Title: Comparative Study of Temozolamide with Concurrent RT vs. Tamoxifen Plus Temozolamide, Concurrent RT in GBM Patients

Authors: Dr Niharika Panda, Dr Samarendra Dash, Dr Lucy Pattanayak

 DOI:  https://dx.doi.org/10.18535/jmscr/v5i5.137

Abstract

Glioblastoma Multiforme (GBM) the most common primary tumour arising in the human brainrepresent a formidable clinical challenge. Despite advances which have been made in conventional surgical, radio therapeutic and chemotherapeutic modalities, the prognosis of such patients remains poor. The present prospective study is aimed at comparing the toxicity profile in GBM patients receiving high dose of Tamoxifen, Temozolamide and RT and secondly comparing the response of GBM patients. Patients with GBM at post operative stage having ECOG performance 0, 1, 2; life expectancy of >8 weeks who attended a regional cancer centre in South Eastern India were included in the study. A total of 30 patients were studied and were divided to two arms arm ‘A’ and arm ‘B’. External beam radiotherapy by cobalt 60 Theratron 780C was given at a dose of 60Gy in 30 fraction per week. Temozolamide was given in dose of 75mg/m2 from day one to day 30 one hour before food and one hour before RT at the same time every day. Tamoxifen was given at dose of 40mg/m2/day from day 1 to day 30 before food in the morning hours. Toxicity was assessed using RTOG and common toxicity criteria. Both toxicity and response was evaluated during RT, six weeks after RT and subsequently at 3 months and 6 months of follow up. It was observed that high dose of Tamoxifen is well tolerated. Gastrointestinal and neurological toxicity were little higher and of grade 1 and 2. No retinopathy was observed. In Tamoxifen arm most patients showed partial response with stable disease.

Keywords- Glioblastoma Multiforme (GBM), Tamoxifen, Temozolamide, RT.

References

1.      Leibel SA, Scot CD, Loeffler JS. Conrtemporary approaches to the treatment of malignant gliomas with radiation therapy. Sem Oncol 1994; 21:198-219

2.      Devita VT, Hellman S, Rosenberg SA. Cancer principles and practice of oncology. 5th Edition, Lippincort Raven; 1997;2023

3.      Baltuch G, Couldwell WT, et al. Protein kinase C inhibitors suppress cell growth in established and low passage from glial cell lines. A comparison between staurosporine and Tamoxifen. Neurosurgery. 1993;33:495-501

4.      Couldwell WT, Antel JP,et al. Enhanced protein kinase C activity correlates with the growth rate of malignant gliomas. Part II. Effects of glioma mitogens and modulators of PKC. Neurosurgery. 1992;31:714-724

5.      Couldwell WT, Uhm J et al. Enhanced protein kinase in C activity correlates with the growth rate of malignant human gliomas. Neurosurgery. 1991;29:880-887

6.      Nishizuka Y. Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science (Washington DC) 1992; 252:607-614

7.      O’Brian CA, Liskamp RM et al. Inhibition of protein kinase C by Tamoxifen. Cancer Res.1985;45:2462-2465

8.      Pollack IF, Randall MS et al. Effect of Tamoxifen on DNA synthesis and proliferation of human malignant glioma lines in vitro. Cancer Res. 1990;50:7134-7138

9.      Vertosik FT, Selker RG et al. The treatment of intracranial gliomas using orally administered Tamoxifen therapy. Preliminary results in a series of failed patients. Neurosurgery. 1992;30:897-903

10.  Couldwell WT, Hinton DR et al. Protein Kinase C inhibitors induce apoptosis in human malignant glioma lines. FEBS Letters. 1994;345:43-46

11.  Robins HI, Peterson CG, Mehta MP. Combined modality treatment for central nervous system malignancies. Semin Oncol. 2003;30 (suppl. 9):11–22. 

12.  Baltuch GH, Dooley NP, Villemure JG, Yong VW. Protein kinase C and growth regulation of malignant gliomas. Can J Neurol Sci. 1995;22:264–271

13.  Gelmann EP. Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma. Semin Oncol. 1997; 24(suppl.):S1-65–S1-70.

14.  Chmura SJ, Mauceri HJ, Advani S, Heimann R, Beckett MA, Nodzenski E, Quintans J, Kufe DW, Weichselbaum RR. Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumour killing by ionizing radiation. Cancer Res. 1997;57:4340–4347

15.  Mastronardi L, Puzzilli F, Couldwell WT, Farah JO, Lunardi P. Tamoxifen and carboplatin combinational treatment of high-grade gliomas: Results of a clinical trial on newly diagnosed patients. J Neuro Oncol. 1998b;38:59–68

16.  Couldwell WT, Hinton DR, Surnock AA, DeGiorgio CM, Weiner LP, Apuzzo ML, Masri L, Law RE, Weiss MH. Treatment of recurrent malignant gliomas with chronic oral high-dose Tamoxifen. Clin Cancer Res. 1996;2:619–622

17.  Chang SM, Barker FG, II, Huhn SL, Nicholas MK, Page M, Rabbitt J, Prados MD. High dose oral Tamoxifen and subcutaneous interferon alpha-2a for recurrent glioma. J Neurooncol. 1998;37:169–176.

18.  Pollack IF, DaRosso RC, Robertson PL, Jakacki RL, Mirro JR, Jr, Blatt J, Nicholson S, Packer RJ, Allen JC, Cisneros A, Jordan VC. A phase I study of high-dose Tamoxifen for the treatment of refractory malignant gliomas of childhood. Clin Cancer Res. 1997;3:1109–1115. 

19.  Gabriel Lacob et al. Current data and strategy in glioblastoma multiforme. Journal of Medicine and Life 2009; 2 (4) 386-393

20.  Alberto Broniscer et al. Radiation Therapy and High-Dose Tamoxifen in the Treatment of Patients With Diffuse Brainstem Gliomas. Results of a Brazilian Cooperative Study. J Clin Oncol;2000:18(6):1246-1253

21.  Alexander M et al. Phase II Study of Concurrent Continuous Temozolomide (TMZ) and Tamoxifen (TMX) for Recurrent Malignant Astrocytic Gliomas. J Neuro Oncology.2004;70(1):91-95

22.  Muanza T, Shenouda G, Souhami L, Leblanc R, Mohr G, Corns R, Langleben A. High dose Tamoxifen and radiotherapy in patients with glioblastoma multiforme: A phase IB study. Can J Neurol Sci. 2000;27:302–306.

23.  Day R, Ganz PA, Costantino JP, Cronin WM, Wickerham DL, Fisher B. Health-related quality of life and Tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659-69.

24.  Nayfield SG et al. Tamoxifen-associated eye disease, a review. J Clini Oncol. 1996; 14(3):1018-1026. 

25.  Ahemed T et al. Phase II trial of thalidomide (TD), Tamoxifen (TX), and Temozolomide (T) for patients with advanced malignant gliomas (MG). Journal of Clinical Oncology 2005; 23(16):1575-1575.

26.  Rabbani G et al. Combination therapy with thalidomide, Temozolomide and Tamoxifen improves quality of life in patients with malignant astrocytomas. Anticancer Res. 2007; 27(4C):2729-36

27.  Patel S et al. Phase I clinical trial assessing Temozolamide and Tamoxifen with concomitant radiotherapy for treatment of high-grade glioma. Int J Radiat Oncol Biol Phys. 2012; 82(2):739-42.

Corresponding Author

Dr Niharika Panda

Associate Professor, Department of Radiotherapy

Plot No. N-3/462, IRC Village, Nayapalli, Bhubaneswar, Odisha, India 751015

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