hadaclinic web journal: thalidomide&celecoxib:PEascites

[Revised English and Japanese Version November 2018]

 

Report of two cases with pleural effusion and ascites that responded dramatically to the combination of thalidomide, celecoxib, irinotecan, and CDDP infused in thoracic and abdominal cavities.

 

Masato Hada, MD, Pharmacist

Author information

Hada Clinic, clinichada@cy.tnc.ne.jp

Abstract

Malignant pleural effusion (PE) and malignant ascites are associated with highly symptomatic, advanced-stage cancers. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. PE and ascites have consistently been shown to indicate a poor prognosis in advanced-stage cancer patients, being associated with high morbidity and mortality. The efficacy of this treatment is variable and does not prolong the survival of cancer patients. Clearly, a more effective therapy for PE and ascites is needed. Vascular permeability factor (VPF) in PE and ascites has been thought to associate with the fluid accumulations. In addition, PE and ascites contain high levels of biologically active vascular endothelial growth factor (VEGF). VEGF was discovered as a potent angiogenesis stimulator and recognized to be the same as VPF. Increased amounts of cyclooxygenase-2 (COX-2) have been detected in epithelial and stromal cells and COX-2 in mammary tissue is sufficient to induce cancer. It is suggested that COX-2 stimulates angiogenesis. A combination of molecular target inhibitors (thalidomide and celecoxib) and standard cytotoxic drugs appear to increase efficacy of each drug, decrease the side effects of cytotoxic drugs and prolong life.

 

Key Words: Thalidomide, Celecoxib, Pleural effusion, Ascites

Introduction

The accumulation of PE and ascites is the sign of poor prognosis and difficult problem in clinical oncology. The massive fluid in pleural and peritoneal cavities causes serious symptoms including abdominal distention, shortness of breath, cachexia, anorexia, and fatigue 1. PE and ascites cause serious symptoms including abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Currently, the modalities employed in the treatment consisted of diuresis, salt restriction, pleurodesis, and peritoneovenous shunts. In 1986, VPF was isolated and hypothesized to be the significantly fluid collecting factor for fluid formation. Later, a potent angiogenetic stimulator VEGF was discovered and found to be same with VPF. High concentration of VEGF is expressed in PE and ascites induced by tumor cells. The nomenclature VPF was subsequently replaced by VEGF and the potent vascular permeability effect was ignored 1.

COX-2 signaling is expressed in the epithelial and stromal compartments and is thought to be the major player in the progression of cancers. It is predicted that COX-2 may be useful for the prevention and treatment of cancer 2 3. It is thought that the combination of molecularly targeted agents and cytotoxic agent will increase the cytotoxicity and attenuate the toxicity of cytotoxic agent and prolong overall survival 4.

We herein report two case studies of two 57 and 37-year-old men affected each by sigmoid and pulmonary adenocarcinoma with multiple metastases who were referred for PE and ascites.  Significant remission of the disease, especially PE and ascites were observed under thalidomide, celecoxib treatment.

 

Case Presentation

Case 1

On August 22, 2001, a 57-year-old male was referred to the emergency unit because of a progressive deterioration (Performance Status: PS 4) of general condition with dyspnea. A computerized tomography (CT) scan of chest and abdomen was done and it indicated that the mass (dimensions: 3cm) arising in the right pleura fluid, malignant peritonitis with ascites, and hepatic metastases. On November 26, 1999, the patient was diagnosed with sigmoid colon and had sigmoidectomy. On August 22, 2001, drainage of right PE (2500ml) was done to relieve the symptoms and infused cisplatin (CDDP) 50mg into pleural cavity. The patient was treated with irinotecan 40 mg given twice a week. Thalidomide and celecoxib were given daily, continuously throughout the cycle. Thalidomide was given at a dose of 200 mg orally at bedtime and celecoxib was given at a dose of 200 mg twice daily after meals. Therapy was continued until evidence of progression or unacceptable toxicity. The patient was discharged from hospital on October 1, 2001, the treatment was continued. Prominent side effects were not observed until August 2003, the treatment was performed outpatient and PS 1 was maintained.

