The efficacy and safety of long-acting propranolol (LA.P), 160 mg once-daily, in the prophylactic treatment of migraine have been tested against placebo in a multicentric, double-blind, randomized study. The two groups are compared in a parallel manner over a treatment period of 12 weeks, following a 4-week placebo run-in period. Fifty-five of the 74 patients who entered the trial were included at the end of the run-in period. Forty-one patients completed the study. None of the 14 patients who withdrew from the study did so because of side effects. The statistical analysis was done according to the "intention to treat" principle. LA.P was significantly more effective than placebo in reducing the frequency of migraine attacks (p = 0.01 by variance analysis). LA.P reduced the average number of monthly crises by 48% on day 84. There was a slight but significant reduction of the systolic blood pressure and heart rate in the erect position, but there was no significant difference between LA.P and placebo regarding either the number of complaints or the number of side effects elicited out of a 17-item questionnaire. None of the observed side effects led to a withdrawal from treatment.
Patients with resectable gastric and rectal cancer undergoing CT/RT followed by surgery are at increased risk for anemia, fatigue, and need for red cell transfusions. Anemia and tumor hypoxia may contribute to adverse treatment outcome. A multi-center, placebo-controlled trial of 184 patients was designed to determine if Procrit treatment can maintain Hb (≥13 gm/dL), reduce the need for PRBC Tx and improve treatment outcome. Procrit was administered weekly (40,000 units starting dose) for 16 wks during CT/RT (5 FU or Xeloda + 45 Gy over 5 weeks) followed by surgery. After 60 pts were randomized, the trial was terminated due to increased incidence of TEE. 59 of these pts (53 rectal and 6 gastric) received at least one dose of treatment; 31 in the placebo and 28 in the Procrit group. Baseline median Hb for the study group was 13 gm/dL. Seven (11.9%) pts experienced venous TEE; 1/31 (3.2%) pts treated with placebo compared with 6/28 (21.4%) pts treated with Procrit (p= 0.045). In exploratory analyses including the multivariate modeling, it was observed that the Procrit treatment was a predictor of TEE (p = 0.060), however this was not observed for Hb (p = 0.998). Using a mixed-effects model, Hb was significantly higher in pts treated with Procrit than pts treated with placebo (p = 0.0004) during CT/RT. In addition, Hb was significantly different across weeks (p < 0.0001). During the study period, there was also a significant treatment by time interaction (p = 0.0061) with Hb maintained/increased in Procrit pts while it steadily decreased in the placebo pts. Four (14.3%) pts treated with Procrit compared with 10 (32.3%) pts treated with placebo required red cell transfusions (p = 0.133). Platelets (PLTs) decreased significantly from baseline during CT/RT (at weeks 4) for the placebo pts and for the pts treated with Procrit who did not experience TEE (p < 0.0001), but there was a trend for an increase in PLT in pts who experienced TEE. The tumor response for rectal ca at MDACC site was similar between both treatment groups with 14/22 (63.6%) in each treatment group (p = 0.777). These findings indicate that treatment with Procrit may prevent anemia during CT/RT/surgery, however there is increased risk for TEE in this setting for prevention of anemia. Correlative analysis is ongoing on biomarkers and molecular markers on biopsy specimens to examine the markers predictive of pathological complete response, TEE, and the treatment outcome.
