HadaClinic Web Journal: Thalidomide & Celecoxibbrain metastsis.

                                            

Case Report

 

 

EnglishVersion

 

A Case Report of Chemotherapy with Thalidomide, Celecoxib and Gemcitabine in the Treatment of Patients with Brain Metastases from Lung Cancer

 

Masato Hada, MD, Pharmacist

Author information

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

Abstract

 

Chemotherapy for the treatment of brain metastases arising from non-small cell lung cancer (NSCLC) has been limited by poor effi cacy and high toxicity. Especially in heavily pretreated patients with brain metastases, further chemotherapy is known to be extraordinarily diffi cult. Expression of vascular endothelial growth factor (VEGF is necessary but not sufficient for production and growth of brain metastasis. Most current preclinical experiments evaluate antiangiogenic drugs used singly or in combination with other antiangiogenic drugs and/ or cytotoxic drugs.

Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. In preclinical experiments, cyclooxygenase (COX) -2 plays an important role in the formation of brain edema. Glioma infiltrating microglia are a major source of PGE2 production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors. Here we report a case of lung cancer patient with brain metastases who had been treated with chemotherapy and whole-brain radiation therapy (WBRT). He was treated with thalidomide, celceoxib and

gemcitabine, after which brain metastases have almost completely disappeared. He tolerated extremely well. This combination may play an important role for patients with NSCLC and brain metastases.

 

Key words : thalidomide, celecoxib, brain metastases

 

Introduction

 

Therapeutic strategy for metastatic brain tumor is mainly surgery and radiation therapy, and chemotherapy cannot be expected its effect except in special cases. Only symptomatic therapy such as use of glucocorticoids is left for the patients with brain edema and risk of cerebral herniation after WBRT and the prognosis is seriously poor. Thalidomide, we used this time for the metastatic brain tumor, is classified as immunomodulatory agent and possesses anti-VEGF, anti- fibroblast growth factor (FGF) and anti- tumor necrosis factor (TNF)-α and show potent antiangiogenesis. Moreover, celecoxib is selective cyclooxygenaseCOX-2 inhibitor, and depresses the production of prostaglandinPGE2  that suppresses blood brain barrier resulting in the improvement of brain edema. Both thalidomide and celecoxib play a pivotal role in antiangiogensis through suppression of NF-kB. We report a case in which thalidomide, celecoxib and gemcitabine were prominently effective in serious brain metastasis of lung cancer, and prolong the patient survival.

 

 

 

 

Fig. 1 A: Chest Xray shows accumulation of right pleural and pericardial effusion, volume decrease of right lung, and enlargement of hilar lymph nodes (the first day of hospitalization). B: Chest Xray shows accumulation of pericardial effusion and atelectasis of the right lower lobe (day 75).

 

 

 

Presentation

 

Chief Complaint: Somnolence

 The patient is a 36 year Japanese male diagnosed with brain metastases from lung cancer. In the middle of August 2002, he underwent right median and lower lobectomy under the diagnosis of lung cancer. Surgical specimen was reported as poorly differentiated non-small-cell lung cancer. The patient was treated with carboplatin and paclitaxel. After the chemotherapy, head MRI indicated multiple brain metastases including brain stem and cerebellum in the middle of January 2003. The patient began to complain of shortness of breath, headache, and vomiting from late January 2003.

Chemotherapy (CDDP. vinorelbine) and WBRT (40 Gy) temporarily improved the symptoms but headache, dizziness and nausea worsened afterwards.

On admission in late February, Karnofsky performance status was 20, and he could barely dialogue. Oral intake was almost impossible, only medication was possible.

Laboratory examination was normal except tumor marker CEA was high 14.8 ng/ml.

Chest X ray shows accumulation of right pleural and pericardial effusion, volume decrease of right lung, and enlargement of hilar lymph node (Fig.1A). CT scan reported bilateral metastatic nodules with lymphangitis carcinomatosa, mediastinal lymphadenopathy with right pleural effusion.

Brain MRI demonstrates multiple ring-shaped metastatic lesions (Fig.2) with brain edema (Fig.3) in the cerebral and cerebellar hemispheres.

 

 

 

Fig. 2 Brain MRI demonstrates multiple ring-shaped

metastatic lesions in the cerebral and cerebellar hemisheres.

The lesions has shrunk under chemotherapy

(A: day 1, B: day 35, C: day 43, D: day 70).

