A Single Institutional Phase II Randomized Trial of Whole Brain Radiation Therapy with or without Irinotecan for the Treatment of Brain Metastases from Solid Tumours

Soheir S. Ismail, Soheir H. Mahmoud, Dina A. Salem, Ahmed E. Essa, Diaa El-Din M. Sherif^*

Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.

DOI: 10.4236/jct.2015.610094                

Abstract

Background: The relatively suboptimal results of whole brain radiation therapy (WBRT) alone in eradication of brain metastases and an attempt to improve outcomes with WBRT have led to studies combining radiotherapy with chemotherapy drugs that could act as radiosensitizers with a rationale of improving local tumor control. Materials and Methods: This randomized phase II study evaluated the use of Irinotecan concomitant with 37.5 Gray (Gy) of WBRT in 2.5 Gy daily fractions × 5 days each week for 3 weeks versus Whole WBRT alone in patients with brain metastasis (BM) from solid tumors. Fifty patients were randomized to receive either WBRT alone or concomitant with three irinotecan IV infusions 80 mg/m², 2 hrs before RT on days 1, 8, and 15. Results: The objective response rate (ORR) was significantly improved in patients receiving Irinotecan with radiotherapy versus radiotherapy alone (48% vs. 28%; p = 0.048). The median time to progression of brain metastasis was significantly longer in the irinotecan and WBRT arm as compared to the WBRT arm (8 vs. 5 months; p < 0.001). There was no significant difference in survival between treatment arms (p = 0.361). Irinotecan with radiotherapy was generally well tolerated and did not interfere with the delivery of WBRT. Conclusions: Irinotecan concomitant with WBRT was well tolerated and significantly improved local control of BM compared with WBRT alone. These findings require confirmation in a phase III trial with addition of quality of life assessment.

