Terstriep, Shelby A.

Background: Mu opioid receptors (MORs) in peripheral tissues mediate adverse effects of opioids that impair health-related quality of life (HRQoL) and may stimulate cancer progression via mitogenic signaling. Naloxegol, a peripherally acting MOR antagonist (PAMORA), is approved for opioid-induced constipation. Safety and efficacy of naloxegol have not been evaluated concurrently with systemic cancer therapy. Methods: We conducted a randomized, double-blind, placebo-controlled trial of naloxegol in patients with advanced lung adenocarcinoma starting first-line systemic therapy. Results: Only 50 patients were enrolled; the trial was terminated early due to slow accrual. Two of the three components of the feasibility primary endpoint were not met (accrual and PRO completion). At 6 months, FACT-L emotional well-being was better with naloxegol (p = 0.0113). There were trends towards better Trial Outcome Index (p = 0.0505) and physical well-being (p = 0.0628) with naloxegol. Bowel function favored naloxegol for constipation (p = 0.0223), rectal pain during defecation (p = 0.0075), and abdominal pain from constipation (p = 0.0113). Adverse event frequency and severity, PRO-CTCAE, urinary hesitancy, pain scores, and progression-free and overall survival were comparable between naloxegol and placebo. Conclusions: Naloxegol appears to be safe and tolerable, with a signal of improved HRQoL and previously unappreciated benefit for emotional well-being, without adverse clinical outcomes. Our findings should be confirmed in larger studies. ClinicalTrials.gov ID: NCT03087708.

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.

10601 Background: Brachial plexopathy is a well-recognized complication of breast cancer, most attributed to late effects of radiation. However, direct involvement of brachial plexus by recurrent breast cancer occurs. Misdiagnoses may lead to inappropriate attribution of the plexopathy to radiation, and therefore inappropriate therapy. Methods: We report fourteen cases of brachial plexopathy secondary to breast cancer diagnosed at the Mayo Clinic-Rochester from 2003 to 2005. Results: Thirteen of fourteen primary tumors and 12/14 recurrences were ER/PR positive. Only 1/14 patient had Her 2 neu overexpression. The median time from the original breast cancer diagnosis to first brachial plexus symptom was 14 years. The median time from the development of symptoms to diagnosis was 8 months with the range being 1 month to 8 years. MRI revealed a distinct mass in 3/13 patients, plexus thickening in 5/13, and was normal in 5/13. Only 5/13 original MRI interpretations suggested tumor. In four patients that the 1.5 T MRI was either interpreted as normal or unlikely cancer the 3 Tesla MRI revealed abnormal uptake suggestive of malignancy. PET scan suggested malignancy in 3/6 patients. Two of these cases had other metastatic disease. In the other three cases that PET scans were done the uptake was mild, suggesting inflammation rather than malignancy. Reinterpretations of the PET scan and MRI in combination by an experienced musculoskeletal radiologist was highly suggestive of malignancy in all cases. Definitive diagnosis was eventually obtained by biopsy of the brachial plexus (7/14) or another site of metastasis in (4/14). Conclusions: The often slowly progressive nature of hormonally driven breast cancer can mimic radiation induced brachial plexopathy. In the cases reviewed, PET was not reliable in differentiating inflammation from tumor. MRI findings are nonspecific and higher resolution 3T MRI may be needed to detect an abnormality. Interpretation of MRI and PET together is useful. Patients with a history of breast cancer, and brachial plexus symptoms should be carefully evaluated with consideration for recurrent disease as a cause. Biopsy of the brachial plexus can be done safely and has an important role in diagnosis. No significant financial relationships to disclose.

