Abstract

Basic science and clinical investigations have demonstrated that 13-cis-retinoic acid (cRA) has activity against malignant gliomas. To assess its effectiveness in the setting of recurrent glioblastoma multiforme (GBM), we performed a retrospective analysis of the medical records and neuroimaging results of patients with recurrent GBM who were treated with cRA. The toxicity profile of cRA, response, and effect on progression-free survival from initiation of treatment were end points of our analysis. Eighty-two of 85 patients with a median age of 51 years received at least 1 full cycle of cRA. At the initiation of cRA treatment, the median Karnofsky performance score was 80. All patients had failed conventional radiotherapy. Seven patients were chemonaïve, whereas 75 patients had received some form of chemotherapy. Radiographic partial responses, minor responses, and stable disease were seen in 4%, 8%, and 34% of patients, respectively. Two patients were not assessable. Progression-free survival and overall survival after initiation of cRA were 10.0 and 24.6 weeks, respectively. Six-month progression-free survival was 19% for the entire group. Grade 3 or 4 toxicity developed in 14 patients (16%), one of whom developed pancreatitis and died. The results of this study demonstrate only modest efficacy for cRA therapy in this cohort of heavily pretreated patients with recurrent GBM. This data supports the use of cRA in such patients, but its further evaluation in larger, prospective, controlled studies with or without other noncytotoxic and cytotoxic agents may be warranted.

References

Alvarez-Dolado, M., Gonzalez-Sancho, J.M., Navarro-Yubero, C., Garcia-Fernandez, L.F., and Munoz, A. (

1999
) Retinoic acid and 1,25-dihydroxy-vitamin D3 inhibit tenascin-C expression in rat glioma C6 cells.
J. Neurosci. Res.
58
,
293
-300.

Benkoussa, M., Brand, C., Delmotte, M.H., Formstecher, P., and Lefebvre, P. (

2002
) Retinoic acid receptors inhibit AP1 activation by regulating extracellular signal-regulated kinase and CBP recruitment to an AP1-responsive promoter.
Mol. Cell. Biol.
22
,
4522
-4534.

Bouillon, M., Tessier, P., Boulianne, R., Destrempe, R., and Audette, M. (

1991
) Regulation by retinoic acid of ICAM-1 expression on human tumor cell lines.
Biochim. Biophys. Acta
1097
,
95
-102.

Brada, M., Hoang-Xuan, K., Rampling, R., Dietrich, P.Y., Dirix, L.Y., Macdonald, D., Heimans, J.J., Zonnenberg, B.A., Bravo-Marques, J.M., Henriksson, R., Stupp, R., Yue, N., Bruner, J., Dugan, M., Rao, S., and Zaknoen, S. (

2001
) Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse.
Ann. Oncol.
12
,
259
-266.

CBTRUS. Central Brain Tumor Registry of the United States (

2002
-2003).
Primary Brain Tumors in the United States: Statistical Report, 1995-1999
(available at http://cbtrus.org/page2t.htm).

Chambaut-Guerin, A.M., Costa, S.L., Lefrancois, T., Fages, C., Gauthereau, X., and Tardy, M. (

2000
) Effects of retinoic acid and tumor necrosis factor alpha on GL-15 glioblastoma cells.
Neuroreport
11
,
389
-393.

Chattopadhyay, N., Butters, R.R., and Brown, E.M. (

2001
) Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocyte growth factor secretion and expression in U87 human astrocytoma cells.
Brain Res. Mol. Brain Res.
87
,
100
-108.

Friedman, H.S. Petros, W.P., Friedman, A.H., Schaaf, L.J., Kerby, T., Lawyer, J., Parry, M., Houghton, P.J., Lovell, S., Rasheed, K., Cloughesy, T., Stewart, E.S., Colvin, O.M., Provenzale, J.M., McLendon, R.E., Bigner, D.D., Cokgor, I., Haglund, M., Rich, J., Ashley, D., Malczyn, J., Elfring, G.L., and Miller, L.L. (

1999
) Irinotecan therapy in adults with recurrent or progressive malignant glioma.
J. Clin. Oncol.
17
,
1516
-1525.