Keywords

Brain Metastasis, Irinotecan, Whole Cranial Irradiation, Concomitant Treatment

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Kyritsis, A.P., Markoula, S. and Levin, V.A. (2012) A Systematic Approach to the Management of Patients with Brain Metastases of Known or Unknown Primary Site. Cancer Chemotherapy and Pharmacology, 69, 1-13. http://dx.doi.org/10.1007/s00280-011-1775-9
[2]	Sheehan, J.P., Sun, M.H., Kondziolka, D., et al. (2002) Radiosurgery for Non-Small Cell Lung Carcinoma Metastatic to the Brain: Long-Term Outcomes and Prognostic Factors Influencing Patient Survival Time and Local Tumor Control. Journal of Neurosurgery, 97, 1276-1281. http://dx.doi.org/10.3171/jns.2002.97.6.1276
[3]	O’Neill, B.P., Iturria, N.J., Link, M.J., et al. (2003) A Comparison of Surgical Resection and Stereotactic Radiosurgery in the Treatment of Solitary Brain Metastases. International Journal of Radiation Oncology*Biology* Physics, 55, 1169-1176. http://dx.doi.org/10.1016/S0360-3016(02)04379-1
[4]	Zimm, S., Wampler, G.L., Stablein, D., et al. (2007) Intra-Cerebral Metastases in Solid Tumor Patients. Natural History and Results of Treatment. Cancer, 48, 384-394. http://dx.doi.org/10.1002/1097-0142(19810715)48:2<384::AID-CNCR2820480227>3.0.CO;2-8
[5]	Xue, J., Peng, G., Yang, J.S., et al. (2013) Predictive Factors of Brain Metastasis in Patients with Breast Cancer. Medical Oncology, 30, 337. http://dx.doi.org/10.1007/s12032-012-0337-2
[6]	Klos, K.J. and O’Neill, B.P. (2004) Brain Metastases. Neurologist, 10, 31-46. http://dx.doi.org/10.1097/01.nrl.0000106922.83090.71
[7]	Eichler, A.F. and Loeffler, J.S. (2007) Multidisciplinary Management of Brain Metastases. Oncologist, 12, 884-898. http://dx.doi.org/10.1634/theoncologist.12-7-884
[8]	Langer, C.J. and Mehta, M.P. (2005) Current Management of Brain Metastases, with a Focus on Systemic Options. Journal of Clinical Oncology, 23, 6207-6219. http://dx.doi.org/10.1200/JCO.2005.03.145
[9]	Murray, K.J., Scott, C., Greenberg, H.M., et al. (2007) A Randomized Phase III Study of Accelerated Hyperfractionation versus Standard in Patients with Unresected Brain Metastases: A Report of the Radiation Therapy Oncology Group (RTOG) 9104. International Journal of Radiation Oncology*Biology* Physics, 39, 571-574. http://dx.doi.org/10.1016/S0360-3016(97)00341-6
[10]	Tsao, M.N., Lloyd, N., Wong, R.K., et al. (2012) Whole Brain Radiotherapy for the Treatment of Newly Diagnosed Multiple Brain Metastases. Cochrane Database of Systematic Reviews, 4, Article ID: CD003869. http://dx.doi.org/10.1002/14651858.cd003869.pub3
[11]	Chen, A.Y., Chou, R., Shih, S.J., et al. (2004) Enhancement of Radiotherapy with DNA Topoisomerase I-Targeted Drugs. Critical Review in Oncology/Hematology, 50, 111-119. http://dx.doi.org/10.1016/j.critrevonc.2003.09.005
[12]	James, J.V., Annick, D., David, A., et al. (2009) Experience with Irinotecan for the Treatment of Malignant Glioma Neuro-Oncology, 11, 80-91.
[13]	Xu, Y. and Her, C. (2015) Inhibition of Topoisomerase (DNA) I (TOPI): DNA Damage Repair and Anticancer Therapy. Biomolecules, 5, 1652-1670. http://dx.doi.org/10.3390/biom5031652
[14]	Chen, A.Y., Ryu, J.K. and Lau, D. (2005) A Phase I/II Trial of Irinotecan and Whole Brain Radiation Therapy in Patients with Brain Metastases. Journal of Clinical Oncology, 23, 1553.
[15]	Cancer Therapy Evaluation Program, Common Terminology Criteria for adverse Events, Version 3.0, 2003. DCTD, NCI, NIH, DHHS. http://cteb.cancer.gov
[16]	Nayak, L., Lee, E.Q. and Wen, P.Y. (2012) Epidemiology of Brain Metastases. Current Oncology Reports, 14, 48-54. http://dx.doi.org/10.1007/s11912-011-0203-y
[17]	Stea, B., Suh, J.H., Boyd, A.P., et al. (2006) Whole-Brain Radiotherapy with or without Efaproxiral for the Treatment of Brain Metastases: Determinants of Response and Its Prognostic Value for Subsequent Survival. International Journal of Radiation Oncology*Biology*Physics, 64, 1023-1030. http://dx.doi.org/10.1016/j.ijrobp.2005.10.004
[18]	Rojas-Puentes, L.L., Gonzalez-Pinedo, M., Crismatt, A., et al. (2013) Phase II Randomized, Double-Blind, Placebo-Controlled Study of Whole-Brain Irradiation with Concomitant Chloroquine for Brain Metastases. Radiation Oncology, 8, 209. http://dx.doi.org/10.1186/1748-717X-8-209
[19]	Antonadou, D., Coliarakis, C., Paraskevaidis, M., et al. (2002) Whole Brain Radiotherapy Alone or in Combination with Temozolomide for Brain Metastases: A Phase III Study. International Journal of Radiation Oncology*Biology* Physics, 54, 93-94. http://dx.doi.org/10.1016/S0360-3016(02)03217-0
[20]	Addeo, R., Caraglia, M., Faiola, V., et al. (2007) Concomitant Treatment of Brain Metastasis with Whole Brain Radiotherapy and Temozolomide Is Active and Improves Quality of Life. BMC Cancer, 7, 18. http://dx.doi.org/10.1186/1471-2407-7-18
[21]	Mehta, M.P., Rodrigus, P., Terhaard, C.H., et al. (2003) Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases. Journal of Clinical Oncology, 21, 2529-2536. http://dx.doi.org/10.1200/JCO.2003.12.122
[22]	Addeo, R., Rosa, C.D., Faiola, V., et al. (2008) Phase 2 Trial of Temozolomide Using Protracted Low-Dose and Whole-Brain Radiotherapy for Nonsmall Cell Lung Cancer and Breast Cancer Patients with Brain Metastases. Cancer, 113, 2524-2531. http://dx.doi.org/10.1002/cncr.23859