Safety of CDK4/6 Inhibitors Combined with Radiotherapy in Patients with Metastatic Breast Cancer: A Review of the Literature.

Recent evidence suggests that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors significantly improve progression-free survival and overall survival among metastatic breast cancer patients. However, given the effects on cell cycle arrest, there is potential for CDK4/6 inhibitors and radiotherapy (RT) to work synergistically, enhancing the effect and toxicities of RT. A comprehensive review of the literature on the combination of RT and CDK4/6 inhibitors was performed with 19 eligible studies included in the final analysis. A total of 373 patients who received radiotherapy combined with CDK4/6 inhibitors were evaluated across 9 retrospective studies, 4 case reports, 3 case series, and 3 letters to the editor. The CDK4/6 inhibitor used, RT target, and RT technique were assessed in terms of toxicities. This literature review demonstrates generally limited toxicities with the combination of CDK4/6 inhibitors and palliative radiotherapy to metastatic breast cancer patients. The current evidence is nonetheless limited, and further results of ongoing prospective clinical trials will help clarify whether these treatments can be safely combined.

Case report: Ultrahypofractionated palliative breast radiotherapy for a fungating invasive mammary carcinoma.

Palliative radiotherapy for symptomatic and intact breast tumors must balance convenience, efficacy, and risk of acute toxicity. This case report presents a patient with metastatic breast cancer and an intact fungating primary tumor. She was treated with an ultrahypofractionated radiation therapy, 26 Gy in 5 consecutive daily fractions, with sequential palliative chemotherapy. This resulted in a minimal toxicity profile and significant reduction of tumor burden and symptoms.

Locoregional Management of Breast Cancer: A Chronological Review.

Locoregional management of breast cancer is founded on evidence generated over a vast time period, much longer than the career span of many practicing physicians. Oncologists rely on specific patient and tumour characteristics to recommend modern-day treatments. However, some of this information may not have been available during prior periods in which the evidence was generated. For example, the comprehensive Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analyses published in the 2000s typically included older trials accruing patients between the 1960s and 1980s. This raises some uncertainty about whether conclusions from studies conducted in prior eras are as relevant or applicable to modern-day patients and treatments. Reviewing the chronological order and details of the evidence can be beneficial to understanding these nuances. This review discusses the evolution of locoregional management through some key clinical trials. We aim to highlight the time period in which the evidence was generated and emphasize the 10-year outcomes for the comparability of results. Evidence supporting surgical management of the breast and axilla, as well as details of radiotherapy are discussed briefly for all stages of breast cancer.

Radiation Therapy With Cyclin-Dependent Kinase 4/6 Inhibitors: A Multi-institutional Safety and Toxicity Study.

PURPOSE: Our purpose was to investigate radiation therapy (RT) toxicity when given with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) compared with RT alone. METHODS AND MATERIALS: We conducted a retrospective cohort study of patients with hormonal receptor-positive and human epidermal growth factor-2 negative metastatic breast cancer treated with RT at 4 cancer centers in Alberta, Canada, between 2016 and 2020. Toxicity in patients treated with RT within 30 days of initiating to discontinuing CDK4/6i (RT + CDK4/6i) was compared with toxicity of RT in CDK4/6i-naïve patients (RT alone). The primary outcome was acute grade (G) 2 or higher, nonhematological toxicity within 30 days of RT. We also explored toxicity based on the timing of RT (prior, concurrent, post) in relation to CDK4/6i. Propensity score matching was applied to create comparable cohorts. A generalized linear mixed model was used to evaluate factors associated with acute toxicity. RESULTS: One hundred thirty-two patients (220 RT sites) in the RT + CDK4/6i and 53 patients (93 RT sites) in RT alone were eligible. The rate of acute G2 or higher nonhematological toxicity was 11.5% versus 7%, respectively (P = .439), and acute G3 or higher nonhematological toxicity was 3.7% versus 0%, respectively (P = .151). Acute toxicity in RT + CDK4/6i group was mainly observed when RT was given concurrently (67%), with most of the G3 toxicity recorded. After propensity score matching, the association of acute toxicity with RT + CDK4/6i versus RT alone was not significant on multivariable analysis (odds ratio, 3.13; 95% confidence interval, 0.74-13.2; P = .121). CONCLUSIONS: We did not observe a significant association between CDK4/6i use and acute G2 or higher nonhematological toxicity in women with metastatic breast cancer receiving palliative RT. Given the findings of G3 toxicity, caution is advised whenever CDK4/6i is given concurrently with RT.

