Elderly Head And Neck Cancer Research Articles

Cost effectiveness and health-related quality of life of chemoradiotherapy versus radiation therapy alone in elderly head and neck cancer patients

PurposeRadiotherapy (RT) constitutes a mainstay in the treatment of elderly patients with head and neck cancer (HNC), but use of simultaneous chemoradiotherapy (CRT) remains controversial. We have conducted a prospective analysis based on real-world patient data to examine the health-related quality of life (HRQoL) and cost effectiveness (CE) of CRT vs. RT in elderly HNC patients.MethodsEligible participants ≥ 65 years treated in a large tertiary cancer center between July 2019 and February 2020 who completed the validated EQ-5D-5L questionnaire (health state index [HI] and visual analog scale [VAS]) before and after RT were included. CE referred to direct medical costs, including diagnosis-related group (DRG)-based billings for inpatients and uniform assessment standard (EBM)-based costs for outpatients. The primary endpoint was cost (euros [€]) per quality-adjusted life year (QALY). The incremental cost-effectiveness ratios (ICERs) were calculated. Costs and QALYs were not discounted for short overall survival (OS).ResultsBaseline HRQoL was 0.878 (±0.11) in the CRT group and 0.857 (±0.17) in the RT group. Upon completion of therapy, HRQoL amounted to 0.849 (±0.14) in the CRT and 0.850 (±0.13) in the RT group. The mean treatment-related cost in the CRT cohort was €22,180.17 (±8325.26) vs. €18,027.87 (±26,022.48) in the RT group. The corresponding QALYs amounted to 2.62 in the CRT and 1.91 in the RT groups. The ICER was €5848.31.ConclusionThis is the first analysis from the German health care system demonstrating that the addition of chemotherapy to RT for selected elderly HNC patients is cost effective and not associated with a significant HRQoL decline.

Age Alone Is Not a Barrier to Concurrent Chemoradiotherapy for Advanced Head and Neck Cancer.

Head and Neck Cancer (HNC) is associated with significant morbidity and mortality, especially when high stage disease is present. There exists a range of options for the management of locoregionally advanced HNC, though doubt remains as to the optimal strategy in the elderly population. To evaluate the benefits imparted by concurrent chemoradiotherapy (CCRT) to the elderly population of HNC patients in Ireland. A retrospective cohort study was conducted using 20 years of cancer registry data provided by the National Cancer Registry of Ireland. Cox multivariate regression analysis was applied to test for the benefits of CCRT in HNC. Survival analysis showed an overall benefit to the use of CCRT in patients with advanced disease over 70 years, particularly when used for hypopharyngeal, oropharyngeal, and laryngeal malignancy. There was a benefit to cancer-specific but not all-cause mortality in those over 75 years, and no benefit was observed to the addition of chemotherapy in those over 80 years; only 8 patients over 80 received CCRT. There was no statistically significant difference in the benefits derived by those over 70 years relative to those under 70 years. CCRT confers significant survival benefits to appropriately selected elderly HNC patients and should therefore not be withheld solely on the basis of age.

Low skeletal muscle mass predicts frailty in elderly head and neck cancer patients

PurposeTreatment of head and neck cancer (HNC) carries a high risk of adverse outcomes in patients, especially in frail elderly. Therefore, it is important to identify patients in which treatment benefits outweigh the risk of any adverse outcome. Although the comprehensive geriatric assessment (CGA) identifies frailty, it is a time-consuming tool. Instead, measurement of skeletal muscle mass and strength (sarcopenia) may be a promising and time-efficient biomarker for frailty. The aim of this study was to examine the association between sarcopenia and frailty assessment tools, such as the CGA, Fried criteria and the Groningen Frailty Indicator (GFI).MethodsA retrospective study was performed in elderly patients (≥ 70-years) with HNC. Sarcopenia was defined as the combination of reduced handgrip strength (HGS) and low skeletal muscle mass (SMM), according to the EWGSOP-2 criteria. SMM was measured on routinely available diagnostic imaging and corrected height: skeletal muscle index (SMI). A CGA was performed by a geriatrician. Frailty screening was performed using the GFI and the Fried criteria.ResultsIn total, 73 patients were included of which 33 were men (45.2%) and 40 women (54.8%). Frail patients diagnosed by CGA were more likely to have low SMI, sarcopenia, more comorbidities and were at high risk for malnutrition (all p < 0.05). In multivariate regression analysis, the only significant predictor for frailty diagnosed by CGA was SMI (OR 0.9, p < 0.01) independent of comorbidity and muscle strength.ConclusionLow SMI and sarcopenia are associated with frailty in elderly HNC patients. Low SMI predicts frailty and is a promising time-efficient and routinely available tool for clinical practice.

