Purpose Bone pain is a common side-effect of pegfilgrastim and can interfere with quality of life and treatment adherence. This study i nvestigated the impact of antihistamine prophylaxis on pegfilgrastim-induced bone pain. Methods This is a two stage enrichment trial design. Patients receiving an initial dose of pegfilgrastim after chemotherapy were enrolled into the observation stage (OBS). Those who developed significant back or leg bone pain (SP) were enrolled into the treatment stage (TRT) and randomized to daily loratadine 10 mg or placebo for 7 days. SP was defined by Brief Pain Inventory as back or leg pain score ≥ 5 and a 2 point increase after pegfilgrastim. The primary end-point of TRT was reduction of worst back or leg bone pain with loratadine, defined as 2 point decrease after treatment compared to OBS. Results 213 patients were included in the final analysis. Incidence of SP was 30.5%. The SP subset had a worse overall Functional Assessment of Cancer Therapy – Bone Pain score (33.9 vs. 51.7, p < 0.001) and a higher mean white blood cell count (15.4 vs. 8.4 K/cm3, p = 0.013) following pegfilgrastim than those without SP. 46 patients were randomized in the TRT. Benefit was 77.3% with loratadine and 62.5% with placebo (p = 0.35). Baseline NSAID use was documented in 4 patients (18.2%) in loratadine arm and 2 patients (8.3%) in placebo arm, with baseline non-NSAID use documented in 5 (22.7%) and 6 (25%) patients respectively. Eight additional patients used NSAIDS by day 8 compared to day 1 (6 in the loratadine and 2 in the placebo arm). A total of 6 additional patients used non-NSAIDS by day 8 compared to day 1 (4 in the loratadine and 2 in the placebo arm). Conclusions Administration of prophylactic loratadine does not decrease the incidence of severe bone pain or improve quality of life in a high-risk patient population.

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The mevalonate pathway plays an important role in cancer biology and has been targeted previously with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. We hypothesize that combination of Simvastatin with Alendronate may have significant synergistic anti-carcinogenic potential in prostate cancer due to sequential blockade in the mevalonate pathway and will serve as a safer and better tolerated alternative than previously tried drugs. Simvastatin and alendronate sequentially inhibit HMG Co-A reductase and farnesyl pyrophosphate synthase enzymes respectively in the mevalonate pathway. This inhibition subsequently reduces isoprenoid synthesis including farnesyl pyrophosphate and geranylgeranylpyrophosphate. Prenylation (isoprenoid attachment) of G protein subunits and nuclear laminins help facilitate protein interactions in addition to termination of small GTPases’ activity. These proteins have important biological roles, including transmembrane signal transduction (RAS), cytoskeletal reorganization (RHO), gene expression (RAS), microtubule organization and nucleocytoplasmic transport. Inhibiting this pathway may have important anti-oncogenic effects through inhibition of processes such as tumor cell adhesion, migration, invasion, proliferation and induction of apoptosis. To test the hypothesis, we plated a predetermined number of 5000 PC3 cells into a 96 well plate and allowed them to adhere to the wells for an initial 24 hour incubation period using standard color free medium. Simvastatin and alendronate were prepared in various dose concentrations (simvastatin; 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, and 5.0µM and alendronate: 1, 2.0, 5.0. 10.0. 20.0, and 40.0µM). The cells were treated with simvastatin or alendronate alone, and then in various dose combinations. The cells with drug free medium were used as control. After 96 hour incubation, the quantity of living cells were determined via standard MTT assay and spectrophotometric analysis at 570nm and compared to the control group. Significant inhibition of PC3 cell growth was observed using simvastatin and alendronate alone as well as in combinations at low doses. Isobologram analysis was utilized as visual assessment of the drugs’ interaction with independent statistical analysis from calculations using total dose in a fixed-ratio combination and with calculated additive total dose for the same effect. Our results demonstrate synergistic inhibition of PC3 cell growth in vitro at various low dose combinations of simvastatin with alendronate. The fact that both of these drugs are commonly used in the population with no reported severe adverse effects from their combination offers a safe, effective and synergistic treatment option in the future treatment of prostate cancer. In vivo studies must be undertaken to explore these effects further. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4407. doi:10.1158/1538-7445.AM2011-4407

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