Mapping the Current State of Canadian Medical School Oncology Interest Groups.

Cancer is the leading cause of mortality in Canada. Undergraduate medical education therefore must ensure adequate oncology education for all physicians and inspire some to make oncology their career specialty, in an effort to ensure public care needs are met in the future. Medical student-led oncology interest groups (OIGs) are a subset of specialty interest groups that supplement formal didactic and clinical learning to increase exposure to oncology and access to mentors. We conducted a survey of OIG leaders to ascertain their goals, activities, barriers, future directions, and perceptions about employment prospects. OIG leaders from 12/17 Canadian medical schools responded. Medical oncology was the most represented specialty in OIGs. Half of OIGs had faculty mentors. Self-reported goals were to increase exposure to oncology disciplines (n = 12), assist students with career selection (n = 11) and finding mentors (n = 7), and enhance oncology education (n = 10). OIGs held on average 5 events per year (range 1-12). Reported barriers were finding time to plan events, declining student interest over academic year, and limited funding. Many OIGs showed interest in more standardized resources about oncology disciplines (n = 9), access to presentations (n = 10), more funding (n = 7), and collaboration (n = 7). Employment in many oncology specialties was perceived poorly, and the most important career selection considerations were ease of employment, practice location, and partner/family preference. Our survey highlights common goals, barriers, and perceptions in OIG medical student leaders across Canada and provides guidance for future interventions.

Acute Care Use by Breast Cancer Patients on Adjuvant Chemotherapy in Alberta: Demonstrating the Importance of Measurement to Improving Quality.

Breast cancer patients receiving adjuvant chemotherapy are at increased risk of acute care use. The incidence of emergency department (ED) visits and hospitalizations (H) have been characterized in other provinces but never in Alberta. We conducted a retrospective population-based cohort study using administrative data of women with stage I-III breast cancer receiving adjuvant chemotherapy. Rates of ED and H use in the 180 days following chemotherapy initiation were determined, and logistic regression was performed to identify risk factors. We found that 47% of women receiving adjuvant chemotherapy experienced ED or H, which compared favourably to other provinces. However, Alberta had the highest rate of febrile neutropenia-related ED visits, and among the highest chemotherapy-related ED visits. The incidence of acute care use increased over time, and there were significant institutional differences despite operating under a single provincial healthcare system. Our study demonstrates the need for systematic measurement and the importance of quality improvement programs to address this gap.

Higher-risk breast cancer in women aged 80 and older: Exploring the effect of treatment on survival.

BACKGROUND: To understand the association between various treatments and survival for older women with higher-risk breast cancer when controlling for patient and tumor factors. MATERIALS AND METHODS: We conducted a retrospective, population-based study. Women aged 80 years or older and diagnosed between 2004 and 2017 with non-metastatic, higher-risk breast cancer were identified form the provincial cancer registry in Alberta, Canada. Higher-risk was defined as any of following: T3/4, node positive, human epidermal factor receptor-2 (Her2) positive or triple negative disease. Treatments were surgery, radiotherapy and systemic therapy (hormonal therapy, and/or chemotherapy and/or trastuzumab) or a combination of the previous. Cox regression models were used to examine the association between treatments and breast cancer specific survival (BCSS) and overall survival (OS). RESULTS: 1369 patients were included. The median age was 84 years. 332 (24%) of women had T3-T4 tumors, 792 (58%) had nodal involvement, 130 (10%) had Her2 positive tumors, 124 (9%) had triple negative tumors. After a median follow-up of 35 months, 29.5% of patients died of breast cancer whereas 34.2% died from other causes. Patients had a lower adjusted hazard for BCSS if they had surgery (hazard ratio [HR] = 0.37 95% confidence interval [CI]: 0.27, 0.51), or systemic therapy (HR = 0.75, 95%CI: 0.58, 0.98). Patients had an increased probability of breast cancer death in the first 5 years after diagnosis compared to death from other causes. CONCLUSIONS: Surgery and systemic therapy were associated with longer BCSS and OS. This suggests that maximizing treatments might benefit higher-risk patients.

Standardized flattening filter free volumetric modulated arc therapy plans based on anteroposterior width for total body irradiation.

