A Phase II study of cisplatin preceded by a 12-h continuous infusion of concurrent hydroxyurea and cytosine arabinoside (Ara-C) for adult patients with malignant gliomas (Southwest Oncology Group S9149)

Abstract

Inhibition of DNA excision repair can modulate resistance to cisplatin. Cytosine arabinoside (Ara-C) and hydroxyurea (HU), in combination, inhibit the excision-repair system and removal of platinum-DNA adducts. Marked cytotoxic synergy had been demonstrated in vitro at clinically achievable levels. The three-drug regimen was found to be feasible in clinical pilot studies. A © Springer Science+Business Media, LLC. 2007 Correspondence to: Lode J. Swinnen, lswinne1@jhmi.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptPhase II study in patients with relapsed or progressive anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) was performed in the Southwest Oncology Group. The primary end point was 6 month survival, historically about 42%. A loading dose of HU 1,260 mg/m 2 IV over 1 h was followed by Ara-C 1,200 mg/m 2 plus HU 5,040 mg/m 2 IV over 12 h, followed by cisplatin 100 mg/m 2 IV over 1 h. A total of 76 patients were registered. The GBM stratum registered 56 patients in a two-stage accrual. Among 51 eligible GBM patients, the 6-month survival probability was 41% (95% CI 28-55%), and median overall survival was 5 months (95% CI 4-6 months). The 6-month progression-free survival probability was 25% (95% CI 14-37%), and median progression-free survival was 2 months (95% CI 2-4 months). One patient achieved a partial response (2%, 95% CI 0-10%), 13 patients had stable disease (25%, 95% CI 14-39%). Twenty-two patients progressed, and 14 were not assessable for response. The AA stratum was closed early after 20 patients due to slow accrual. Among 19 eligible patients, the 6-month survival probability was 58% (95% CI 36-80%), and median overall survival was 7 months (95% CI 7-14 months). The 6-month progression-free survival probability was 26% (95% CI 6-46%), and median progression-free survival was 3 months (95% CI 2-5 months). No responses were seen. Six patients (32%) had stable disease (95% CI 13-57%), 11 progressed, and 2 were not assessable for response. Of the 70 patients evaluable for toxicity, two died of infection. Twentythree patients (33%) experienced Grade 4 toxicities, primarily hematological. Cisplatin combined with HU and Ara-C did not improve the 6 month survival rate in patients with relapsed or progressive AA or GBM. Significantly more hematological toxicity was seen than expected from cisplatin alone. Although benefit might be possible in a more platinum-sensitive tumor type, further clinical trials with this regimen for patients with glioblastoma multiforme or anaplastic astrocytoma are not justified.

Cyanide, Peroxide and Nitric Oxide Formation in Solutions of Hydroxyurea Causes Cellular Toxicity and May Contribute to Its Therapeutic Potency

“…It is interesting to note that NO, CO 2 , formamide and hydroxylamine are all generated during enzymatic HU decomposition in vivo 31. The finding of CN, NO and peroxides in aqueous solutions of HU should be an important consideration when HU is infused intravenously using pre-made aqueous solutions, which are stored before use for up to one week 66–70 or are prepared beforehand as liquid formulation for infants 30.…”

Recapitulation of Tumor Heterogeneity and Molecular Signatures in a 3D Brain Cancer Model with Decreased Sensitivity to Histone Deacetylase Inhibition

“…The proliferation of tumor cells grown in 3D spheroids is typically slower than that of monolayer cultures, exhibits different metabolic profiles and typically displays reduced sensitivity to chemotherapy and radiotherapy [7], [16], [17], [18], [19], [20]. For example, cytosine arabinoside (Ara-C) and Taxol which inhibit proliferation of glioblastoma cell lines in 2D cultures, but have failed clinical trials, show markedly reduced sensitivity in 3D cultures; an Ara-C dose 10 times higher than the effective dose in 2D cultures was necessary to reduce tumor cell proliferation [21], [22], [23]. A more recent 3D spheroid culture system from the Eccles and colleagues has provided automated, quantitative imaging capability that is potentially compatible with high-throughput preclinical targeting studies and may reduce the requirement of animal studies.…”

Cisplatin treatment of C6 rat glioma in vivo did not influence copy number alterations and growth pattern of tumor-derived resistant cells

“…Cisplatin combined with cytosine arabinoside and hydroxyurea did not improve the six-month survival rate in patients with relapsed or progressive high-grade glioblastomas. Signifi cant hematological toxicities were observed [31]. Finally, the recent medulloblastoma trial demonstrated that the cumulative cisplatin dose was not associated with overall survival [32].…”