Franz-Hospital, Onkologische Abteilung, Dülmen, Germany
Correspondence to: Dr G. Dresemann, Department of Hematology/ Oncology, Franz-Hospital Dülmen, Innere Abteilung, Vollenstrasse 10, D-48249 Dülmen, Germany. Tel: +49-2594-92-3480; Fax: +49-2594-92-1489; E-mail: gdresemann{at}aol.com
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Abstract |
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Patients and methods: We tested the combination of hydroxyurea and imatinib in 30 grade IV progressive GBM patients refractory to chemo- and radiotherapy. All 30 patients were evaluable after a median 19 weeks observation time.
Results: Combination therapy with imatinib and hydroxyurea resulted in a 20% response rate, including complete and partial responses. Patients experiencing response or stable disease yielded a combined clinical benefit rate of 57%. Median time to progression was 10 weeks and median overall survival was 19 weeks. Three patients continue to survive on combination therapy, with the shortest duration being 106 weeks. Six-month and 2-year progression-free survival rates were 32% and 16%, respectively.
Conclusion: The efficacy results, combined with findings that imatinib and hydroxyurea were well tolerated, suggest that this combination shows promise as therapy for GBM.
Key words: efficacy, glioblastoma multiforme, hydroxyurea, imatinib, PDGFRs, safety
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Introduction |
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Preclinical investigations have focused on gaining insight into the molecular basis for glioblastoma oncogenesis with the aim of identifying potential therapeutic targets. There is considerable support for the hypothesis that platelet-derived growth factor (PDGF) autocrine signaling plays a role in the transformation of gliomas [512
]. This has prompted the notion that inhibition of PDGF receptors (PDGFRs) might directly arrest GBM by interrupting an autocrine growth cycle [13
, 14
]. Alternatively, inhibition of PDGFRs may affect GBM tumor growth by indirect mechanisms relating to the tumor stroma or vasculature [15
17
].
Imatinib is a small molecule inhibitor of PDGFR and ß, as well as KIT, ABL, BCR-ABL and ARG tyrosine kinases [18
, 19
]. Imatinib is indicated for treatment of chronic myelogenous leukemia [20
23
] and unresectable or metastatic gastrointestinal stromal tumor (GIST) [24
26
].
Preliminary trials with imatinib as monotherapy for treatment of GBM have been conducted [27]. A multi-center phase II study of imatinib in 51 patients with recurrent GBM, obtained confirmed partial responses in two patients treated with imatinib 600 mg and in one patient treated with imatinib 800 mg for longer than 10 months. Prolonged tumor stabilizations for longer than 6 months were reported in one patient taking imatinib 600 mg and in four patients taking imatinib 800 mg. An earlier phase I trial examined 40 patients with malignant primary brain tumors, including 24 with GBM, treated with imatinib [28
]. Among 31 evaluable patients, 14 maintained stable disease and of those, four maintained stability for as long as 24 weeks.
The reasons underlying this level of efficacy with imatinib monotherapy for treatment of GBM are not clearly understood. Interestingly, a recent phase II trial investigating the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, as monotherapy for recurrent GBM, yielded modest results in a subpopulation of patients [29]. Together, results from these trials with targeted kinase inhibitors for recurrent/relapsed GBM patients suggest that perhaps such agents may be expected to exhibit efficacy as monotherapy in only subsets of patients. Whether related to tumor complexity or variability, these results raise the possibility that a combinatorial approach may be more beneficial.
Preclinical studies provide evidence that imatinib increases the chemo- or radiosensitivity of glioblastoma cells as well as of soft tissue sarcomas and leukemic cells in culture [3034
], suggesting that imatinib may enhance the activity of chemotherapeutic agents used to treat GBM. Hydroxyurea, a cytotoxic agent that inhibits DNA synthesis, is widely used in cancer therapy and penetrates the bloodbrain barrier [35
, 36
]. This patient series investigated the combination of imatinib and hydroxyurea in patients with progressive temozolomide-resistant GBM.
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Patients and methods |
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Patients were treated with imatinib 400 mg once daily and hydroxyurea 500 mg twice daily and were monitored by clinical examination, weekly blood cell counts, and MRI every 6 weeks for as long as patients remained clinically stable on treatment. SWOG criteria were used for evaluation of objective tumor response to treatment. All scans were evaluated by a radiologist and reviewed by the investigator. Scans were subsequently blinded for independent radiological evaluation by Gregory Sorensen (Massachusetts General Hospital, Charlestown, MA, USA). Clinical benefit was defined to include both partial and complete responses as well as stable disease lasting at least 3 months. Patients with tumor growth, detected by MRI, that did not satisfy SWOG criteria of progressive disease and did not lead to a decrease in performance status (no increased steroid dose required) were treated with imatinib 600 mg/day with no change in hydroxurea dose.
