Loprinzi, Charles L.

e20605 Background: Intravenous (IV) fosaprepitant is a potent antiemetic, commonly used in patients receiving chemotherapy. The purpose of this study was to investigate the incidence of IV fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin and cyclophosphamide (AC) chemotherapy at Mayo Rochester. Methods: A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC chemotherapy from January 2011 to April 2012. Data collected from the EMR included baseline demographics, antiemetic regimen, documentation of ISAEs and type of IV access (peripheral vs. central). Descriptive statistics (mean and standard deviation or percentages) were summarized overall and by type of IV access and initially administered antiemetic. Results: 148 patients were included, with a median age of 54 years (range 28-76). 98 patients initially received IV fosaprepitant; 44 oral aprepitant; 6 neither. 132 (89%) initially had peripheral IV access and 16 (11%) had central venous access. Overall, 33 patients (34%) experienced an IV fosaprepitant associated ISAE including: erythema (n=22), pain (n=26), swelling (n=12), infusion site hives (n=5), extravasation (n=4), deep venous thrombosis (n=3), superficial thrombosis (n=7), phlebitis/thrombophlebitis (n=5), venous discoloration (n=1), venous engorgement (n=1), venous hardening/induration (n=4) and local scarring (n=1). Only 1 patient (2%) experienced an oral aprepitant associated ISAE, which was infusion site pain. This patient had previously had a fosaprepitant associated ISAE at the same site. All experienced ISAEs occurred in patients with peripheral IV access. Conclusions: The incidence and severity of ISAEs associated with IV fosaprepitant administration among a group of patients receiving doxorubicin/cyclophosphamide chemotherapy is significant and is appreciably higher than what has been noted in other reports. The higher incidence observed is likely related to the predominance of peripheral venous access used in the studied cohort.

e17538 Background: Adherence to guideline-consistent chemotherapy-induced nausea and vomiting (CINV) prophylaxis is suboptimal. The primary aim of this study was to evaluate the magnitude of compliance to institutional guideline-directed antiemetic prophylaxis using a computerized physician order entry system at a single tertiary care institution. A nurse survey was also performed to evaluate how oncology practices, within a cooperative group, manage clinician orders for the prevention of CINV. Methods: The electronic medical records of 100 consecutive patients were evaluated. The primary endpoint was the incidence of compliance to provide all aspects of institutional guideline-directed antiemetic prophylaxis for acute (Day 1) and delayed (Days 2-4) CINV for patients receiving high, moderate, low, and minimally-emetogenic chemotherapy (HEC/MEC/LEC/MinEC). Noncompliance was declared if a recommended antiemetic was not prescribed per the guidelines or if additional antiemetics were prescribed. Descriptive analyses were performed on the convenience sample. Logistic regression was applied to determine the association of potential factors with noncompliance. Results: The incidence of compliance on Days 1-4 was 94%. Half of the noncompliant events occurred on Day 1 alone and involved the omission of pre-chemotherapy prochlorperazine in patients receiving LEC (3 of 6, 50%). There was a high-degree of compliance to institutional guidelines for delayed CINV (97%). Patients receiving doxorubicin/cyclophosphamide were numerically less likely to receive institutional guideline-directed antiemetic prophylaxis, compared to patients receiving other chemotherapy regimens (OR: 0.24 (0.04, 1.36), p-value: 0.05). No other factors were significantly predictive for compliance. The nurse survey demonstrated significant variability amongst the involved institutions, with regards to antiemetic prescribing practices. Conclusions: Computerized physician order entry is associated with impressive adherence to clinician prescribing practices, according to institutional guideline-directed antiemetic prophylaxis, for preventing acute and delayed CINV.