Results of a survey on elderly head and neck cancer patients on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

SUMMARYObjectiveOver the years, evidence-based data and technical improvements have consolidated the central role of radiation therapy (RT) in head and neck cancer (HNC) treatment, even in the elderly. This survey aimed to describe the management of the elderly HNC patients among Italian Radiation Oncology Departments (RODs) and provide possible suggestions for improvement.MethodsAn online survey based on 43 questions was sent to RODs via email. For each RODs, a radiation oncologist with expertise in HNC was invited to answer questions addressing his/her demographic data, ROD multidisciplinary unit (MU) organisation and ROD management policy in elderly HNC patients.ResultsIn total, 68 RODs answered, representing centres located in 16 Italian regions. MU was considered the core of HNC patient management in almost all the entire country. However, in many RODs, there was minimal access to a routinely comprehensive geriatric assessment at diagnosis. Most treatments were reported by respondents as curative (89% on average) and the preferred treatment technique was intensity modulated radiation therapy (IMRT). A considerable variation between RODs was found for RT target volumes. There was a relation between the specialist’s years of experience and type of concomitant systemic therapy prescribed.ConclusionsSubstantial differences in elderly HNC management have been found, especially concerning patient clinical evaluation and target volume delineation. This survey shows the necessity to design a prospective national trial to provide a uniform treatment strategy and define an effective patient-centred approach.

1110O - Personalized treatment according to geriatric assessment in first-line recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC) patients aged 70 or over: ELAN (ELderly heAd and Neck cancer) FIT and UNFIT trials

