hadaclinic web journal: thalidomide&celecoxib:pancgem

 

A case of advanced pancreatic cancer with remarkable response to thalidomide, celecoxib and gemcitabine.

Jpn J Cancer Chemother 31(6):959-961, June, 2004    [Revised English Version October, 2018]

Masato Hada, MD, Pharmacist         

Author information

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

Abstract

Advanced human pancreatic cancer is considered a chemoresistant disease. To date, no treatments have had a significant efficacy on the disease. Patients with pancreatic cancer, however, experienced an improvement in the related symptoms with gemcitabine. Thalidomide has been shown to have antiangiogenic and immunomodulatory effects, including the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor alpha. The reported biological consequences of COX-2 up-regulation include inhibition of apoptosis, increased metastatic potential and promotion of angiogenesis. These events may contribute to cell transformation and tumor progression. Antiangiogenesis represents a significant new strategy for cancer treatment; however, most tumors are biologically heterogeneous, especially in endothelial cell diversity. As vessels of most solid tumors are structurally and functionally abnormal, tumor vessels differ from normal blood vessels in their responses to antiangiogenic agents. Therefore, it is important to accept a wide range of different inhibitors, such as thalidomide and selective COX-2 inhibitors, with conventional cytotoxic agents. Here we show a case of advanced pancreatic cancer with remarkable improvement in tumor shrinkage, CA19-9, and a cessation of dirty exudate from umbilicus. We have experienced a case that we could observe the course of more than 1 year and 3 months, so I report the case here.

 

Key words: Thalidomide, Celecoxib, Pancreatic cancer

 

要旨

症例は65歳男性。2002111日臍部より悪臭を伴った汚泥物質の分泌があり近医を受診。肺肝転移を伴った手術不能膵癌の診断を受ける。2002218日よりthalidomide:200mg/日就寝前celecoxib:400mg/日朝夕gemcitabine:1g/10日ごと点滴静注の併用療法を施行した。併用療法開始1か月後(gemcitabineとして3g 投与)には著明な腫瘍縮小CA19-9の低下と臍部分泌物の消失がみられ、13か月にわたり経過観察し得た1例を経験したのでここに報告する。

 

Introduction

Clinical trials using gemcitabine sponsored by Eli Lilly Japan for advanced pancreatic cancer has been confirmed effective from the beginning of 2000 1. Symptoms and the survival benefit associated with pancreatic cancer are better than the conventional 5-FU therapy. Gemcitabine is a highly tolerable agent with few side effects, and available literature reported that overall response rate was 33% and the median overall survival was 11 months 2. In order to promote the clinically meaningful survival benefit of gemcitabine-based regimens, fixed dose-rate infusion and the combination of other cytotoxic agents such as cisplatin, oxaliplatin, irinotecan, docetaxel, 5-fluorouracil, capecitabine, or pemetrexed are investigating 3.

Here we report a case of advanced pancreatic cancer resulted in excellent results with the combination of thalidomide, celecoxib, and low dose cytotoxic drug gemcitabine.

Case Report

A 65-year-old man presented with persistent umbilical discharge. He was diagnosed to be inoperable pancreatic cancer with pulmonary and hepatic metastases. At this time, CEA: 1,200ng/ml and CA19-9: 430,000U/ml were elevated and other biochemical test was normal. An abdominal computed tomography (CT) scan on February 20, 2002 revealed a lobulated pancreatic mass between pancreatic tail and spleen without obstruction of the bile, pancreatic, and common bile ducts (Fig.1). The patient started treatment with thalidomide (200 mg/day, before sleep) and celecoxib (400 mg/day, morning and evening) every day. Gemcitabine was administered at the low dose of 1,000 mg over 150 minutes every 10 day. One month later, the tumor of the pancreatic tail was prominently shrunk up to 30% in size and metastatic lesion in the liver also shrunk. Moreover umbilical discharge stopped in about 1 month. These lesions remained in the shrinking state and tumor markers showed the lowest value as CEA: 531ng/ml, CA 19 - 9: 58,000 U/ml on May10, 2002 (Fig.2).On chest CT the nodules of the left upper lobe, which were observed on admission, disappeared during follow-up observation.

As adverse events on the 5th day of hospitalization on February 22, 2002, small rash was found in both limbs and trunk, and disappeared with steroid administration systemically on the 23rd. Hair loss of grade 2 was also recognized. Even after discharge on April 30, 2002, the outpatient management was continued. The patient was admitted to hospital on February 10, 2003 with severe pain by right iliac bone metastasis. Instead of gemcitabine irinotecan is used and pain control using narcotics was delivered and he was discharged on April 30.2003. However the patient passed away with malignant cachexia on May 30, 2003.