The patient was discharged from hospital on October 1, 2000, the treatment was continued as shown. The hepatic metastases were also remarkably shrunk from September 2001, but it had gradually increased in size since February 2003. Ascites was completely disappeared and confirmed on CT examined on September 25, 2001. Ascites fluid accumulation did not occur until August 2003.

 

Fig.1 Chest X ray and Chest CT

a: August 21, 2001

b: April 11, 2003

 

c: August 21,2001

d: February 6,2002

e: May 20,2003

 

 

Case 2

The 37 year-old-male had the left anterior chest pain. The patient was diagnosed signet -ring cell lung cancer by the biopsy of left transpulmonary approach. Later for 1 year he had folk remedy, however October 10, 2002 remarkable left PE was found and underwent drainage and adhesion with OK - 432. Ascites began to accumulate from mid-January 2003. On February 4, 2003, he was hospitalized (PS 4) and stomach endoscopic examination was carried out because pathological finding was signet-ring cell. However, no abnormality was pointed out. On chest and abdominal CT examination, left lung tumor mass, lymph node metastases around trachea and bronchi, malignant pleuritis and peritonitis with PE and ascites, and multiple liver metastases were shown (Fig3). In ascites cytology, findings suspected of malignancy were not observed. On February 5, 2003, drainage of ascites (3000 ml) was done to relieve the symptoms and infused cisplatin (CDDP) 25mg into peritoneal cavity. The patient was treated with irinotecan 40 mg given twice a week. Thalidomide and celecoxib were given daily, continuously throughout the cycle. Thalidomide was given at a dose of 200 mg orally at bedtime and celecoxib was given at a dose of 200 mg twice daily after meals. Oral feeding was almost impossible and therefore total parenteral nutrition was performed. Ascites is completely controlled with a single treatment, thereafter no accumulation of ascites was observed until July 1, 2003 and the PS 3was retained. Fig.4 shows progress from October 2003 to June 2018. Liver metastases and lymph node enlargement was not greatly changed by treatment. PE and ascites indicate the terminal condition of malignancies and prognosis is poor. The production of malignant PE requires tumor cells to invade the pleura and elevated expression of VEGF. Low invasive properties and low expression of VEGF are demonstrated in squamous cell carcinoma 7. Tumor-derived VEGF is essential for ascites accumulation but not for ovarian cancer cell proliferation in peritoneal cavity 6a.

 

 

Fig.2 CEA change

 February 6, 2003

April 9, 2003

June 6, 2003

Fig.3 chest and abdominal CT

Consideration

VEGF is also VPF, and is overexpressed in a variety of tumors. It plays an important role in angiogenesis and accumulation of PE and ascites 5. Its permeability is caused by strong induction of endothelial fenestrations 6, and its ability is estimated to be more 10,000-50,000 times than histamine. Highly expressed VEGF is observed in malignant PE and ascites, therefore it is possible to control these fluids by inhibiting the production of VEGF 1. Tumor-derived VEGF is essential for ascites accumulation but not for ovarian cancer cell proliferation in peritoneal cavity 6a. Arachidonic acid is catalyzed and synthesized from prostaglandin (PG) by COX-2. COX-2 is not constitutively expressed, however it is induced by a variety of inflammatory stimuli including LPS, cytokines, growth factors 3. PG is produced in large amount in cancer tissue and supplies oxygen and nutrients to the cancer tissue by angiogenesis and inhibits immune surveillance mechanism and apoptosis. However, precise mechanism is not clarified yet. The selective COX-2 inhibitor celecoxib possesses potent   antiangiogenesis and antitumor effects 8. The mechanism of action of thalidomide has not been clearly elucidated. However, thalidomide has been known to interact with TNF-α 9, VEGF and bFGF resulting in antiangiogenesis which inhibits the invasion, proliferation and metastasis10. Tumor angiogenesis results from the activity of multiple angiogenic proteins. A combination of antiangiogenic agents induces more effective growth suppression. Thalidomide can potentially inhibit COX-2 expression and PG production. COX-2 inhibitors suppress angiogenesis and inflammation. It may be possible to obtain potent antiangiogenic effect in combination of thalidomide and celecoxib11. Also thalidomide 13 and celecoxib 14 reduce the side effects of irinotecan including gastrointestinal symptoms, especially diarrhea.