Hematopoietic growth factors (HGF) G-CSF and GM-CSF have been utilized widely to facilitate mobilization of progenitor cells that can be used to support high dose CT. Recently long-acting HGF neulasta (pegfilgrastim) and aranesp (darbepoetin alfa) were developed to reduce the frequency of administration. While these agents are effective in reducing CT-induced neutropenia and anemia similar to their parent compounds, very little is known about their efficiency in mobilizing progenitor cells. The purpose of this study was to evaluate biologic effects of these agents, used in combination with CT, on progenitor cells. Chemo-naïve sarcoma patients receiving adriamycin and ifosfamide (AI) were treated once per cycle with aranesp (500 mcg) SC prior to initiating CT (day 0) and neulasta (6 mg) SC after completion of CT (day 4). BM and peripheral blood (PB) samples were studied at the baseline and around day 14 (at the time of WBC recovery) for progenitors and mediators of response. The treatment was associated with a significant increase in PB CD 34 + cells (median increase 36-fold, p=0.005) and marked mobilization (p=0.003) of CFU-GM (24-fold), BFU-E (22-fold), and CFU-GEMM (62-fold) (n=14). To better understand the biology and nature of response, we examined BM before and at the time of mobilization (n=12). There was an expansion of multi-lineage BM progenitors (p=0.06) and CD 34+ cells (P=0.001). BM exam at the time of recovery showed increased cellularity (2-fold) with increased granulopoietic elements. An increased expression of MMP-9 but unchanged expression of TIMP-1 was observed by Immunohistochemistry (IHC). c-kit ligand level by Elisa was decreased in the BM supernatant. In addition, phospho c-kit (phospho site 568) was increased in the myeloid and erythroid precursors by IHC but phospho site 823 was unaltered, indicating the specificity of activation of the downstream pathway in response to c-kit ligand-receptor activation, possibly leading to expansion of progenitor cells. Interestingly, expression of CXCR4 at the protein level (flow cytometry and western blot) and RNA level (RT-PCR) was decreased (p<0.05) in the BM at the time of mobilization (day 14) as compared to the baseline. These findings indicate that long-acting HGFs, administered once per cycle of CT, are a potent stimulus for mobilization of myeloid, erythroid, and multipotential progenitors. Our findings also suggest that increased myelopiesis in the regenerating BM may be associated with increased protease activity such as MMP-9 that may result in the cleavage of c-kit leading to activation of c-kit receptors and expansion of progenitors, and the cleavage of CXCR-4 leading to release of progenitors from the BM anchorage and mobilization into PB.
Background: Chemo-naïve sarcoma patients (pts) experience severe anemia during front-line chemotherapy (CT) with doxorubicin and ifosfamide (AI). In our prior study with AI, vast majority of pts (65 of 68, 93%) who received >1 cycle of CT, required PRBC transfusions. Anemia has significant negative impact on pts quality of life (QOL) and neurocognitive (NC) functions. Prior studies have shown that cancer pts receiving CT experience decline in NC functions and QOL. Preclinical studies suggest that treatment with erythropoietic stimulating agents (ESA) may protect NC functions. The purpose of the present study was to evaluate the effects darbepoetin alfa (DA) administered once per cycle as prophylaxis on the prevention of anemia, need for transfusions, symptom burden and NC functions in sarcoma pts receiving AI. Methods: DA (initial dose 500 mcg SC) was administered once per cycle before CT (day 0) starting from cycle-1(n=26) or cycle 2 (n=23) and continued up to max 6 cycles. Pts underwent a complete battery of neuropsychological tests and assessment of symptoms via the MD Anderson Symptom Inventory (MDASI) and quality of life with the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale at baseline, during CT (after 3 cycles) and at the end of study. At baseline, the median hemoglobin (Hb) was 13.2 g/dL, and only 5 of 49 pts were anemic to a level <11 g/dL. However, significantly more NC deficits or symptoms, including memory loss (29% of pts), fatigue (24%), pain (21%), distress (16%), and sadness (16%) were seen in pts at baseline as compared to normal populations. Pts with higher baseline Hb values had significantly less sadness (p=0.008) and less shortness of breath (p=0.003). Of the 45 pts that received > 1 cycle of CT (median, 4; range, 2–6 cycles), 38% avoided PRBC transfusions. Patients who avoided transfusions had less distress (p=0.032) and less sadness (p=0.01) during treatment. Patients with higher Hb nadir during treatment had less numbness and tingling (p=0.006). Overall, there was a significant decline in verbal fluency, non-dominant hand dexterity (p<0.001), and memory recall (p=0.018). Interestingly, there was a significant improvement in several symptoms including distress (p=0.001), sadness (p=0.032), and pain (p=0.004) during treatment as compared to baseline. These findings suggest that cancer pts can have NC deficits prior to CT. Prevention or early intervention with ESA may avoid the need for transfusions, reduce symptom burden and NC deficit.
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