 

clinical course (Fig.4)

 

From the first day of hospitalization thalidomide 300 mg / day, celecoxib 600 mg /day were administered daily in combination with intravenous hyperalimentation and gemcitabine 1g was infused every 10 day.

Significant diuretic effect was expelled on the 16th day of hospitalization and chemotherapy, up to 10,000 ml (urine specific gravity 1.031) urine urinated in 2 days.  At the same time, the state of consciousness improved markedly, and the brain symptoms before hospitalization completely disappeared. PS had recovered to 40. Meanwhile, on MRI reexamination, the metastatic lesion shrinked (Fig.2) and edema disappeared (Fig.3B) with the chemotherapy. However, pulmonary lesions exacerbated, and in mid-May 2003, he passed away with respiratory failure.

 

Fig. 3 A and B reveal remarkable disappearance of brain edema (A: day 2, B: day 54).

Discussion

 

To proliferate and metastasize, malignant tumors must secure blood supply by angiogenesis that are developed by a dozens of angiogenic factors including VEGF, FGF, COX-2 and TNF-α. Thalidomide inhibits the processing of mRNA encoding these factors 2. Thalidomide reduces loss of appetite and general malaise and improves the general condition, since thalidomide suppresses TNF-α production. Metastatic cells possess a series of severe pathological sequential steps in metastases. In the processes of brain metastasis VEGF expression is necessary, however not sufficient for the production of brain metastasis 4 5. Anti-VEGF and anti-TNF-α action of thalidomide can be expected to have a great effect on improvement of general condition and metastasis when used for metastatic brain tumors.

COX -2 plays an important role in carcinogenesis affecting many processes including cell proliferation, angiogenesis, apoptosis, immune function and tumor invasiveness. In rodent glioma model, microglia is involved in edema formation around the tumor, where PGE 2 is produced in a COX-2 dependent pathway. It is speculated that this PGE 2 will cause cerebral edema 5. The use of  COX-2 inhibitor celecoxib in the treatment of brain edema strongly support to avoid the use of glucocorticoids with various adverse event and short-term effects1.

Patients with brain metastases revealed seriously poor prognosis with median survival of about 3-4 months when treated with either radiation or surgery 3.

The patient with brain metastasis treated with WBRT, thereafter fell in critical condition. However the patient could survive with thalidomide and celecoxib, shrinking the metastases and disappearing brain edema.

The patient experienced grade 2 anemia, grade 1 nausea, and hair loss, without serious adverse events.

Finally, to the fact that patient with no means of chemotherapeutic modalities, we conducted sufficient informed consent for the patient family where we were voluntarily requested the thalidomide treatment, confirmed matters in writing.

References

1Badie B, Schartner JM, Hagar AR, Prabakaran S, Peebles TR, Bartley B, Lapsiwala S, Resnick DK, Vorpahl J

Microglia cyclooxygenase-2 activity in experimental gliomasPossible role in cerebral edema formation.

 Clin Cancer Res 9872-877, 2003

Abstract/FullText

2Eisen T, Boshoff C, Mark I, Sapunar F, Vaughan MM, Pyle L, Johnston SR, Ahern R, Smith IE, Gore ME

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer

Br J Cancer 82812-817, 2000 

   Abstract/FullText

3Lutterbach J, Bartelt S, Ostertag C

Long-term survival in patients with brain metastases.

 J Cancer Res Clin Oncol 128417-425, 2002

Abstract/FullText

4Price JE, Aukerman SL, Fidler IJ

Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements.

Cancer Res 465172-5178, 1986

Abstract/FullText

5Yano S, Shinohara H, Herbst RS, Kuniyasu H, Bucana CD, Ellis LM, Davis DW, McConkey DJ, Fidler IJ

Expression of Vascular Endothelial Growth Factor Is Necessary but not Sufficient for Production and Growth of Brain Metastasis

Abstract/FullText

 

 

The day was the 17th day since we began the chemotherapy, I was so surprised to find the patient laughing and enjoying TV program with clear consciousness at the morning round.  I heard the brook chirping in the hospital room. That was the sound of urine stream from urination tube.

The combination of thalidomide, celecoxib, valproic acid or/and low dose cytotoxic drug could be the promising modalities from cancer to intractable inflammatory disease. I think that Welfare Bureaucrats in Japan lack knowledge on medicines and intellectual ability. I wrote this paper expecting that researchers in the world would acknowledge the effectiveness of my regimen and as a result I would like to be able to conduct clinical trials in Japan.

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