3618 Background: Current prognostic tools and staging systems in CC use relatively few patient (pt) characteristics; including additional covariates may improve prediction. Using the large ACCENT database, we constructed clinically based NGs for OS and TTR in stage III CC that better separate pts into risk groups compared to AJCC v7 staging. Methods: 15,936 stage III pts accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, BMI, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number/location of primary tumors (any multiple versus single left, right, or transverse), and treatment (5FU variations vs. 5FU with oxaliplatin or irinotecan). Missing data (<18%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions included if p < 0.001. Final models were internally validated via bootstrapping for corrected calibration and C-indices for survival data. NG-defined risk tertiles were compared to AJCC v7 stage III for observed 3-year (yr) TTR and 5-yr OS for a subset of 7400 pts with complete data. Results: All variables were statistically and clinically significant for OS; age and race did not predict TTR. No meaningful interactions existed. NGs for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, vs. 0.58 and 0.59 for AJCC. NG risk tertiles were better separated than AJCC groups, (3-yr TTR, 5-yr OS below), with fewer mid-risk NG pts. Removing treatment from NGs did not affect performance (C=0.66 for OS and 0.65 for TTR). Conclusions: The proposed ACCENT NGs are internally valid and have the potential to aid prognostication, decision-making, and patient/physician communication in pts with stage III CC. [Table: see text]

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]

9075 Background: Chemotherapy-induced peripheral neuropathy (CIPN), a common dose-limiting side effect of chemotherapy, remains without known effective interventions. Preliminary data support that Scrambler therapy, a device which treats pain via non-invasive cutaneous electrostimulation, is beneficial for the treatment of CIPN. This pilot trial was performed to investigate the effect of Scrambler therapy for the treatment of CIPN. Methods: Eligible patients included those age ≥18 years, ECOG PS ≤2, life expectancy ≥3 months, with pain or CIPN symptoms of ≥1 month duration and tingling or pain ≥4/10 during the prior week. Patients were treated with Scrambler therapy to the affected area for up to 10 daily 30 minute sessions. Symptoms were monitored daily during therapy using a questionnaire to measure symptoms of neuropathy with a numerical analogue scale. Results: We report on the first 11 CIPN patients, enrolled between 7/18/2011 and 12/12/2011, 3 men and 8 women; mean age 57 years. Patients had history of exposure to various chemotherapeutic agents and the majority had symptoms >2 years. The table portrays data at baseline, at the end of the 10 planned days of therapy, and the percent changes from baseline to the end of treatment, regarding patient reported pain, tingling, and numbness over the preceding 24 hours. There were no adverse events. Persistent benefit out to 5 weeks was seen in some patients; maturing data will be available by May 2012. Descriptive summary statistics formed the basis of data analysis. Further patients are being entered on this trial. Conclusions: Scrambler therapy appears to be beneficial in the treatment of CIPN. A prospective placebo-controlled clinical trial should be performed to confirm these preliminary findings. [Table: see text]

9001 Background: Ginseng is popularly used as a treatment for fatigue, one of the most common and disabling symptoms in people diagnosed with cancer. It is termed an “adaptogen”, thought to help the body combat negative effects of stress. This trial was to evaluate 2,000 mg American Ginseng versus placebo for cancer-related fatigue (CRF). Methods: Patients with cancer undergoing or having completed curative intent treatment and experiencing fatigue, rated at least 4 on a numeric analogue fatigue scale (1-10) for ≥1 month, were eligible. Exclusion criteria included CNS lymphoma, brain malignancies, or prior use of ginseng or chronic systemic steroids. Other etiologies for fatigue, such as pain and sleep, were also excluded. Patients were randomized to receive, in a double blind manner, 2,000 mg/d of American Ginseng or placebo in BID dosing for 8 weeks. The primary endpoint was change from baseline in the general subscale of the Multidimensional Fatigue Symptom Inventory (MFSI) at 4 weeks. Other MFSI subscales and the fatigue-inertia subscale of the Profile of Mood States (POMS) were also analyzed. Data were transformed to a 0-100 scale. Results: 364 patients were enrolled from 10/2008 to 07/2011. Data at 4 and 8 weeks are provided for several fatigue endpoints in the table below; higher numbers are better. Mental, emotional and vigor subscales of the MFSI were not significantly different between arms. There were no statistically significant differences in any grade of toxicity or self reported side effects between ginseng and placebo. Conclusions: This trial provides data to support that American Ginseng reduces general and physical CRF over 8 weeks without side effects. The treatment did not provide significant reductions in fatigue at 4 weeks and did not impact mental, emotional, and vigor dimensions of fatigue. [Table: see text]