 

Fig.1 abdominal CT

February 20, 2002

July 29, 2002

April 10, 2003

Fig.2 change of tumor markers

 

 

 

Discussion

Various factors are listed as carcinogenic factors for pancreatic cancer, but none of them are definitive. COX - 2 is highly expressed in the epithelium and stromal cells of cancer tissue and is involved in the growth and proliferation of cancer, and it is expected that selective COX - 2 inhibitors will be useful for the prevention and treatment of cancers 4. Moderate to high expression of COX-2 is present in 90% of pancreatic cancer 5. COX-2 and NF-KB overexpression is common in pancreatic cancer. However it is reported that the combination of a COX-2 inhibitor does not add any valuable activity to a gemcitabine/oxaliplatin combination, even in patients with COX-2 and NF-KB overexpressing tumors 5a. This reason is because COX-2 and NF-KB inhibitors are not used in combination. COX-2 expression has been directly linked to chronic inflammation, angiogenesis and carcinogenesis 6. Well-differentiated adenocarcinomas contains more COX-2 staining than the poorly differentiated ones 7. However, in pancreatic cancer COX-2 expression is expressed regardless of pathology 5. Thalidomide possesses various pharmacological effects and has begun to be used as an antiangiogenic and immunomodulatory agent. There is accumulating evidence that thalidomide has anti-cancer effect through its antiangiogenic and immunomodulatory effects 8. Although definite mechanism of action has not been elucidated, thalidomide shows improvement of cachexia and general malaise caused by-TNF-α, and suppresses angiogenesis by VEGF and bFGF.9 10 11 12 More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis. These proteins include VEGF, bFGF, transforming growth factor (TGF)-α, TGF-β, TNF-α, platelet-derived growth factor (PDGF), EGF 13a and COX-2 13b. Therefore most solid tumors are highly vascular, structurally and functionally abnormal 13. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 13c. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 13d 13e 13f.

COX-2 inhibitor nimesulide reduced the IC50 values of various anticancer agents when used in combination at clinically achievable concentrations 14.  

The combination of COX-2 inhibitor and gemcitabine significantly inhibits cell proliferation, lowering IC 50 more about 2 times than using gemcitabine alone 15.

We infused gemcitabine 1g/body after fixed dose-rate infusion16 every 10 day with thalidomide 200mg/day and celecoxib 400mg/day p.o every day. A large mass at the tail of the pancreas and liver metastases were markedly shrunk throughout the first 1 month of hospitalized treatment. The discharge was thought to be from Sister Mary Joseph’s nodule (malignant metastatic umbilical nodule) which is a rare but important physical sign because it is a sign of advanced stage of malignancy. Umbilical discharge also stopped in about 1 month.

The difficulty of treating pancreatic cancer is thought to be caused by jaundice due to stenosis or occlusion of the common bile duct. Exacerbation of jaundice may contribute to poor outcomes, causing cholangitis, decreased quality of life and increased mortality. As a result pancreatic chemotherapy results in poor effectiveness 16a. The longer the distance from the pancreatic head to the primary lesion through which the common bile duct passes, the longer the period of chemotherapy and overall survival can be. Therefore, it is considered that bypass operation of the common bile duct is essential at the first time of pancreatic operation. Eczema characteristically caused by thalidomide and celecoxib was controlled by steroid administration. Other side effects such as myelosuppression, vomiting and diarrhea were not observed.

The difficulty of chemotherapy in advanced pancreatic cancer is due to the delay of development of effective drugs.

Recently in Japan and other foreign countries gemcitabine has been recognized as the first-line chemotherapy of advanced pancreatic cancer.

However, gemcitabine alone does not prolong survival as expected. Therefore, we combined antiangiogenic agent thalidomide and COX-2 inhibitor celecoxib with gemcitabine.

 As a result, shrinkage of primary lesion was observed in a short period, suggesting that this strategy is a useful treatment for advanced pancreatic cancer.

Upon use of unapproved drugs thalidomide and celecoxib, the patient express willingness to be a part of the study, and the same was duly documented.

 

 

References

 

1) Okada S,Ueno H,Okusaka T,et al:

Phase I trial of gemcitabine in patients with advanced pancreatic cancer.

Jpn J Clin Oncol 31(1):7-12, 2001.

Abstract/FullTex

 

2) Feliu J, Mel R, Borrega P, et al:

Phase II study of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur in advanced carcinoma of the pancreas.

Ann Oncol 13:1756-1762, 2002.

PubMed

 

3) Heinemann V:

Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of

randomized trials.

 Semin Oncol 29(6 Suppl 20):9-16, 2002.

PubMed

 

4) Liu CH,Chang SH,Narko K,et al:

Overexpression of cyclooxygenase-2is sufficient to induce tumorigenesis

in transgenic mice.