 Potent cytotoxic effect can be available with thalidomide 200mg/day and celecoxib 400mg/day p.o every day and cytotoxic agents.

Cell-free and concentrated ascites reinfusion therapy (CART) is approved only in Japan for the management of malignant ascites. CART is one of the types of apheresis therapy, by which filtered and concentrated ascites containing albumin and globulin is reinfused intravenously to patients. VEGF also pass through the filter. Concentrated VEGF exacerbates the accumulation of ascites 6b 6c. CART has been a promising strategy for Equipment Maker Asahikasei Medical with massive income but has been annoying the patients with more massive peritoneal fluid. If possible, 25 to 75 mg of CDDP should be infused after drainage of PE or ascites. Effective control of PE and ascites could be obtained with cytotoxic agent. In case of irinotecan, the dose should be repressed with 40 mg twice a week up to 320mg /month.

Grade 2 leukopenia and hair loss, and grade 1 vomiting and diarrhea were observed as adverse events.

When using off-label prescriptions with thalidomide and celecoxib, we provided full disclosure to patients and shared decision-making in situations of medical uncertainty.

 

 

References

1) Verheul HM,Hoekman K,Jorna AS,et al:

Targeting vascular endothelial growth factor blockade:ascites

and pleural effusion formation.

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PubMed

 

2) Liu CH, Chang S, Narko K, et al:

Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice.

J Biol Chem 276(21):18563-18569, 2001.

PubMed Abstract/FullText

 

3) Fujita J,Mestre JR,Zeldis JB,et al:

Thalidomide and its analogues inhibit lipopolysaccharide-mediated induction of cyclooxygenase-2.

Clin Cancer Res Nov;7(11):3349-3355, 2001.

PubMed Abstract/FullText

 

4) Chabner BA:

Cytotoxic agents in the era of molecular targets and genomics.

Oncologist 7(Suppl 3):34-41,

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5) Nagy JA, Masse EM, Herzberg KT, et al:

Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation.

Cancer Res 55(2):360-368,1995.

PubMed Abstract/FullText

 

6) Esser S, Wohlburg K, Wohlburg H, et al:

Vascular endothelial growth factor induces endothelial fenestrationin vitro.

 J Cell Biol 140(4):947-959, 1998.

PubMed PMC free article

 

6a) Mesiano S, Ferrara N, Jaffe RB.

Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization.

Am J Pathol. 1998 Oct;153(4):1249-56.

PubMed PMC free article

 

6b)Yamaguchi H, Kitayama J, Emoto S,et al

Cell-free and concentrated ascites reinfusion therapy (CART) for management of massive malignant ascites in gastric cancer patients with peritoneal metastasis treated with intravenous and intraperitoneal paclitaxel with oral S-1.

Eur J Surg Oncol. 2015 Jul;41(7):875-80.

PubMed

 

6c) Ito T, Hanafusa N

CART: Cell-free and Concentrated Ascites Reinfusion Therapy against malignancy-related ascites.

Transfus Apher Sci. 2017 Oct;56(5):703-707.

PubMed

 

7) Yano S,Shinohara H,Herbst RS,et al:

Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells.

Am J Pathol157(6):1893-1903, 2000.

PubMed PMC free article

 

8) Masferrer JL, Leahy KM, Koki AT, et al:

Antiangiogenic and antitumor activities of cycolooxygenase-2inhibitors.