BackgroundThe main challenges in patients (pts)>= 70y are to cope with the treatment benefit/risk ratio and tumor related symptoms; no standard systemic treatment has been validated. With GERICO-GORTEC groups, we developed a large prospective clinical program named ELAN to improve the management of elderly HNSCC using an adapted geriatric evaluation feasible in daily practice and to set new standards of care for these pts. We report the results of ELAN FIT and UNFIT trials dedicated to elderly R/M HNSCC pts.Table: 1110OTable: 1110OELAN-FIT trialELAN-UNFIT trial N=82Carbo-5FU-cetux (n=78)CX arm (n=41)MTX arm (n=41)Pts PS ECOG 0-1 (n=47) (2 arms together)Pts PS ECOG 2 (n=35) (2 arms together)Adverse events>=grade 424%27%22%13%40%Objective response rateAt W12: 38% (central review)12%15%13%14%OS median (months)14.7 (95%CI=11.0-18.2)4.6 (95%CI=2.4-7.3)4.6 (95%CI=2.3-7.7)7.3 (95%CI=4.6-9.6)2.1 (95%CI=1.5-3.2)1-year OS rate58% (95%CI=46%-68%)22.5% (95% CI=12.3%-37.5%)14.6% (95% CI=6.9%-28.4%)27.7% (95% CI=16.9%-41.8%)5.9% (95% CI=1.6%-19.1%)PFS median (months)7.1 (95%CI=5.5-8.2)2.4 (95%CI=1.5-3.8)2.8 (95%CI=1.6-4.2)3.8 (95%CI=2.6-5.5)1.5 (95%CI=1.2-2.3)1-year PFS rate24.5% (95%CI=15.5%-34.6%)7.5% (95% CI=2.6%-19.9%)7.3% (95% CI=2.5%-19.4%)12.8% (95% CI=6.0%-25.2%)0% MethodsTo be included in one of the 2 trials, 1st line R/M SCCHN pts>= 70y must first be enrolled in ELAN-ONCOVAL study where they were classified as fit or unfit, using the ELAN geriatric evaluation (EGE). Comprehensive Geriatric Assessment was optional. Fit pts were proposed to be enrolled in the 2-stage phase II ELAN-FIT trial, which evaluated the cetuximab-carboplatin-5FU (EXTREME) combination in terms of efficacy (objective response at 12 weeks) and safety assessed by lack of grade>=4 toxicity and lack of loss of independence. Unfit pts were proposed to be enrolled in the randomized phase III ELAN-UNFIT trial, that compared 2 monotherapies, cetuximab (Cx) 500mg/m² every 2 weeks versus weekly methotrexate (MTX) 40mg/m² in terms of failure free survival (failures are progression, treatment stop, loss>= 2 points in Activities in Daily Living scale or death). Results160 pts were enrolled in the trials. The UNFIT trial was stopped after futility analysis. Main results are shown in the table. ConclusionsFit elderly pts as selected using EGE, benefited from carboplatin based EXTREME regimen, with promising overall survival (OS), which compares favourably with that of younger pts. For unfit elderly pts, there was no efficacy difference of Cx and MTX. PS ECOG 2 pts did not benefit from systemic treatment. New therapeutic options should be explored for ECOG 0-1 unfit elderly pts. Clinical trial identificationELAN-UNFIT: NCT01884623 ELAN-FIT: NCT01864772. Legal entity responsible for the studyGustave Roussy and GORTEC. FundingINCA PAIR, Merck, Sandoz, GEMLUC-GEFLUC. DisclosureJ. Guigay: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Innate Pharma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck. C. Even: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Innate Pharma. L. Geoffrois: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Ipsen; Honoraria (self): Novartis; Travel / Accommodation / Expenses: Merck Serono. C. Sire: Travel / Accommodation / Expenses: Merck. J. Fayette: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Innate; Honoraria (self), Advisory / Consultancy: Biogen. F. Peyrade: Advisory / Consultancy: MSD; Advisory / Consultancy: Merck. P. Debourdeau: Non-remunerated activity/ies: Pfizer; Honoraria (self): Leo Pharma; Honoraria (self): Bayer. Y. Pointreau: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD. All other authors have declared no conflicts of interest.

Pretreatment obesity prolongs survival in elderly patients (≥65 years) with head and neck cancer (HNC).

6052 Background: Pre-treatment Body mass Index (BMI) is an important prognostic factor in HNC with variable survival benefit reported till date. Despite increasing incidence of HNC in geriatric patients there is limited information on prognostic variables in this group. Methods: This is a single center, retrospective cohort study of patients with HNC≥65 years of age at their diagnosis from 2012 to 2016. Patients were stratified by BMI (Class 1- BMI&lt;25 kg/m2 (underweight &amp; normal), Class 2- BMI≥25-29.9 kg/m2 (overweight), Class 3- BMI≥30 kg/m2 (obese) ). Various variables were collected &amp; appropriate statistical analysis was done. Results: 188 elderly HNC patients with non-metastatic disease were stratified into three BMI groups (Table) &amp; found to have evenly distributed co-variates. The Median OS was significantly higher in class 3 patients (53 months) compared to class 1 (21 months) (p =0.02). In multivariate analysis, class 3 was an independent good prognostic indicator (Hazard ratio=0.44;Range-0.21-0.90, p=0.03). Stage, CCI score &amp; gastrostomy tube were adverse prognostic factors in the study. Conclusions: Obese elderly HNC patients have survival benefit over normal/underweight patients. Predictive prognostic models incorporating BMI with other prognostic factors are needed to determine appropriate management in these patients. [Table: see text]

Treatment of inoperable elderly head and neck cancer patients.

