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increase in the proportion of long-term survivors with Sigmond et al. demonstrated that gemcitabine could
[29]
the addition of chemotherapy, from less than 5 percent to pass the blood-tumor barrier in GBM patients. In tumor
approximately 15-20 percent, regardless of the patient’s samples, concentrations of gemcitabine and its active
performance status, the histological features of the tumor, metabolite dF-dCTP were high enough to enable radio
the duration of symptoms or age (up to 65 years). [5] sensitization, which warrants clinical studies using
gemcitabine in combination with radiation.
However, the combination of radiotherapy with TMZ
[30]
[24]
completely changed standard therapy, since this improved Weller et al. and Metro et al. indeed showed that
the median survival and overall survival. However, gemcitabine combined with RTH was an active regimen,
[2]
not all patients benefit since an unmethylated promoter but whether it was more effective than RTH alone remained
of methylguanine methyltransferase (MGMT) enables elusive. The combination gemcitabine-RTH followed by
[30]
extensive repair of TMZ-adducts and these patients do temozolomide showed promising activity. Preliminary
not benefit from temozolomide and are eligible for results of another phase I study showed that gemcitabine
[6]
development of alternative therapies. Moreover, TMZ combined with radiotherapy is efficient and tolerable in
[31]
is relatively a poor radiosensitizer compared with other high grade glioma. The aim of our study was to evaluate
cytotoxic drugs, However, the group of nucleoside analogs, the activity of gemcitabine with RTH as a treatment
[7]
including gemcitabine are excellent radiosensitizers. [8,9] modality in newly diagnosed high- grade gliomas and
temozolomide was administered after progression only.
Gemcitabine has been evaluated as a radiosensitizer for
several tumor types, both in model systems and patients. [8,10] METHODS
Gemcitabine, an analogue of deoxycytidine, enters the cell
by the action of a nucleoside transporter and it is activated This was single center, phase II, open label, one arm
[11]
by phosphorylation in a reaction catalyzed by deoxycytidine non-randomized trial designed to determine the efficacy
kinase (DCK), to gemcitabine monophosphate (dFdCMP) and safety of gemcitabine combined with therapy in the
and subsequently phosphorylated to the 5’-diphosphate treatment of patients with newly diagnosed malignant
(dFdCDP) and triphosphate (dFdCTP) derivatives. [12,13] glioma. The Research Ethics Board of Assiut University
Gemcitabine exerts its cytotoxicity mainly through the Hospital approved the study. All patients gave written
irreversible incorporation of the activated triphosphate informed consent before starting treatment.
into DNA, resulting in chain termination. Due to a
number of self-potentiating mechanisms, gemcitabine Patients
exhibits prolonged intracellular retention, a property likely Eligible patients had histologically proven malignant
partially responsible for gemcitabine’s broad spectrum of glioma (grade 3 or 4). Patients were at least 18 years of
activity. [14,15] age; had the Eastern Cooperative Oncology Group (ECOG)
performance status < 3, had adequate bone marrow reserves
9
The standard dose of gemcitabine (1,000 mg/m ) given (hemoglobin > 9 g/dL, absolute granulocytes > 1.5 × 10 /L,
2
over 30 min results in high gemcitabine peak levels platelets > 100 × 10 /L), and acceptable serum chemistries
9
(> 20 µmol/L), which rapidly decline below 1 µmol/L (serum calcium in normal range (8.8-10.2 mg/dL), serum
within 2 h. [16,17] However, DCK is saturated at much lower creatinine < l.5 × upper limit of normal, bilirubin < 1.5 ×
gemcitabine levels and in vitro and in vivo sensitivity to upper limits of normal and AST (aspartate transaminase) <
gemcitabine is most optimal at prolonged exposure to low 3 × upper limits of normal).
drug levels in the nanomolar range. [18-20] Therefore, it was
reasoned that prolonged infusion of gemcitabine, which Patients were excluded if they were < 18 years old, had
would result in prolonged but lower plasma concentrations previous invasive malignancies or received previous
of gemcitabine, would be advantageous. [16,21] The fixed chemotherapy or radiotherapy, had poor medical conditions,
dose rate of 10 mg/m /min infusion of gemcitabine or were pregnant, nursing or not practicing effective
2
contraception if appropriate.
gives this pharmacodynamic advantage over the 30
min infusion, resulting in a prolonged formation and Assessments and treatment plan
[16]
retention of gemcitabine nucleotides which favour the Pre-treatment evaluation included a history and physical
activity of gemcitabine. A phase II trial showed that fixed and neurological examination, laboratory (complete blood
dose rate gemcitabine can improve survival in patients picture, liver and kidney function, serum calcium level)
with pancreatic adenocarcinoma but the difference was not and imaging studies (baseline CT and MRI brain) and a
significant in a randomized study. Single agent studies baseline toxicity evaluation.
[22]
of gemcitabine in high grade glioma did not show any
benefit, [23,24] so that development of gemcitabine for this After surgery of patients with malignant gliomas for either
disease was discontinued. However, gemcitabine has shown cytoreduction or a biopsy, patients received fractionated
a radiosensitizing effect in a number of human glioma cell local RTH at a daily dose of 2 Gray (GY) per fraction,
lines [25-27] and in an animal model system. [28] five days per week for six weeks (total dose of 60 GY).

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 18, 2016 ¦ 189