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Thalidomide in the Treatment of High-Grade Gliomas

United States Food and Drug Administration Rockville, MD

To the Editor:A phase II trial of thalidomide in the treatment of recurrent high-grade gliomas was published in the second February issue of the Journal of Clinical Oncology.¹ Important outcomes included objective partial responses in two of 36 assessable patients, a median survival of 28 weeks, and a greater than 1-year survival in eight of 36 patients. On the basis of this experience, the authors concluded that thalidomide had sufficient activity to recommend future study, with radiation therapy and other chemotherapy, in newly diagnosed, high-grade glioma patients. Are these conclusions justified?

High-grade gliomas include glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). These two histologic diagnoses are associated with very different prognoses. Curran et al² analyzed the survival outcome of 1,578 patients entered onto three Radiation Therapy Oncology Group malignant glioma trials. For specific prognostic groups of GBM patients, median survival ranged from 4.3 months to 17.6 months and 2-year survival ranged from 4% to 35%. For comparable AA patients, median survival ranged from 11.2 months to 58.6 months and 2-year survival ranged from 15% to 76%. In the current thalidomide report, neither responders nor survivors are identified by histology.

In addition to histology, other prognostic factors for response and survival include performance status, age (patients 50 years old have a better prognosis than those > 50), symptom duration, extent of surgical resection, and response to primary therapy.^3,4 Given these variables, the thalidomide study population was relatively favorable, with a median age of 49, a performance status of 80 to 100 in 77% of patients, and no prior chemotherapy in 49%.

Recently, a phase II trial was submitted to the United States Food and Drug Administration in support of an indication for the use of temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) for the treatment of relapsed, chemotherapy-refractory (carmustine [BCNU] and procarbazine) AA patients. Among 54 such patients, the objective response rate was 22%, with five patients (9%) having a complete response. The median duration of complete response was 348 days (range, 112 to 797 days). These results seem superior to those of the thalidomide study, in which no complete responses were noted among the 14 patients with AA or anaplastic mixed gliomas and in which response durations were, almost certainly, less than 1 year.

The modest thalidomide efficacy results in recurrent disease seem insufficient to warrant a recommendation that the drug be incorporated into first-line therapy. Perhaps additional studies might be done in the recurrent disease population to determine whether thalidomide is additive or synergistic when used with other Food and Drug Administration–approved glioma chemotherapies, such as Gliadel, a carmustine (BCNU)-impregnated biodegradable polyanhydride (poly[bis(p-carboxyphenoxy)] propane-sebacic acid) copolymer that, in wafer form, is applied directly to residual tumor after surgical resection.⁵

REFERENCES

1. Fine HA, Figg WD, Jaeckle K, et al: Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18: 708-715, 2000[Abstract/Free Full Text]

2. Curran WJ Jr, Scott CB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85: 704-710, 1993[Abstract/Free Full Text]

3. MRC Brain Tumour Working Party: Prognostic factors for high-grade malignant glioma: Development of a prognostic index. J Neurooncol 9: 47-55, 1990[Medline]

4. Perry JR, DeAngelis LM, Schold SC Jr, et al: Challenges in the design and conduct of phase III brain tumor therapy trials. Neurology 49: 912-917, 1997

5. Brem H, Piantadosi S, Burger PC, et al: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345: 1008-1012, 1995

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