Elderly head and neck cancer (HNC) patients are very rarely enrolled in clinical trials, and even more so in dedicated trials in curative or palliative setting. As a result, no standards of treatment exist for this population and thus, adaptation of standard treatments is commonly used. The choice between a monotherapy and a platinum-cetuximab combination is based on the performance status, which is not suitable and/or sufficient to evaluate the patient ability to receive a systemic treatment combined or not with radiotherapy. The evaluation of functional age using geriatric assessment is recommended. However, access to comprehensive geriatric assessment is limited in many centers, and the choice of the type of treatment is often not based on objective and reproducible criteria. As a result, fragile elderly HNC patients may be overtreated with a risk of increased toxicity and fit patients proposed for suboptimal treatment with a risk of failure of tumor control. It is therefore crucial to develop and evaluate customized treatments by enrolling elderly HNC patients in dedicated therapeutics trials, such as the ELAN (Elderly Head and Neck Cancer) studies or new approaches involving promising immunotherapies. To administer the most suitable therapy, a simple and reproducible geriatric assessment could efficiently guide practitioners.

Study of surgical treatment for elderly patients with head and neck cancer

The aim of this study was to evaluate the clinical results of surgery for head and neck cancer (HNC) in elderly patients and to determine whether surgery for elderly HNC patients is safe and what types of surgery result in the most favourable outcomes for this age group. The cases of 637 elderly patients who were diagnosed with HNC and underwent surgical treatment were studied retrospectively. Patient demographic characteristics and treatment data were extracted from the appropriate patient records and analysed. Age did not significantly predict postoperative complications or death rates. Flap reconstruction surgery had no significant association with necrosis, haemorrhage, infection, need for rescue treatment, or length of intensive care unit stay. Age was not a risk factor for surgical treatment of HNC in the elderly patients. Flap reconstruction should not be considered riskier for elderly patients. The treatment choice for elderly patients with HNC should be based on medical assessments but not on age.

An Introduction to a Head and Neck Cancer-Specific Frailty Index and Its Clinical Implications in Elderly Patients: A Prospective Observational Study Focusing on Respiratory and Swallowing Functions.

Frailty refers to a decreased physiologic reserve in geriatric patients and its importance in terms of treatment planning and outcome prediction has been emphasized in oncologic practices for older patients with cancer. We investigated the clinical implications of a head and neck cancer (HNC)-specific frailty index suggested by prospective clinical and functional evaluations of HNC patients. We analyzed data on 165 elderly patients with HNC who were prospectively enrolled in our hospital from 2010 to 2013. Pretreatment functional evaluations were performed according to all comprehensive geriatric assessment (CGA) domains. We additionally evaluated the patients' respiratory and swallowing functions using pulmonary function tests, voice handicap index (VHI), MD Anderson Dysphagia Inventory (MDADI), and other associated tests. Factors affecting the 2-year morbidity and mortality were also analyzed. Respiratory and swallowing problems were major causes of 2-year morbidity. Pretreatment performance status, VHI ≥8, MDADI <70, dental problems, and chemotherapy were significantly associated with early morbidity and mortality (all p < .05). CGA-assessed frailty was found in 72 patients (43.6%) and was significantly associated with 2-year mortality (p = .027) but not with morbidity (p = .716). The high-risk group according to our new HNC-specific frailty index that included functional evaluations of respiration and swallowing showed significantly higher 2-year morbidity (p = .043) and mortality (p < .001). Pretreatment functional disabilities related to respiration and swallowing were significantly associated with early morbidity and mortality. The suggested index would be more useful for assessing frailty in elderly HNC patients. This study is the first report in terms of suggesting a new frailty index focusing on respiratory and swallowing functions in elderly patients with head and neck cancer. This study shows that functional disabilities associated with respiration and swallowing significantly affected early morbidity and mortality in these elderly patients. The head and neck cancer-specific frailty index described in this report, which includes functional evaluations of respiration and swallowing, significantly predicted both early morbidity and mortality.

Effect of polypharmacy and potentially inappropriate medications on treatment and posttreatment courses in elderly patients with head and neck cancer.