In this work, the feasibility of using flattening filter free (FFF) beams in volumetric modulated arc therapy (VMAT) total body irradiation (TBI) treatment planning to decrease protracted beam-on times for these treatments was investigated. In addition, a methodology was developed to generate standardized VMAT TBI treatment plans based on patient physical dimensions to eliminate plan optimization time. A planning study cohort of 47 TBI patients previously treated with optimized VMAT ARC 6 MV beams was retrospectively examined. These patients were sorted into six categories depending on height and anteroposterior (AP) width at the umbilicus. Using Varian Eclipse, clinical 40 cm × 10 cm open field arcs were substituted with 6 MV FFF. Mid-plane lateral dose profiles in conjunction with relative arc output factors (RAOF) yielded how far a given multileaf collimator (MLC) leaf must move in order to achieve a mid-plane 100% isodose for a specific control point. Linear interpolation gave the dynamic MLC aperture for the entire arc for each patient AP width category, which was subsequently applied through Python scripting. All FFF VMAT TBI plans were then evaluated by two radiation oncologists and deemed clinically acceptable. The FFF and clinical VMAT TBI plans had similar Body-5 mm D98% distributions, but overall the FFF plans had statistically significantly increased or broader Body-5 mm D2% and mean lung dose distributions. These differences are not considered clinically significant. Median beam-on times for the FFF and clinical VMAT TBI plans were 11.07 and 18.06 min, respectively, and planning time for the FFF VMAT TBI plans was reduced by 34.1 min. In conclusion, use of FFF beams in VMAT TBI treatment planning resulted in dose homogeneity similar to our current VMAT TBI technique. Clinical dosimetric criteria were achieved for a majority of patients while planning and calculated beam-on times were reduced, offering the possibility of improved patient experience.

Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.

PURPOSE: Optimal local management for young women with early-stage breast cancer remains controversial. This study examined 15-year outcomes among women younger than 40 years treated with breast-conserving surgery plus whole-breast radiation therapy (BCT) compared with those treated with modified radical mastectomy (MRM). METHODS AND MATERIALS: Women aged 20 to 39 years with early-stage breast cancer diagnosed between 1989 and 2003 were identified in a population-based database. Primary outcomes of breast cancer-specific survival (BCSS), overall survival (OS) and secondary outcomes of local relapse-free survival (LRFS), locoregional relapse-free survival (LRRFS), and distant relapse-free survival (DRFS) were calculated using Kaplan-Meier methods and compared between BCT and MRM cohorts using log-rank tests. A planned subgroup analysis was performed on patients considered "ideal" for BCT (ie, T1N0, negative margins and no extensive ductal carcinoma in situ) and in whom local therapy may have the largest impact on survival because of low systemic risk. RESULTS: 965 patients were identified; 616 had BCT and 349 had MRM. The median follow-up time was 14.4 years (range, 8.4-23.3 years). Overall, 15-year rates of BCSS (76.0% vs 74.1%, P=.62), OS (74.2% vs 73.0%, P=.75), LRFS (85.4% vs 86.5%, P=.95), LRRFS (82.2% vs 81.6%, P=.61), and DRFS (74.4% vs 71.6%, P=.40) were similar between the BCT and MRM cohorts. In the "ideal" for BCT subgroup, there were 219 BCT and 67 MRM patients with a median follow-up time of 15.5 years. The 15-year BCSS (86.1% vs 82.9%, P=.57), OS (82.6% vs 82.9%, P=.89), LRFS (86.2% vs 84.2%, P=.50), LRRFS (83.1% vs 78.3%, P=.24), and DRFS (84.8% vs 79.1%, P=.17) were similar in the BCT and MRM cohorts. CONCLUSIONS: This population-based analysis with long-term follow-up confirmed that women younger than 40 years treated with BCT had similar 15-year outcomes compared with MRM. Young age alone is not a contraindication to BCT.

The Distribution and Patterns of Practice of Stereotactic Ablative Body Radiotherapy in Canada.

PURPOSE: The aim of this study was to evaluate the distribution, adoption, and utilization of stereotactic ablative body radiotherapy (SABR) in Canada. MATERIALS AND METHODS: All Canadian radiotherapy centres (N = 41) were sent electronic surveys regarding their use of SABR. RESULTS: Eighty-eight percent of centres responded, and 34% are using SABR. Only 50% of Canada's 10 provinces have SABR centres. Ten centres began SABR programs during the previous 3 years, and within 5 years the number of SABR centres is expected to nearly double. The lung is the most common site treated (13 centres) followed by the liver (9) and spine (6). The most common dose fractionation for the lung and liver are 48 Gy/4 and 45 Gy/3, respectively. No centres treating spine use the same most common schedule. All centres use volumetric on-board imaging. A minority of centres are engaged in peer review of treatment volumes, dose distributions, and/or outcome tracking. Among centres not using SABR, a lack of required technology is the most common reason reported. CONCLUSIONS: Currently, access to SABR varies considerably by health care jurisdiction. However, the number of SABR centres is expected to increase markedly. Centres using SABR have uniform access to advanced technology for treatment planning and delivery. These results vary from the United States where access to SABR is similar geographically, whereas the use of advanced planning and delivery technology is variable.

