍付近のリンパ節（傍リンパ節）を切除
2群リンパ節郭清：D2：癌のある腸管を栄養する血管に沿うリンパ節（中間リンパ節）までを切除
3群リンパ節郭清：D3：栄養血管の根元にあるリンパ節（主リンパ節）までを切除

病理

95%が腺癌。高分化型が多い。

症状

腫瘍の局在	右側結腸	左側結腸	S状結腸・直腸
症状	自覚症状に乏しい（貧血、腹部腫瘤、腹痛、まれに腸重積)	イレウス多い、左下腹部痛	血便/粘結弁
症状	下痢	便秘、便通過障害(下血・血便)	便通異常(下痢・便秘、腹部膨満感、しぶり腹、輪状狭窄、糞柱の狭小化)

検査

血液検査

Hb：貧血の徴候がないか

腫瘍マーカー

便潜血

免疫学的便潜血反応：抗ヒトヘモグロビン法

単純X線検査

apple core sign

診断

生検結果による(内視鏡生検)

治療

原則として以下の治療を選択するが、必要に応じて、手術療法、化学療法、放射線療法を組み合わせる。(SSUR.550)

Stage0,StageIの一部：内視鏡的切除

StageI,II：手術療法

StageIII：手術療法＋化学療法

StageIV：手術療法、化学療法、および放射線療法の組み合わせ

早期癌

内視鏡的治療

原則

リンパ節メタなく、腫瘍を一括切除できること。

病期

stage 0 ～ stage I and SM軽度浸潤 and 最大径 2cm以下

適応基準

( M or SM ) and ( 最大経≦2cm ) and ( 肉眼型は問わない )

進行癌

化学療法 (参考3)

補助化学療法：5-FU　＋　ロイコボリン、テガフール・ウラシル(UFT)　＋　ロイコボリン、カペシタビン capecitabine
切除不能進行再発大腸癌：

FOLFIRI療法　→　FOLFOX療法　、　FOLFOX療法　→　FOLFIRI療法　。一次治療にはベバシズマブ、二次治療にはセツキシマブの併用を推奨

FOLFOX療法：fluorouracil(5-FU)、levofolinate(L-LV)、oxaliplatin(L-OHP)
FOLFIRI療法：fluorouracil(5-FU)、levofolinate(L-LV)、irinotecan(CPT-11)

放射線療法
手術療法

stage I～IVで行われる。
原発巣の切除とリンパ節の郭清を行う
転移巣(肝臓、肺)、局所再発に対して：根治性が得られるなら切除。得られないのであれば姑息的治療(肝転移の場合なら、経カテーテル的肝動脈塞栓術
(姑息的に？結腸癌の進展による直腸の狭窄が考慮される場合には)Hartmann手術をおこなう。
(大腸癌の肝転移例に対する手術適応)原発巣が根治的に処理されている場合には積極的に肝切除を行う。肝切除ができない場合は経カテーテル的冠動脈塞栓術を施行(QB.A-194)

術式

結腸癌

結腸部分切除術
回盲部切除術
結腸右半切除術
結腸左半切除術
S状結腸切除術
結腸全摘術

検診

スクリーニング

USPSTF

50-75歳の成人に便潜血・大腸内視鏡を推奨する(A)
85歳以上の高齢者には推奨しない(D)
リスクが有る患者には40歳、ないし発症した親族の年齢の10年前から大腸内視鏡を5年ごとに行う

リスク：2人の大腸癌ないし腺腫性ポリープの家族歴あり

大腸内視鏡であれば10年毎でよいが、これをやらない場合には毎年の便潜血を。

参考

1. がん情報 - 結腸および直腸 Colon and Rectum（C18-C20）

http://ganjoho.ncc.go.jp/data/hospital/cancer_registration/odjrh3000000hrgr-att/20070723022_c18colon_and_rectum.pdf

2. 大腸低分化腺癌,印環細胞癌の臨床病理学的検討

山形県立中央病院外科

平井一郎　池田栄一　飯澤肇　佐藤敏彦　岡部健二　石田卓也　太田陽一

最近11年間の大腸癌手術症例1,260例のうち,低分化腺癌(por)93例,印環細胞癌(sig)7例を臨床病理学的に検討した.また間質結合織の多寡で髄様型(med),中間型(int),硬性型(並1)に3分類した。por,sigはs(a2)以深の進行例が多く,早期癌203例中1例のみであり,癌発生直後より急速に進展すると考えられた。5生率は高分化:67.9%,中分化:423%,por,sig:37.4%で,por,sigは有意に予後不良であった。間質別5生率はmedで79.6%と極めて予後良好だったが,sciには3年生存例がなく,med,int,並i間に有意差が認められた。組織発生の検討では,intは分化型腺癌の浸潤先進部の分化度が低下し低分化部分が優勢となったもので,med,sciは発生初期から低分化腺癌の形態をとる症例が存在すると考えられた。大腸低分化腺癌,印環細胞癌の間質組合織の多寡による3分類は予後,癌組織発生の点で重要である。

http://journal.jsgs.or.jp/pdf/028040805.pdf

3. 大腸癌治療ガイドライン - 日本癌治療学会

http://www.jsco-cpg.jp/guideline/13.html

ガイドライン

大腸癌治療ガイドライン - 日本癌治療学会