1557 Background: Peripheral neuropathy (PN), a common and intrusive side effect of chemotherapy in clinical trials, has been assessed via the clinician-rated common terminology criteria for adverse events (CTCAE) and/or patient-reported outcome (PRO) measures (Morton, ASCO, 2005). We assessed the relative sensitivity of CTCAE and PRO measures for evaluating interventions for preventing and ameliorating CIPN. Methods: Data from285 patients in two prevention trials (N05C3, N04C7) and 432 patients from three intervention trials (N00C3, N01C3, N06CA) were analyzed separately. CTCAE version 3.0 item for neuropathy was compared to 2 NCCTG numerical analogue CIPN items, 6 EORTC CIPN20 individual items, 2 McGill Pain Questionnaire items, and one Brief Pain Inventory item. The sample size provided over 80% power to detect a true Spearman rank correlation of 0.15 assessed the relationship between CTCAE and PRO measures. Results: Results from both the prevention and treatment trials were similar in terms of the relationship between the CTCAE and PRO measures. No correlation coefficients between the CTCAE and any of the PRO items at baseline were above 0.35, with the majority around 0.2. Higher scores for the numbness items were observed than for the CTCAE in 47% of the patients at baseline and 39% during treatment in the treatment trials. Many patients had severe numbness PRO scores but mild CTCAE scores (12%) at baseline and (8%) during treatment in the treatment trials. Results for the numbness and tingling PRO measures were redundant. The correlations of the CTCAE with pain were weak, all below 0.35 at baseline with differences as much as 29 points on average on a 0-100 transformed scale. Conclusions: The CTCAE and PRO measures of PN measure different constructs. The CTCAE includes both functional and ADL/motor aspects which may or may not be related to the singular constructs of pain, numbness, tingling, or adjectival characteristics of pain assessed by the PRO measures. The two measures cannot be used in place of each other.

9513 Background: The need for more research in N/V control is exemplified by agents that are costly, interfere with cytochrome P450 metabolism, and inadequately address delayed N/V. Based on pilot data, there was justification for evaluating whether gabapentin could improve the prevention of delayed N/V from highly emetogenic chemotherapy (HEC). Methods: Patients (pts) about to receive HEC were randomized to prophylactic treatment with 20 mg of dexamethasone (dex) and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by either gabapentin (gaba) 300 mg BID and dex or placebo (plac) and dex. Gaba/plac was started the evening of the day of chemotherapy and continued through day 5 of the first chemotherapy cycle. Dex was given at 8 mg BID days 2-3, then 4 mg BID for day 4, in both arms. The primary endpoint was complete response (CR), defined as no emesis and no rescue medications day 2-6, using a nausea and vomiting diary. The percent of CR were compared in each group by Fisher’s exact test. Secondary outcomes included the Functional Living Index-Emesis (FLIE), satisfaction, and a side effect questionnaire. Results: 430 pts were enrolled in this study between 5/2009 and 2/2011. 47% of pts in the gaba arm and 41% in the plac arm had a CR (p=.23). At some time during days 2-6, 30% in the gaba and plac arms experienced emesis, and 45% and 53% in the gaba and plac arms, respectively, took rescue medication. Mean diary nausea scores over days 2-6 ranged from 0.9 – 1.2 (gaba arm) and 1.0-1.3 (plac arm)(7 = the worst); mean number of diary emetic episodes ranged from 0.1 -0.3 (gaba arm) and 0.1-0.2 (plac arm). The FLIE was not significantly different between arms. Mean vomiting satisfaction was 9.1 in both arms and for nausea was 8.3 for gaba, 8.1 for plac (10= totally satisfied). There were no significant differences in toxicities by CTCAE provider grading or by self-report. Conclusions: In this study, gaba did not improve delayed N/V. Overall, there was little emesis and nausea severity was low. Patients were satisfied with the control of their N/V, irrespective of arm. The use of standard prophylactic guidelines that include a 5HT3RA and dex provided good control of N/V for most patients. Clinical trial information: NCT00880191.

526 Background: Antidepressants do not adequately alleviate all HFs. Based on placebo-controlled data demonstrating that GABA is an alternative therapy for HFs, this trial was initiated to test whether the combination of an antidepressant and GABA was better than GABA alone in PTS with inadequate HF control on an antidepressant alone. Methods: Eligible PTS on antidepressants with bothersome HFs were randomized to two groups. PTS kept a daily HF diary during a baseline wk (while continuing their antidepressant). Following the baseline wk, all PTS were given GABA 300 mg at hs for 3 days, then BID for 3 days, and then TID for 22 days. One group continued their antidepressant while the other group was weaned off it over several days. PTS continued a daily HF diary during this 4-wk period. Efficacy was measured using the mean daily HF number and score; the latter measured by assigning points (1–4, for mild to very severe) to each HF and then adding the points for a given time. The study design provided 80% power to detect a difference in the changes from baseline at 4 wks between the two groups of 1.2 HFs/day, or 3 points/day in HF scores. Results: 115 PTS were randomized and given GABA. PTS continuing their antidepressant reported a 48% mean reduction in HF score after 4 wks, vs 49% for PTS stopping it (p=0.97). Mean HF numbers were reduced 50% and 47%, respectively (p=0.54). 16 other symptoms and quality of life items were measured by PT-completed weekly questionnaires, with the only suggestive changes from baseline between the two arms being more mood troubles after 2 wks of treatment (p=0.06) and more nervousness after 4 wks of treatment (p=0.01) in PTS stopping their antidepressant. Also, a mild temporary increase in dizziness after 1 wk of treatment was observed in the same group (p=0.08) suggestive of an antidepressant withdrawal reaction. Conclusion: This trial failed to provide any evidence that the combination of GABA and an antidepressant decreased HFs any more than did GABA alone in PTS who had inadequate HF control with an antidepressant alone. The 50% reduction in HFs in both arms is commensurate with the efficacy of GABA delineated in other published reports. No significant financial relationships to disclose.

19613 Background: Paclitaxel therapy often results in a unique sub-acute pain syndrome, whose pathophysiology is unknown. While this syndrome is often termed as a ‘myalgia’ or ‘arthralgia’, it has not been demonstrated to be associated with any structural injury of muscles or joints. Identifying the pathophysiology mechanisms that result in the paclitaxel-acute pain syndrome might be a positive step in the development of effective prevention and/or treatment strategies. With the hypothesis that the paclitaxel-acute pain syndrome occurs as a result of nerve injury, an observational study to clarify the clinical characteristics of this syndrome was initiated. Methods: Oncology patients who were treated with at least one dose of paclitaxel and reported developing sub-acute pain were questioned using a detailed structured interview. Various aspects of the pain, including the time of onset, duration, location, severity, and exacerbating factors were evaluated. Data were tabulated descriptively. Results: Eighteen patients were interviewed. The onset of pain typically occurred 1–2 days after therapy and lasted for a median of 4–5 days. Pain was most commonly located in the back, hips, shoulders, thighs, legs and feet, with the most common descriptors used being ‘aching’ or ‘deep pain’. Commonly used adjectives to describe the pain were: ‘radiating’, ‘shooting’, ‘aching’, ‘stabbing’ and ‘pulsating’. Some patients described increased pain with weight bearing or walking. Fifteen of 18 patients specifically denied localization of pain to either joints or muscles. Conclusions: The nature of the pain, i.e. , generalized, deep aching pain, the notation of increased sensitivity with weight bearing (mechanical hyperalgesia) and the lack of localization to joints or muscles, support the hypothesis that the paclitaxel-acute pain syndrome results from a hyperalgesic dysfunction of nociceptive receptors, their fibers, or the spinothalamic system. These clinical conclusions are supported by the recent findings that markers of cellular injury can be identified in peripheral nerve tissues shortly following paclitaxel administration in an animal model (Peters CM, et al., Exp Neurol. 2007 Jan;203(1):42- 54). No significant financial relationships to disclose.