Abstract Background: Aromatase inhibitors are a mainstay hormone receptor-positive breast cancer treatment. AIA occur in up to 50% of patients (pts), adversely affecting quality of life and treatment compliance. A small phase II clinical trial of oral testosterone unedeconate appeared to improve AIA over placebo (P), with no significant androgenic side effects. The current study was performed to confirm these findings. Methods: This randomized P-controlled trial enrolled postmenopausal women on adjuvant anastrozole or letrozole and experiencing moderate-to-severe AIA (≥5 on 0-10 scale). Pts were initially randomized to receive a subcutaneous pellet containing T 120 mg + anastrozole 8 mg (T+AIpellet) or P at the end of the first week on study (after obtaining baseline hot flash data) and at 3 months (mo). Due to slow accrual, the protocol was amended to change the route of delivery to topical T or P applied to the skin once daily for 6 mo. Baseline and monthly questionnaires were administered, including: Modified Brief Pain Inventory for aromatase arthralgia (BPI-AIA), prolife of mood states (POMS), the menopause specific quality of life questionnaire (MENQOL), a hot flash diary, the hot flash related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in joint pain at 3 mo, compared using a two-sample t-test. Results: 227 pts were accrued between 9/1/2013-11/29/2017. 55 pts were randomized prior to the protocol amendment and received T+AIpellet or P. Baseline characteristics were balanced between arms, with the exceptions of median weight, BMI, hemoglobin (all higher in T arm), and breast tenderness, dissatisfaction with personal life/depression, and skin changes (all higher in P arm). Compared to baseline, there were no significant differences between T and P in average pain or joint stiffness at 3 (p=0.483) or 6 mo (p=0.573). Average pain was significantly lower each month compared to baseline, irrespective of treatment arm. There were no significant differences in any other items evaluated by BPI-AIA, POMS, MENQOL, hot flash diary or HFRDIS. Similarly, there were no substantial differences in toxicity. A subset analysis of the 55 pts randomized to receive T+AIpellet or P identified significant reductions in average pain scores with T+AIpellet during the first month (p=0.038), but not thereafter. T+AIpellet pts had significantly more reduction in reported % of baseline hot flash frequency (p=0.034) and score (p=0.031), nausea (p=0.019), fatigue (p=0.042), mood swings (p=0.026), hand/feet swelling (p=0.009), stress urinary incontinence (p=0.039) and changes in appearance, texture or tone of their skin (p=0.0083), than pts on P. Conclusions: Overall, T did not improve AIA or menopausal symptoms compared to P. While there was significant improvement in AIA over the study period, T did not facilitate this process. However, T+AIpellet was associated with improvement in short-term AIA and several menopausal symptoms compared to P, suggesting that subcutaneous T combined with anastrozole may be superior to transdermal T alone. Support: UG1CA189823, U10CA180820, U10CA189809; ClinicalTrials.gov Identifier: NCT01573442 Citation Format: Leon-Ferre RA, Le-Rademacher J, Terstriep S, Glaser R, Novotni P, Giuliano A, Copur MS, Jones C, Page S, Mitchell W, Birrell SN, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of testosterone (T) for aromatase inhibitor-induced arthralgias (AIA) in postmenopausal women: Alliance A221102 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-01.

CRA9015 Background: Hot flashes are a common symptom during the menopause transition or following breast cancer treatment that can negatively impact the quality of life for many women. Preliminary data have suggested that flaxseed, a rich source of dietary lignans, may be a potentially effective treatment for hot flashes. Methods: A phase III randomized, placebo controlled trial was conducted to evaluate the efficacy of flaxseed in reducing hot flashes. Postmenopausal women were randomly assigned to a flaxseed bar (providing 410 mg of lignans) for 6 weeks vs a placebo bar. Participants completed daily prospective, self report hot flash diaries during the baseline week and then began eating one study bar per day for 6 weeks, while continuing to record their daily hot flashes. The intra-patient difference in hot flash activity between baseline and the last treatment week was the primary endpoint. Side effects of the bars were evaluated through self report and CTC assessment. Results: Between October and December 2009, 188 women were enrolled onto this trial. Mean hot flash scores were reduced by 4.9 units in the flaxseed group and 3.5 in the placebo group (p=0.29). In both groups, a little over a third of the women received a 50% reduction in their hot flash scores. Only one side effect was significantly different between groups, that being grade 1 pruritis, which was more common (7%) in the placebo group versus 1% in the flaxseed group. Both groups reported increased abdominal distension, flatulence, diarrhea and nausea. Adherence and ability to detect treatment assignment did not differ between groups. Conclusions: The results of this trial do not support the use of 410 mg of flaxseed lignans for the reduction of hot flashes. The gastrointestinal side effects seen in both groups were likely due to the fiber content in the flaxseed and placebo bars.

BACKGROUNDDespite targeted antiemetics, data support an unmet need related to the management of delayed nausea and vomiting (NV). Promising pilot data informed this phase III trial evaluating gabapentin for delayed NV from highly emetogenic chemotherapy (HEC).METHODSParticipants were randomized to receive prophylactic treatment with 20 mg of dexamethasone and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by gabapentin 300 mg twice a day and dexamethasone (dex) or placebo and dex after HEC. Gabapentin/placebo was started the day of chemotherapy and continued through day 5 for the first chemotherapy cycle, whereas dex was titrated down on days 2‐4. The primary end point was complete response (CR), defined as no emesis and no use of rescue medications on days 2‐6, using an NV diary. The percentages of those in each group with a CR were compared by Fisher's exact test.RESULTSFour hundred thirty patients were enrolled in this study. Forty‐seven percent of patients in the gabapentin arm and 41% in the placebo arm had a CR (P = .23). Mean number of emesis episodes was <0.5 daily, and mean nausea severity was < 2 (mild). In both arms, patient satisfaction with NV control was greater than 8 (with 10 being perfectly satisfied). There were no significant differences in unwanted side effects.CONCLUSIONSIn this study, gabapentin did not significantly improve delayed NV. Patients were satisfied with the control of their nausea and vomiting irrespective of arm. The use of a 5HT3 RA and dexamethasone provided good control of nausea and vomiting for most patients. Cancer 2014;120:3575–3583. © 2014 American Cancer Society.