Cancer Res 60(5):1306-1311, 2000.

PubMed Abstract/FullText

 

9) Sampaio EP,Sarno EN,Galilly R,et al:

Thalidomide selectively inhibits tumor necrosis factorα productionby stimulated human monocytes. J Exp Med 173(3)699-703, 1991.

PubMed PMC free article

 

10) D’Amato RJ, Loughnan MS, Flynn E, et al:

Thalidomide is an inhibitor of angiogenesis.

Proc Natl Acad Sci USA 91(9):4082-4085, 1994.

PubMed PMC free article

 

11) Pavlakovic H,Havers W and Schweigerer L:

Multiple angiogenesis stimulators in a single malignancy: implications for anti-angiogenic tumour therapy.

Angiogenesis4(4):259-262, 2001.

PubMed PMC free article

 

12) Hida T, Kozaki K, Muramatsu H, et al:

cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines.

Clin Cancer Res 6(5):2006-2011, 2000.

PubMed Abstract/FullText

 

13) Govindarajan R, Heaton KM, Broadwater R, et al:

Effect of thalidomide on gastrointestinal toxic effects of irinotecan.

Lancet (9229):566-567, 2000.

PubMed

 

14) Trifan OC,Durham WF,Salazar VS,et al:

Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11.

Cancer Res (20):5778-5784, 2002.

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Article in Japanese

 

Jpn J Cancer Chemother 31(4):613-617, April, 2004

 

Thalidomide Celecoxib IrinotecanCDDP

胸腹腔内投与が著効を呈した癌性胸水腹水の2

 

羽田正人

はだクリニック       

 

要旨 癌性腹水胸水は予後不良兆候の一つでこれをコントロールすることは非常に困難である。さらには腹部膨満感、呼吸困難、食欲不振、悪液質、発熱などの著しい不快な癌症状を引き起こす。現在利尿剤、塩分制限、胸腹膜癒着術、腹腔-静脈シャント術などが行われているが根治的な効果は得られていない。

血管内皮増殖因子(VEGF)は血管透過性因子(VPF)として1983年報告されて以来研究が進み両者は同一物質であり、血管の新生ならびに血管透過性に大きな役割を担い胸水・腹水中に高度に発現している。

cyclooxygenase-2COX-2)は癌組織の上皮ならびに間質細胞に多く発現しており癌発現増殖に関与している。それゆえ癌の予防と治療に役立つ酵素ではないかと予測されている。

癌治療において分子標的阻害剤と従来の抗癌剤の組み合わせは腫瘍選択性を高くし、しかも腫瘍の薬剤耐性を少なくし抗癌剤の毒性を減弱し生存期間を延長するだろうと報告されている。thalidomide celecoxib連日経口投与に抗癌剤特にirinotecan 40mg/回を週に2回、1か月間に320mg 以下の量を投与することにより効果的に胸水腹水をコントロールでき著明な全身状態の改善が得られる。抗VEGF 作用を有するthalidomideと選択的COX-2阻害剤であるcelecoxibに従来の抗癌剤を併用して胸水・腹水を治療し良好な経過をとった2例を経験したので症例を呈示しながらこの治療を報告したい。

 

はじめに

 

癌性腹水、癌性胸水(胸腹水)は予後不良兆候の一つでこれをコントロールすることは非常に困難である。さらには腹部膨満感、呼吸困難、食欲不振、悪液質、発熱などの著しい不快な癌症状を引き起こす1。現在利尿剤、塩分制限、胸腹膜癒着術、腹腔-静脈シャント術などが行われているが、根治的な効果は得られていない。血管内皮増殖因子(VEGF)は血管透過性因子(VPF)として1983年報告されて以来研究が進み両者は同一物質であり血管の新生ならびに血管透過性に大きな役割を担い胸腹水中に高度に発現している1