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

PubMed Abstract/FullText

 

5) Okami J, Yamamoto H, Fujiwara Y, et al:

Overexpression of cyclooxygenase-2 in carcinoma of thepancreas.

Clin Cancer Res 5(8):2018-2024, 1999.

Abstract/FullText

5a) added article later

Cascinu S, Scartozzi M, Carbonari G, et al

COX-2 and NF-KB overexpression is common in pancreatic cancer but does not predict for COX-2 inhibitors activity in combination with gemcitabine and oxaliplatin.

Am J Clin Oncol. 2007 Oct;30(5):526-30.

PubMed

 

6) Yip-Schneider MT, Barnard DS, Billings SD, et al:

Cyclooxygenase-2 expression in human pancreatic adenocarcinomas.

Carcinogenesis (2):139-146,2000.

PubMed

 

7) Wolff H,Saukkonen K,Anttila S,et al:

Expression of cyclooxygenase-2 in human lung carcinoma. Cancer

Res (22):4997-5001, 1998.

PubMed

 

8) Verheul HM,Panigrahy D,Yuan J,et al:

Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits.

Br J Cancer (1):114-118, 1999.

PubMed Abstract/FullText

 

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

Thalidomide selectively inhibits tumor necrosis factor α production by stimulated human monocytes.

J Exp Med 173(3):699-703, 1991.

PubMed PMC free article

 

10) Kruse FE, Joussen AM, Rohrschneider K, et al:

Thalidomide inhibits corneal angiogenesis induced byvascular endothelial growth factor.

Graefes Arch Clin Exp Ophthalmol 236(6)61-466, 1998.

PubMed PDF

 

11) 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

 

12) Peuckmann V,Fisch M and Bruera E:

Potential novel uses of thalidomide: focus on palliative care.

Drugs (2):273-292, 2000.

PubMed PDF

 

13) Onn A, Tseng JE and Herbst RS:

Thalidomide, cyclooxygenase-2, and angiogenesis:potential for therapy.

Clin Cancer Res 􌏟:3311-3313, 2001.

PubMed Abstract/FullText

 

13a)Ismaili N, Amzerin M, Flechon A,

Chemotherapy in advanced bladder cancer: current status and future.

J Hematol Oncol. 2011 Sep 9;4:35.             back

Abstract/Full Text

 

13b) Xu L, Stevens J, Hilton MB, et al

COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models

Sci Transl Med. 2014 Jun 25;6(242):242ra84

PubMed  Abstract

 

13c) Gupta D, Treon SP, Shima Y, Hideshima T, et al

Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications

Leukemia. 2001 Dec;15(12):1950-61

Abstract/Full Text

 

13d) Sobolewski C, Cerella C, Dicato M,,et al

The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies

Int J Cell Biol. 2010;2010:215158

Abstract/Full Text

 

13e) Cao Y, Cao R, Hedlund EM.

Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways

J Mol Med (Berl). 2008 Jul;86(7):785-9.

Abstract

 

13f) De Benedetti F, Falk LA, Ellingsworth LR, et al

Synergy between transforming growth factor-beta and tumor necrosis factor-alpha in the induction of monocytic differentiation of human leukemic cell lines

Blood. 1990 Feb 1;75(3):626-32.                

PubMed Abstract  PDF

 

14) 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 (5): 2006-2011, 2000.

PubMed Abstract/FullText

 

15) Yip-Schneider MT, Sweeney CJ, Jung SH, et al:

Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells.

J PharmacolExp Ther (3):976-985, 2001.

PDF

 

16) Tempero M,Plunkett W,Ruiz Van Haperen V,et al:

Randomized phaseU comparison of dose-intense gemcitabine: Thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma.

J Clin Oncol (18):3402-3408, 2003.

PubMed

16a) B. R. Boulay.M. Parepally

Managing malignant biliary obstruction in pancreas cancer: Choosing the appropriate strategy

World J Gastroenterol. 2014 Jul 28; 20(28): 9345–9353.

Abstract/FullText

 

 

 

Cozy Relationship and Revolving Doors

Thalidomide was Approved with Sontaku in Japan.

Professor Tetsuya Kusakabe日下部哲也

who is familiar with

Fabrication and Execution of Pharmaceutical Affairs Law Violation

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

Millennium company supported by kazuhiko Mori and Haruo Yamashita

with Sontaku, Cozy Relationship and Revolving Doors

Haruo Yamashita was parachuted into Fujimoto Pharmaceutical Co.

Fujimoto Pharmaceutical corporation

Kazuhiko Mori

approved thalidomide with Cozy relationship between Koroshou and Fujimoto