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Results |
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Discussion |
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This investigational series of treatment-refractory GBM patients treated with imatinib plus hydroxyurea yielded a clinical benefit rate, defined as either tumor response (partial or complete response) or as stable disease lasting at least 3 months, in 57% of patients. Among 30 patients, five patients achieved partial and one patient achieved complete response that lasted approximately 3 months for a total response rate of 20%. The 6-month progression-free survival rate was 32% and the 2-year progression-free survival rate was 16%. These results are comparable with published studies in investigational trials with recurrent or relapsed GBM patients [1, 4
, 41
, 42
].
Combination therapy with these two agents was well tolerated with no grade 3 or 4 toxicities. Two patients died of pulmonary embolism, a well-known complication with progressive GBM [3739
]. A relationship between pulmonary embolism and treatment was considered unlikely.
Because the patients in this study were relatively young (median 44 years) and with good initial performance status, it is likely that the proportion of secondary GBM was higher in this population compared with a more elderly population [43]. Nevertheless, previous studies have observed no difference in the prognostic significance between primary and secondary grade IV GBM among age-matched patients. This suggests that the prognosis among patients in this series was likely to be similar [44
]. Moreover, while one of the youngest patients attained disease control for a period, the other never responded and neither patient is among the longest-lived subset. It is possible that a subset of patients in this series may have been predisposed to respond to PDGFR inhibition and that this sensitivity was contingent on whether the GBM was primary or transformed [5
12
, 43
]. Future studies may resolve this issue.
Several possible explanations could underlie the positive results obtained with the combination of hydroxyurea and imatinib compared with single-agent imatinib. Although the extent to which imatinib penetrates the bloodbrain barrier in GBM is unknown, hydroxyurea, by virtue of its ability to traverse the bloodbrain barrier, may enhance the crossing of imatinib by inhibiting activity of ABCG2 ATP or P-glycoprotein, multidrug transporters with affinity for imatinib [45, 46
]. Imatinib also inhibits ABCG2 activity, indicating the potential for a complex cumulative interaction of hydroxyurea and imatinib that elevates and prolongs central nervous system concentrations of both agents. During combination therapy imatinib may reach target cells somehow differently than in the single-agent setting, possibly by an adjuvant-type interaction [47
].
It should also be noted that the majority of patients in this series were treated with enzyme-inducing anticonvulsants. The effect of these agents on the pharmacokinetics and pharmacodynamics of imatinib plus hydroxyurea in GBM patients is presently unknown but is a factor to consider with respect to the mechanism of action of this combination.
In the brain, imatinib may engage its potential array of antitumor mechanisms that may include direct or indirect effects on tumor growth through inhibition of PDGFRs. PDGFR signaling has been demonstrated to directly promote glioblastoma cell survival and growth in culture as well as in living mice [811
], whereas inhibition of PDGFR signaling suppresses cell growth [7
, 14
]. The hypothesis that aberrant PDGFR signaling may be involved in glioblastoma transformation is consistent with observations that human glial tumors overexpress PDGFRs compared with normal brain tissue [6
, 48
].
In addition to the direct role that PDGFR signaling may play in the proliferation of brain tumor cells, there is also the possibility that indirect mechanisms of PDGFR signaling contribute to brain tumor growth. Inhibition of PDGFRs expressed on pericytes associated with blood vessel endothelial cells might suppress brain tumor growth via an anti-angiogenic mechanism [49]. Furthermore, expression of PDGF and PDGFRs on tumor stromal cells can also affect tumor growth by regulating interstitial fluid pressure or other tissue factors that influence uptake of drugs into tumors [50
].
Another possible mechanism of action of imatinib, which is likely to be independent of PDGFRs, is suggested by evidence that in isolated cells in culture, imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism, or more recently reported, to radiotherapy [30, 33
, 34
]. In this series of patients, cytotoxicity would not be expected to play a major role in defeating GBM because all patients were refractory to nitrosourea. However, combination therapy with imatinib may have potentiated the chemosensitivity of tumor cells [31
, 32
, 34
].
While the precise mechanisms and interactions relevant to imatinib efficacy in this series of patients are not clear, the observations indicate that the combination of hydroxyurea and imatinib shows promise as a safe and effective therapy for a subpopulation of otherwise treatment refractory GBM patients. This is accomplished either through the induction of response or disease control with concomitant long-term survival in this subset of patients. Trials are underway to evaluate further this combination as treatment of GBM, as well as to characterize better the subpopulation of responding patients to perhaps select for those most likely to benefit from the combination in the future.
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Acknowledgements |
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Received for publication March 9, 2005. Revision received June 6, 2005. Accepted for publication June 9, 2005.
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