cyclooxygenase-2COX-2)は癌組織の上皮ならびに間質細胞に多く発現しており癌発現増殖に関与している2。それゆえ癌の予防と治療に役立つ酵素ではないかと予測されている3。癌治療において分子標的薬と従来の抗癌剤の組み合わせは腫瘍選択性を高くし、しかも腫瘍の薬剤耐性を少なくし、しかも抗癌剤の毒性を減弱し生存期間を延長するだろうといわれている4。抗VEGF 作用をもつthalidomideと選択的COX-2阻害剤であるcelecoxibに従来の抗癌剤を併用して胸腹水を治療し良好な経過をとった2例を経験したので症例を呈示しながらこの治療を報告したい。

 

T. 症 例

 

症例1: 57歳、男性、大腸癌。

19991126S 状結腸癌(中分化腺癌)でS 状結腸を切除する。

2001822日呼吸困難で入院。入院時performance statusPS4であった。胸腹部CT 検査で右胸水、癌性胸膜炎(右胸腔横隔膜に接して径約3cm の腫瘤)腹水、癌性腹膜炎、多発性肝転移を認めた(図1)。胸水細胞診では悪性を疑う所見は認められなかった。

2001822日右胸腔ドレナージ施行約2,500ml の排液後cisplatinCDDP)50mg を注入した。同時にthalidomide 200mg/celecoxib 400mg/日連日経口投与を開始した。それとともにirinotecan 40mg を週2回点滴静注した。2001101日退院以後図2のごとく加療を継続した。20038月まで特に指摘できる副作用もなく順調に外来で加療しておりPS 1である。胸腹水の再貯留はこの2年間ない。肝転移巣も20019月ごろから著明に縮小した状態が続いていたが20032月ごろより徐々に増大している。腹水については穿刺排液をせずに経過観察を行ったところ2001925日のCT 検査で完全に消失していることを確認し、20038月まで再貯留を認めていない。

 

症例2: 37歳、男性、印環細胞型肺癌。

200110月左前胸部痛を生じる。左胸腔穿刺生検で印環細胞型肺癌が検出される。その後1年間民間療法をしていたが20021010日左胸水貯留が著しくドレナージとOK-432による癒着術を受ける。20031月中旬より腹水貯留が始まった。

200324日入院PS 4で印環細胞癌ということで胃内視鏡検査を施行するも異常はなかった。胸腹部CT では左肺内腫瘤、左肺門・気管・気管支気管支分岐部リンパ節転移、左胸水・癌性胸膜炎、多発性肝転移、胃周囲リンパ節転移、癌性腹膜炎、腹水貯留がみられた(3)。腹水細胞診では悪性を疑う所見は認められなかった。200325日腹腔ドレナージを施行約3,000ml の腹水を除去、その後腹腔内に25mg CDDP を注入した。同時にthalidomide 200mg/celecoxib 400mg/日連日経口投与を開始した。それとともにirinotecan40mg を週2回点滴静注した。経口摂取はほとんど不可能であったため中心静脈栄養を行った。腹水は1回の処置で完全にコントロールされ200371日まで再貯留はなくPS 3である。図4200324日より200363日までの経過を示した。肝転移巣ならびにリンパ節腫大は加療によって大きな変化はない。

 

 

U.考 察

 

VEGF VPF とも呼ばれ多くの悪性腫瘍に過剰発現し腫瘍の血管新生と胸腹水の貯留に大きな役割を担っている5。その透過性は上皮細胞間の開窓化によるものといわれ6 透過性強度はヒスタミンの10,000倍とも50,000倍ともいわれている。胸腹水貯留は癌の終末状態で生命予後は限られている。VEGF は大腸癌、胃癌、卵巣癌において著明に上昇しており胸水は非小細胞肺癌で貯留しやすく扁平上皮癌ではしにくい。扁平上皮細胞は胸腔に浸潤しないためとVEGF の発現が低いからである7。悪性疾患に伴う胸腹水中には高濃度のVEGF が検出されておりVEGF を阻害することで胸腹水をコントロールできる可能性がある1。胸腹水の治療は臨床上非常に難しく胸水穿刺を施行した後何らかの治療を行わないと90%の症例で1か月以内に再穿刺を必要とするようになる。またVEGF は卵巣癌の場合腹水貯留には必須であるが、卵巣腫瘍自体の増殖には必須でないといわれ、原疾患のコントロールの難しさにも悪影響を及ばされる。