Multi-institutional quantitative evaluation and clinical validation of Smart Probabilistic Image Contouring Engine (SPICE) autosegmentation of target structures and normal tissues on computer tomography images in the head and neck, thorax, liver, and male pelvis areas.

PURPOSE: Clinical validation and quantitative evaluation of computed tomography (CT) image autosegmentation using Smart Probabilistic Image Contouring Engine (SPICE). METHODS AND MATERIALS: CT images of 125 treated patients (32 head and neck [HN], 40 thorax, 23 liver, and 30 prostate) in 7 independent institutions were autosegmented using SPICE and computational times were recorded. The number of structures autocontoured were 25 for the HN, 7 for the thorax, 3 for the liver, and 6 for the male pelvis regions. Using the clinical contours as reference, autocontours of 22 selected structures were quantitatively evaluated using Dice Similarity Coefficient (DSC) and Mean Slice-wise Hausdorff Distance (MSHD). All 40 autocontours were evaluated by a radiation oncologist from the institution that treated the patients. RESULTS: The mean computational times to autosegment all the structures using SPICE were 3.1 to 11.1 minutes per patient. For the HN region, the mean DSC was >0.70 for all evaluated structures, and the MSHD ranged from 3.2 to 10.0 mm. For the thorax region, the mean DSC was 0.95 for the lungs and 0.90 for the heart, and the MSHD ranged from 2.8 to 12.8 mm. For the liver region, the mean DSC was >0.92 for all structures, and the MSHD ranged from 5.2 to 15.9 mm. For the male pelvis region, the mean DSC was >0.76 for all structures, and the MSHD ranged from 4.8 to 10.5 mm. Out of the 40 autocontoured structures reviews by experts, 25 were scored useful as autocontoured or with minor edits for at least 90% of the patients and 33 were scored useful autocontoured or with minor edits for at least 80% of the patients. CONCLUSIONS: Compared with manual contouring, autosegmentation using SPICE for the HN, thorax, liver, and male pelvis regions is efficient and shows significant promise for clinical utility.

Radiotherapy for intubated patients with malignant airway obstruction: futile or facilitating extubation?

INTRODUCTION: The optimal approach to patients with malignant airway obstruction who require intubation and mechanical ventilation but are ineligible for bronchoscopic interventions is uncertain. Radiotherapy (RT) may be delivered but requires substantial resources in this patient population. In the absence of evidence, it is unknown whether RT facilitates extubation or delays an appropriate transition to end-of-life care. METHODS: We performed a 10-year retrospective review of intensive care unit (ICU) patients treated with RT while on mechanical ventilation for malignant airway obstruction. Primary study endpoints were overall survival (OS) and extubation success (ES), defined as 48 hours or more without reintubation or death. Secondary endpoints included rates of discharge from the ICU and to home. Logistic regression and Cox regression analyses were performed to identify factors associated with OS and ES. RESULTS: Twenty-six patients were eligible for analysis. Seven patients (27%) were extubated; extubations occurred between days 4 and 22 after RT initiation. All patients were discharged from the ICU and most (n = 6) were also discharged home. An association between higher radiation doses and ES was observed (odds ratio per 5 Gy increase: 0.63; p = 0.080). Median OS was only 0.36 months (range, 0-113 months), and 6-month OS was 11%. On Cox regression analysis, increased radiation dose was predictive of improved OS (hazard ratio per 5 Gy increase: 0.74; p = 0.016). CONCLUSIONS: A significant minority of patients receiving RT were successfully extubated. Higher radiation doses were predictive of improved OS and showed a trend for increased ES. Survival beyond 6 months was uncommon, however, the majority of patients with ES were able to be discharged home.

Cost-effectiveness of adding cetuximab to platinum-based chemotherapy for first-line treatment of recurrent or metastatic head and neck cancer.

