Biology Reference
In-Depth Information
ating starting point for future well-designed survival studies. In a randomized,
placebo-controlled trial of darbepoetin alfa for patients with lung cancer
receiving cisplatin-based chemotherapy, Vansteenkiste et al. observed a longer
survival in patients with small-cell lung cancer receiving darbepoetin alfa with
chemotherapy compared with patients receiving chemotherapy alone [29].
This trial is similarly hypothesis-generating, especially when considered in
light of the preclinical evidence, cited above, that hypoxia compromises the
cytotoxic effects of cisplatin. Several randomized trials of erythropoietic
agents for patients undergoing radiotherapy for cervical, head-and-neck, and
stage III lung cancers are underway or planned, as are trials in patients under-
going chemotherapy for breast and lung cancer.
EPO and EPOR are expressed in non-hematopoietic cells in the central
nervous system, where EPO is believed to play a role in maintenance, protec-
tion, and damage-repair. When administered systemically, both rHuEPO and
darbepoetin alfa penetrate the cerebrospinal fluid in concentrations believed to
be protective [112]. In murine and rat models, systemically administered epo-
etin alfa has been shown to decrease the extent of brain injury resulting from
ischemia, blunt trauma, and the administration of neurotoxins [113, 114]. In
the oncology setting, these considerations have resulted in speculation that
erythropoietic agents, in addition to decreasing fatigue and transfusion risk,
may decrease the incidence of chemobrain, a syndrome of decreased memory
and executive function detectable on high-sensitivity cognitive screens for up
to two years after chemotherapy, which has been observed primarily after
adjuvant chemotherapy for breast cancer [115]. It is not clear whether the syn-
drome results entirely from a direct chemotherapy effect on the brain or the
effects of sleep disturbances associated with chemotherapy-induced
menopause. Nevertheless, a sound pre-clinical basis exists for postulating a
role of erythropoietic therapy in decreasing the incidence of cognitive dys-
function after chemotherapy. Parenthetically, the kinetics of erythropoietic
agents crossing the blood-brain barrier and the available pre-clinical models
suggest that higher systemic doses, such as those proposed in front-loading
approaches, may be more effective in neuro-protection. Optimal hematopoiet-
ic support may provide optimal central nervous system protection.
New agents
Several erythropoietic molecules, including modified EPO and peptides unre-
lated to EPO that interact with EPOR, exist. Continuous EPOR activator is a
pegylated EPO molecule with a serum half-life in normal volunteers of at least
80 hours. It is likely that results from clinical trials in oncology with new mol-
ecules will be available soon and may shed additional light on the optimal
approach to treatment.