COX-2arachidonic acidよりprostaglandinPG)を合成する酵素で通常の生理的条件では人体には存在せずサイトカインや増殖因子によって急速に癌組織に誘導される3PG は癌組織で多量に産生され血管新生作用により酸素と栄養素を癌組織に供給するとともに免疫監視機構とアポトーシスを阻害する。しかしながら癌誘発の詳しいメカニズムはわかっていない。選択的COX-2阻害剤celecoxibは強力な血管新生抑制作用と抗腫瘍効果を有する8

thalidomideの作用機序は明確には解明されていない。しかしながら抗TNF-α 9による解熱、悪液質改善、全身倦怠感の改善やVEGF や塩基性線維芽増殖因子(bFGF)10による血管新生を抑制するという。抗癌剤を使用する際、少ない副作用で強力な抗癌作用を引きだすことが大切である。種々の血管新生抑制剤を併用することでこの目的を達することができる11

thalidomideの血管新生抑制作用はCOX-2阻害を介して起こり、thalidomideCOX-2mRNA の安定性を減弱するが完全にCOX-2活性を阻害せず、またPG の生合成を阻害しないのでCOX-2阻害剤の併用が勧められる3。また腫瘍血管は種々の変化を有する細胞から構成されており、単一の血管新生抑制剤ではそれに対応できないため併用して使用することが重要である。COX-2阻害剤は種々の抗癌剤のIC50を低下させ併用療法の有効性が報告されている12。またthalidomide13.celecoxib14irinotecanの消化管症状、特に下痢を減少させる。

thalidomide 100200mg/日、celecoxib 200400mg/日連日経口投与に従来の抗癌剤を併用することで少ない副作用で強力な抗癌作用が得られる。*[特に胸腹水の場合これを抜き去り濃縮還元することが肝要であり患者の全身状態が許されるならば胸腹水を抜いた後に]2575mg CDDP を注入し癒着を促すようにするとよい。この状態で抗癌剤特にirinotecan 40mg を週に21か月間に320mg 以下の量を投与することにより効果的に胸腹水をコントロールでき著明な全身状態の改善が得られる。副作用はgrade 2の白血球減少と脱毛であり嘔吐下痢はgrade 1前後であった。

未承認薬thalidomide celecoxibの使用に際しては十分なインフォームドコンセントの上書面での了解と確認を行った。

 

*訂正:この記述には間違いがあります。濃縮還元する場合胸腹水中の悪性細胞は取り除かれますが、胸腹水中のVEGFは取り残され再注入されます。その結果胸腹水の貯留が増悪し、患者さんをなお一層苦しめることになります。旭化成のCARTは絶対避けるべきと考えます。

 

忖度・癒着・天下り

藤本製薬のサリドマイド認可

大阪市立大学   医学研究科   臨床医科学専攻   教授

日下部 哲也 (クサカベ テツヤKUSAKABE Tetsuya)

医薬品行政:薬事法違反立案を地方薬務課に強制した教授(元厚生官僚)

藤本製薬

(Fujimoto Pharmaceutical Co.)

山下治夫と森和彦が天下りと癒着で目指す千円企業

サリドマイド治験開始へ

記者会見する藤本製薬

山下治夫薬事法規部長

     元大阪府保健衛生部薬務課長)

 

藤本製薬

癒着と天下りで

利益を目指す

千円企業

 

森和彦大臣官房審議官(医薬担当)

医薬食品局審査管理課長

厚生労働省と藤本製薬との癒着でサリドマイドは認可されました。