PURPOSE: To assess the cost effectiveness of adding cetuximab to platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) from the perspective of the Canadian public healthcare system. METHODS: We developed a Markov state transition model to project the lifetime clinical and economic consequences of recurrent or metastatic HNSCC. Transition probabilities were derived from a phase III trial of cetuximab in patients with recurrent or metastatic HNSCC. Cost estimates were obtained from London Health Sciences Centre and the Ontario Case Costing Initiative, and expressed in 2011 CAD. A three year time horizon was used. Future costs and health benefits were discounted at 5%. RESULTS: In the base case, cetuximab plus platinum-based chemotherapy compared to platinum-based chemotherapy alone led to an increase of 0.093 QALY and an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of $386,000 per QALY gained. The cost effectiveness ratio was most sensitive to the cost per mg of cetuximab and the absolute risk of progression among patients receiving cetuximab. CONCLUSION: The addition of cetuximab to standard platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic HNSCC has an ICER that exceeds $100,000 per QALY gained. Cetuximab can only be economically attractive in this patient population if the cost of cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of cetuximab to chemotherapy.

Systematic review of the cost-effectiveness of positron-emission tomography in staging of non--small-cell lung cancer and management of solitary pulmonary nodules.

Implementation of positron-emission tomography (PET) is variable depending on jurisdiction in part due to uncertainty about cost-effectiveness. Our objective was to perform a systematic review describing cost-effectiveness of PET in staging of non-small-cell lung cancer (NSCLC) and management of solitary pulmonary nodules (SPN). Systematic literature searches were conducted using separate search strategies for multiple databases. Our validity criteria included measurement of study quality by means of the validated Quality of Health Economic Studies (QHES) instrument. Metrics such as mean PET costs, median average cost savings per patient, incremental cost-effectiveness ratio based on life years saved and quality-adjusted life years were calculated. Eighteen studies met our inclusion criteria with average QHES scores > 75. Studies were primarily based on the national health insurance payer perspective from 10 different countries. Cost-effectiveness was assessed primarily using decision-tree modeling and sensitivity analysis to determine the effects of changing variables on expected cost and life expectancy. After adjusting for currency exchange rates and inflation to 2010 United States dollars, the mean cost of PET was $1478. The cost-effectiveness metrics used in these studies were variable depending on sensitivity and specificity of diagnostic tests used in the models, probability of malignancy, and baseline strategy. Despite observed study heterogeneity, the consensus of these studies conclude that the additional information gained from PET imaging in the staging of NSCLC and diagnosis of SPNs is worth the cost in context of proper medical indications.

Hypofractionated radiotherapy with or without concurrent temozolomide in elderly patients with glioblastoma multiforme: a review of ten-year single institutional experience.

The landmark Stupp study demonstrated a survival advantage with concomitant and adjuvant temozolomide (TMZ) with standard radiotherapy (RT) in glioblastoma multiforme (GBM) patients but excluded those older than 70 years. The prospective Roa study of older GBM patients treated with hypofractionated 3-week course RT demonstrated equivalence to standard 6-week course RT. Taken together, these trials suggest hypofractionated RT with TMZ may be a reasonable treatment option for elderly GBM patients. We conducted a retrospective review of GBM patients (age ≥60 years) treated with hypofractionated RT and temozolomide at our institution between 2000 and 2010. We identified 112 patients who received hypofractionated RT, with 57 receiving concurrent and adjuvant TMZ and 55 without concurrent chemotherapy. Of the 55 patients who received hypofractionated RT alone initially, 24 subsequently received TMZ as salvage treatment at time of progression. Among the concurrent RT + TMZ patients, mean age was 70 years (range 60-86), median KPS was 80 (range 30-100) and 24/57 (42%) received prior debulking surgery. Median overall survival (OS) among the RT + TMZ patients was 6.9 months (95% CI, 4.5-8.6). Patients without concurrent chemotherapy were similar in demographics (age, sex, corticosteroid use, KPS) except 34/55 (62%) were debulked (P-value 0.045.) Median OS was 9.3 months (95% CI, 5.9-11.8) (P-value 0.351). Sub-group analysis revealed patients treated with initial hypofractionated radiation with salvage TMZ had increased median OS of 13.3 months (95% CI, 9.9-19.3) (P-value 0.012). Our results suggest concurrent and adjuvant TMZ does not confer a survival benefit in elderly GBM patients. A sequential approach may be a more effective and efficient strategy by selecting responding patients who may benefit most from subsequent salvage chemotherapy.

Brachytherapy with permanent gold grain seeds for squamous cell carcinoma of the lip.