Fulton, D., Urtasun, R., and Forsyth, P. (

1996
) Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma.
J. Neurooncol.
27
,
149
-155.

Gundimeda, U., Hara, S.K., Anderson, W.B., and Gopalakrishna, R. (

1993
) Retinoids inhibit the oxidative modification of protein kinase C induced by oxidant tumor promoters.
Arch. Biochem. Biophys.
300
,
526
-530.

Lamszus, K., Laterra, J., Westphal, M., and Rosen, E.M. (

1999
) Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas.
Int. J. Dev. Neurosci.
17
,
517
-530.

Lippman, S.M., and Meyskens, F.L., Jr. (

1987
) Treatment of advanced squamous cell carcinoma of the skin with isotretinoin.
Ann. Intern. Med.
107
,
499
-502.

Lippman, S.M., Kessler, J.F., Al-Sarraf, M., Alberts, D.S., Itri, L.M., Mattox, D., von Hoff, D.D., Loescher, L., and Meyskens, F.L., Jr. (

1988
) Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: A phase II randomized trial.
Invest. New Drugs
6
,
13
-17.

Osoba, D., Brada, M., Yung, W.K., and Prados, M.D. (

2000
) Health-related quality of life in patients with anaplastic astrocytoma during treatment with temozolomide.
Eur. J. Cancer
36
,
1788
-1795.

Prados, M.D., Schold, C., Spence A.M., Berger, M.S., McAlister L.D., Mehta, M.P., Gilbert, M.R., Fulton, D., Kuhn, J., Lamborn, K., Rector, D.J., and Chang, S.M. (

1996
) Phase II study of paclitaxel in patients with recurrent malignant glioma.
J. Clin. Oncol.
14
,
2316
-2321.

Rodriguez, L.A., Prados, M.D., Silver, P., and Levin, V.A. (

1989
) Reevaluation of procarbazine for the treatment of recurrent malignant central nervous system tumors.
Cancer
64
,
2420
-2423.

Tallman, M.S. (

1994
) All-trans-retinoic acid in acute promyelocytic leukemia and its potential in other hematologic malignancies.
Semin. Hematol.
31
(4 Suppl. 5),
38
-48.

Warnick, R.E., Prados, M.D., Mack, E.E., Chandler, K.L., Doz, F., Rabbitt, J.E., and Malec, M.K. (

1994
) A phase II study of intravenous carboplatin for the treatment of recurrent gliomas.
J. Neurooncol.
19
,
69
-74.

Yung, W.K.A., Lotan, R., Lee, P., Lotan, D., Steck, P.A. (

1989
) Modulation of growth and epidermal growth factor receptor activity by retinoic acid in human glioma cells.
Cancer Res.
49
,
1014
-1019.

Yung, W.K.A., Mechtler, L., and Gleason, M.J. (

1991
) Intravenous carboplatin for recurrent malignant glioma: A phase II study.
J. Clin. Oncol.
9
,
860
-864.

Yung, W.K., Kyritsis, A.P., Gleason, M.J., and Levin, V.A. (

1996
) Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid.
Clin. Cancer Res.
2
,
1931
-1935.

Yung, W.K.A., Albright, R.E., Olson, J., Fredericks, R., Fink, K., Prados, M.D., Brada, M., Spence, A., Hohl, R.J., Shapiro, W., Glantz, M., Greenberg, H., Selker, R.G., Vick, N.A., Rampling, R., Friedman, H., Phillips, P., Bruner, J., Yue, N., Osoba, D., Zaknoen, S., and Levin, V.A. (

2000
) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.
Br. J. Cancer
83
,
588
-593.

Author notes

Departments of Neuro-Oncology (S.-J.S., V.A.L., W.-K.A.Y., M.D.G.) andBiostatistics (K.R.H.), University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA