Loprinzi, Charles L.

e24115 Background: Paclitaxel, a widely used chemotherapeutic agent, is associated with an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is no standard of care for P-APS. Commonly used analgesics, including NSAIDs and narcotics, have considerable toxicity profiles. Omega-3 fatty acids, a common dietary supplement, have well established anti-inflammatory and neuroprotective properties. The primary aim of the study was to assess if omega 3 fatty acids could prevent P-APS. Methods: Patients scheduled to receive weekly paclitaxel (70-90mg/m2) were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior to starting paclitaxel and continued until paclitaxel was discontinued. Patients completed acute pain questionnaires at baseline, Days 2-7, prior to each subsequent treatment and one month after completion of therapy. The EORTC- QLQ CIPN 20 questionnaire was completed prior to each dose of paclitaxel and 1 month after completion. The primary objective was to compare the effect of omega 3 fatty acids, versus placebo, on the maximum pain score for the week following the 1st treatment and each subsequent paclitaxel treatment, and to compare pain medication use between the 2 arms. The secondary objective was to compare the effect of the intervention on the severity of CIPN. Results: 49 patients were randomized to treatment versus placebo. Linear mixed effects models were applied with the addition of a bootstrap approach to overcome limitations in the distributional assumptions to compare outcomes between treatment groups. Placebo results were similar to the reported natural history of P-APS. There was no significant difference in trends over time between the 2 groups in the maximum pain score at week 1 (p = .14) and over 12 weeks (p = .21). There was also no difference noted in the rates of use of over the counter analgesics (p = .39) and narcotics (p = .46). CIPN results did not differ between the 2 groups (p = .08). Conclusions: The results of this pilot study do not support the use of omega-3 fatty acids for the prevention of paclitaxel-associated pain syndrome. Clinical trial information: NCT01821833 .

e24103 Background: Many of the 200,000 patients diagnosed with breast cancer (BC) annually in the United States receive anthracycline-based therapy, increasing their risk of future congestive heart failure. N-terminal brain natriuretic peptide (NT-proBNP) has been used as a biomarker of asymptomatic cardiac dysfunction in the general population and is of interest to identify patients who might benefit from echocardiography during survivorship. This study aimed to assess how age, baseline comorbidities, and time since BC diagnosis impact NT-proBNP levels after anthracycline-based chemotherapy. Methods: This retrospective study, using samples collected in our ongoing prospective Mayo Clinic Breast Disease Registry, included 20 survivors of non-metastatic BC patients per year for each of the first 5 years after anthracycline-based chemotherapy (n=100 total). NT-pro-BNP levels were assessed using a Roche immunoassay. Cardiac risk factors were obtained by chart review. Multivariable linear regression models assessed associations between NT-proBNP values and these independent variables: baseline cardiac risk factors (including hypertension, hyperlipidemia, obesity, diabetes mellitus, and smoking), tumor ER status (surrogate for possible endocrine therapy), time between diagnosis and serum collection, T and N status, use of trastuzumab, and age. Results: The mean age at the time of BC diagnosis was 52.2 (SD 9.8). 13% of tumors were human epidermal growth factor receptor (HER2)-positive and 71% were estrogen receptor (ER) positive. NT-proBNP was elevated in 34%. Mean NT-BNP level was higher (p=0.047) for those in years 4-5 (158 pg/mL) compared to those in years 1-3 (106 pg/mL) (See Table.) Models revealed years from diagnosis to serum draw (p=0.026), older age (p=0.006), more cardiac risk factors (p=0.064), and N2-3 (p=0.001) were associated with elevated NT-pro-BNP level. Use of trastuzumab, ER status, and tumor size were not associated with NT-proBNP. Conclusions: NT-proBNP is elevated in 1/3 of survivors who received anthracycline therapy for BC. As expected, cardiac risk factors and advancing age are associated with higher NT-proBNP. NT-proBNP values >300 were only found in patients who were 4-5 years after diagnosis. Additional research will be needed to further define the diagnostic and prognostic merit of NT-proBNP in survivors after receipt of anthracycline therapy. [Table: see text]

e24086 Background: Nasal vestibulitis has been infrequently described as a side effect of cancer-directed therapy; however, a preliminary study reported that 71% of patients undergoing taxane chemotherapy experienced nasal vestibulitis symptoms. This natural history trial describes the incidence, characteristics, and severity of nasal vestibulitis symptoms among patients undergoing paclitaxel, docetaxel, and non-taxane chemotherapy. Methods: Eligible participants who reported baseline (prior to starting chemotherapy) nasal symptoms ≤ 2 on a 10-point scale were enrolled in this trial upon initiation of a new treatment regimen, involving paclitaxel or docetaxel, or non-taxane chemotherapy. Participants completed nasal symptom logs each time they received a dose of therapy until either the regimen was stopped or four months had passed. The proportion of patients reporting new nasal symptoms was estimated within each cohort with the 95% exact confidence interval (CI). A cumulative incidence model was utilized to quantify the incidence of treatment-emergent nasal symptoms within each cohort, while controlling for age, sex, smoking history, and history of asthma or allergies. Results: Thirty-five participants received paclitaxel, 21 received docetaxel, and 25 received other types of chemotherapy. 86.4% of participants were female, mean age was 60.2 ± 11.2 years; 93.8% of participants completed 2 or more surveys. A higher percentage of participants in the paclitaxel cohort experienced new nasal vestibulitis symptoms than participants in the other two cohorts. The percentage (95% CI) of participants with nasal symptoms, for patients receiving paclitaxel, docetaxel, and non-taxane chemotherapy were 74.3% (56.7%, 87.5%), 47.6% (25.7%, 70.2%), and 44.0% (24.4%, 65.1%), respectively. Epistaxis was reported by 60% of participants in the paclitaxel cohort. Paclitaxel-receiving participants also reported nasal dryness (48.6%), scabbing (40.0%), and pain (20.0%). Nearly half of participants reported moderate symptoms (4-7 out of a 10-point scale), with 8.6% reporting symptoms as severe (8-10 on a 10-point scale). Conclusions: Nasal vestibulitis is a common side effect of chemotherapy, especially paclitaxel chemotherapy.

12007 Background: Up to 96% of patients with high grade glioma (HGG) report moderate to severe fatigue. Armodafinil, the R-enantiomer of modafinil, is a psychostimulant with low potential for abuse that has shown potential for improving severe fatigue in HGG patients. Methods: In this phase III double blinded placebo-controlled study, adults with HGG and moderate to severe fatigue, > 4 weeks after completing radiotherapy, were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo for a total of 8 weeks. The primary outcome was efficacy in treating severe fatigue. Secondary outcomes included evaluation of tolerability, neurocognitive function, and quality of life. Patients were evaluated at baseline, 4 and 8 weeks. Results: A total of 328 patients were enrolled between 6/3/13-3/1/19. There were 103 (150 mg arm), 97 (250 mg arm) and 97 (placebo arm) evaluable patients with primary endpoint data available. The median age was 60 years (20-85) with a median Brief Fatigue Inventory (BFI) worst fatigue score of 8 (6-10). 60.3% were male, 80.5% received concomitant chemotherapy, and 39.7% were on corticosteroids. The global fatigue score at end of weeks 4 and 8 were lower than at baseline (p<0.0001) and in the 250 mg arm than placebo (p=0.0356) and was higher for corticosteroid users than non-users (p=0.0002). There was no statistically significant difference for clinically meaningful improvement in BFI usual fatigue score from baseline to end of week 8 between the three arms (p=0.9601). Patients reported an improvement in concentration at week 4 from baseline on the 150 mg arm(P=0.0311). There was no statistically significant difference on neurocognitive tests from baseline to end of week 4 (p>0.05) or week 8 (p>0.05) between arms. More patients reported insomnia on the 250 mg arm (p=0.0083). Conclusions: There is no meaningful benefit of the use of armodafinil to reduce moderate to severe fatigue in patients with HGG. In certain cases there may be benefit of armodafinil 150 mg to aid concentration without the risk of insomnia.Support: UG1CA189823;U10CA180868 (NRG). Clinical trial information: NCT01781468 .

1044 Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.

PURPOSE To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer. METHODS A systematic review of the literature collected evidence regarding nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment. RECOMMENDATIONS Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.

8534 Purpose: Tumor necrosis factor (TNF) is a putative mediator of the cancer anorexia/weight loss syndrome. This study was designed to determine if etanercept (a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton TNF receptor linked to the Fc portion of human IgG1) could palliate this syndrome. Methods: 63 evaluable patients were randomly assigned to etanercept 25 mg SQ twice/week versus a comparably-administered placebo, both of which were to be given for at least 12 weeks. All patients had an incurable malignancy, acknowledged loss of weight and/or appetite as a concern, and reported weight loss of > 5 pounds over 2 months and/or a daily intake of < 20 calories/kg body weight. The above sample size provided 81% power to detect a 24% difference in the percentage of patients who gained >/= 10% of baseline weight. Results: At baseline, groups were comparable on age, gender, tumor type, and degree of weight loss. Over time, weight gain was minimal in both groups; no patient gained >/= 10% baseline weight. Appetite questionnaires (the NCCTG Anorexia/Cachexia Questionnaire and FACT-AN) revealed negligible improvements in both groups. Median survival was comparable: 175 days versus 148 in etanercept-treated and placebo-exposed patients, respectively (p=0.82). Finally, preliminary data on adverse events showed that etanercept-treated patients had higher rates of neurotoxicity (29% versus 0%) but lower rates of anemia (0% versus 19%) and thrombocytopenia (0% versus 14%). Infection rates were negligible in both groups. Clinical correlative data on TNF genotyping will be available at the time of the meeting. Conclusion: This TNF inhibitor does not appear to palliate the cancer anorexia/weight loss syndrome. The study was supported by CA37404, the American Institute for Cancer Research, and Amgen. No significant financial relationships to disclose.

8530 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose limiting complication of chemotherapy. Lamotrigine (an anti-convulsant drug) appears to have some benefit when used to treat pain from neuropathy due to various etiologies. Based on these data, we conducted a phase III randomized placebo controlled study to determine the efficacy of lamotrigine in treating symptoms from CIPN. Methods: Patients with CIPN for 1 month or more were randomly assigned to lamotrigine (target dose 300 mg/day, increased by 50 mg/2 weeks) or placebo for 10 weeks. The co-primary endpoints were differences in average CIPN symptoms assessed by pro-rated area under the curve (AUC) of a numerical pain rating scale (NRS) and the Eastern Cooperative Oncology Group sensory neuropathy (ESN) scale. Accrual of 60 patients per group provided t-tests with 80% power to detect a difference of 0.57 standard deviation for each co-primary endpoint (moderate effect size) with a type I error of 0.025. Results: 131patients were enrolled, with complete data available for analysis in 93 (72%). Analyses were limited to this cohort but will be updated. Chemotherapy drugs considered to be causative of the CIPN were vinca alkaloids (30%), taxanes (25%), platinum-agents (7%), combinations (34%), and others (3%). Patients were equally matched with regards to baseline characteristics. Patients who enrolled had severe symptoms, with a baseline median ESN at enrollment of 3 (out of 3) in both groups. Toxicities were similar in both groups, however, more patients discontinued lamotrigine due to toxicities/refusals than those on placebo (32% vs 13% resp; p=0.04) and were therefore less likely to complete the 10 weeks therapy (60% vs. 78% resp, p=0.08). Average AUC of NRS score for patients on lamotrigine and placebo was 30.5 and 33.7 resp (p=0.48). The corresponding average AUC of the ESN scores were 12.4 and 14.5 (p=0.23). The proportions of patients with a 10 point (of 100) improvement in worst pain score (39% vs 36%) and a 1 point change in ESN (25% vs 27%) were similar between the lamotrigine and placebo arms, resp. Conclusions: These results suggest that lamotrigine is not effective for managing pain and symptoms due to CIPN. No significant financial relationships to disclose.

8507 Background: Problems with sexual functioning are an issue negatively affecting the quality of life of female cancer survivors. Testosterone has been implicated as an important hormone in sexual functioning such as libido. Studies of transdermal testosterone have shown benefit in enhancing libido in women who have been diagnosed with hypoactive sexual desire disorder after bilateral oophorectomy. This phase III placebo-controlled clinical trial evaluated whether transdermal testosterone would increase libido in female cancer survivors. Methods: Women with a history of cancer, currently without evidence of disease, were eligible if they reported a decrease in sexual desire and had a sexual partner. Women must have been postmenopausal. Eligible women were randomized to receive 2% testosterone in Vanicream (10 mg daily) versus placebo Vanicream for four weeks, then crossed over to the opposite treatment. The primary endpoint, libido, was measured via the desire subscales of the Changes in Sexual Functioning Questionnaire (CSFQ), which were completed at baseline and at the end of 4 and 8 weeks of treatment. The primary endpoint was the average intra-patient change from baseline to four weeks in the CSFQ subscales between the two arms. A total of 64 patients per group were needed to provide 80% power to detect a difference of 8 units between the treatment means. Two-sided alternative hypothesis testing and a 5% Type I error rate were used. Results: One hundred fifty women were enrolled onto this study. Complete data were available for 132 women. For those on active testosterone cream, serum bioavailable testosterone levels increased significantly over placebo, with a mean change from baseline of 12 and 10 ng/dl for the first and second period, respectively (p<.0001). The average intra-patient change from baseline to week 4 in libido was 5.5 on testosterone and 4.4 on placebo (p=0.58). No carryover effect was detected. The difference in average intra-patient changes from baseline for the entire crossover design between the two arms was only 1.1 points (95% confidence interval of -1.2 to 3.4, p=0.35). Conclusion: Testosterone is not a panacea for libido troubles in women with a history of cancer. Further studies are needed to determine whether there is a role for transdermal testosterone in this population. No significant financial relationships to disclose.