PURPOSE: To describe the use of radioactive gold grain implantation for squamous cell carcinoma of the lip. METHODS: Retrospective review of 51 patients treated with permanent gold ((198)Au) grain implant brachytherapy. The seed arrangement delivered a dose of 5500 cGy at 0.5 cm from a single plane. Primary endpoints were local recurrence and cosmetic outcome. RESULTS: Median follow-up was 27 months. Median age was 69 years. The majority (90%) were T1 lesions. None of the patients had evidence of regional lymph node or distant metastasis. Twelve patients had recurrent disease with prior surgery and five patients had previous head and neck radiation. Local control was achieved in 49 patients. Good cosmesis was achieved in 48 patients. Two-year actuarial estimates for local failure-free survival, disease-free survival and overall survival were 97.9%, 94.1% and 87.9%, respectively; no deaths were attributable to lip cancer. CONCLUSIONS: Gold grain interstitial low-dose rate brachytherapy provides excellent local control and cosmesis in patients with squamous cell carcinoma of the lip. This technique provides an excellent option for patients that are elder or live remotely. It is particularly useful for lesions that are small, in previously radiated areas, or treated with prior surgery.

Stereotactic body radiotherapy versus surgery for medically operable Stage I non-small-cell lung cancer: a Markov model-based decision analysis.

PURPOSE: To compare the quality-adjusted life expectancy and overall survival in patients with Stage I non-small-cell lung cancer (NSCLC) treated with either stereotactic body radiation therapy (SBRT) or surgery. METHODS AND MATERIALS: We constructed a Markov model to describe health states after either SBRT or lobectomy for Stage I NSCLC for a 5-year time frame. We report various treatment strategy survival outcomes stratified by age, sex, and pack-year history of smoking, and compared these with an external outcome prediction tool (Adjuvant! Online). RESULTS: Overall survival, cancer-specific survival, and other causes of death as predicted by our model correlated closely with those predicted by the external prediction tool. Overall survival at 5 years as predicted by baseline analysis of our model is in favor of surgery, with a benefit ranging from 2.2% to 3.0% for all cohorts. Mean quality-adjusted life expectancy ranged from 3.28 to 3.78 years after surgery and from 3.35 to 3.87 years for SBRT. The utility threshold for preferring SBRT over surgery was 0.90. Outcomes were sensitive to quality of life, the proportion of local and regional recurrences treated with standard vs. palliative treatments, and the surgery- and SBRT-related mortalities. CONCLUSIONS: The role of SBRT in the medically operable patient is yet to be defined. Our model indicates that SBRT may offer comparable overall survival and quality-adjusted life expectancy as compared with surgical resection. Well-powered prospective studies comparing surgery vs. SBRT in early-stage lung cancer are warranted to further investigate the relative survival, quality of life, and cost characteristics of both treatment paradigms.

Blockade of neuropeptide Y(2) receptors and suppression of NPY's anti-epileptic actions in the rat hippocampal slice by BIIE0246.

Neuropeptide Y (NPY) has been shown to suppress synaptic excitation in rat hippocampus by a presynaptic action. The Y(2) (Y(2)R) and the Y(5) (Y(5)R) receptors have both been implicated in this action. We used the non-peptide, Y(2)R-selective antagonist, BIIE0246, to test the hypothesis that the Y(2)R mediates both the presynaptic inhibitory and anti-epileptic actions of NPY in rat hippocampus in vitro. NPY and the Y(2)R-selective agonist, [ahx(5-24)]NPY, both inhibited the population excitatory postsynaptic potential (pEPSP) evoked in area CA1 by stratum radiatum stimulation in a concentration-dependent manner. BIIE0246 suppressed the inhibitory effects of both agonists, suppressing the maximal inhibition without causing a change in the agonist EC(50), in a manner inconsistent with competitive antagonism. BIIE0246 washed out from hippocampal slices extremely slowly. Application of agonist at high concentrations (1 - 3 microM) for prolonged periods did not alter the rate of washout, but did partially overcome the antagonism, inconsistent with an insurmountable antagonism by BIIE0246. In the stimulus train-induced bursting (STIB) model of ictal activity in hippocampal slices, both NPY and [ahx(5-24)]NPY inhibited primary afterdischarge (1 degrees AD) activity. BIIE0246 (100 nM) completely suppressed the actions of NPY and [ahx(5-24)]NPY in this model. In contrast, the potent Y(5)R-selective agonist, Ala(31)Aib(32)NPY, affected neither 1 degrees AD activity in the presence of BIIE0246, nor, by itself, even the pEPSP in CA1. BIIE0246 potently suppresses NPY actions in rat hippocampus, suggesting a dominant role for Y(2)R there. The apparently insurmountable antagonism observed may result from the lipophilic nature of the antagonist.