The use of excessive and inappropriate medications is a common problem in elderly populations. The use of polypharmacy (PP) and potentially inappropriate medication (PIM) may affect treatment-related morbidities in elderly cancer patients, which has rarely been studied in patients with head and neck cancer (HNC). Here, we evaluate the effects of PP and PIM on treatment and posttreatment courses in elderly HNC patients. This study included 229 elderly HNC patients who underwent definitive treatment. Medications were carefully recorded, and the prevalences of PP and PIM are reported. We evaluated the associations between PP, PIM, treatment, and posttreatment course in terms of comorbidities, treatment-related toxicity, prolonged hospitalization, and posttreatment noncancer health events. The prevalences of PP and PIM in our elderly HNC patients were 29.3 and 24.0 %, respectively, and frequently described PIMs include aspirin (12.2 %), calcium channel blockers (4.8 %), benzodiazepines (4.3 %), and nonsteroidal anti-inflammatory drugs (3.9 %). PP and PIM were not significantly associated with treatment-related toxicity, but were associated with modestly increased prolonged hospitalization [odds ratio [OR] 2.30 (95 % confidence interval 0.89-5.95); P = 0.080] and noncancer health events [OR 1.81 (0.99-3.31); P = 0.052], respectively. Among high-risk medications, benzodiazepine [OR 5.09 (1.21-21.5); P = 0.015] and calcium channel blockers [OR 5.69 (1.07-33.25); P = 0.031) were significantly associated with prolonged hospitalization. Neither PP nor PIM are significantly associated with treatment-related toxicity in elderly HNC patients, but these are associated with modest increases in prolonged hospitalization and noncancer health events.

Low level laser therapy against radiation induced oral mucositis in elderly head and neck cancer patients-a randomized placebo controlled trial

ObjectivesRadiotherapy (RT) is treatment of choice for Elderly Head and Neck Cancer (HNC) patients. Oral mucositis (OM) during RT affects patient’s routine oral activities and overall health. Low Level Laser Therapy (LLLT) provided some promising results against cancer therapy induced OM in children and adults. No study specifically evaluated effects of LLLT against RT induced OM in elderly HNC patients until date, hence we did this study. Material and methodsThis double blinded study randomized 46 elderly HNC patients scheduled for RT [Dosage=66 Gray (2Gy/fraction), 5 fractions/week, total 33 fractions for 6.5weeks], into laser (22) and placebo (24) groups. Laser group patients received LLLT [Helium–Neon, λ=632.8nm, power density=0.024W/cm2, dosage=3.0J/point at six anatomical sites bilaterally i.e. 12 locations, total dose/session=36J, beam aperture diameter=0.6mm, beam spot size=1cm2, irradiated area diameter=1cm2, irradiation time/point=125s, 5 sessions/week, non-contact method-distance between probe and irradiated tissues <1cm, whereas placebo group did not receive laser. OM grades (RTOG/EORTC Scale), oral pain, weight loss, need for morphine analgesics and tube feeding, and RT break were recorded by a blinded assessor. Descriptive statistics and repeated measures ANOVA were used for analysis keeping p<0.05. ResultsSignificant reduction in the incidence and duration of severe OM (p=0.016) and severe pain (p=0.023) and weight loss (p=0.004) was observed in laser than placebo group. No difference was found for enteral feeding use (p=0.667) between two groups. ConclusionsLLLT decreased the severity of OM and oral pain in elderly HNC patients. Also, lesser weight loss, morphine analgesic use and radiation break happened in laser group.

Perioperative survival of elderly head and neck squamous cell carcinoma patients

To evaluate the survival benefit of surgery for elderly head and neck cancer (HNC) patients. Retrospective national database cohort study of HNC patients. The study is a retrospective cohort review of the Surveillance, Epidemiology, and End-Results (SEER) database from 2004 to 2009. We developed an estimated perioperative window, based on the institutional database at a tertiary academic center. The average time to surgery among HNC patients at this center correlated with SEER's 3-month post diagnosis. From this estimate, we calculated postoperative (3 months), 2-year, and 5-year overall survival (OS) for patients receiving HNC surgery from 2004 to 2009 in the SEER database. Patients were matched for sex, tumor grade/stage, primary location, and radiation treatment status. Overall, after matching we found a statistically significant decrease in 3-month OS for the elderly patients versus younger controls who received surgery (P < .05). However, a matched analysis of elderly patients alone found a significant increase in OS for elderly patients who received surgery compared to those who did not (P < .05). Surgery appears to offer overall benefit to elderly HNC patients. These patients have a significantly worse postoperative OS than their younger counterparts, but the clinical significance appears to be limited. The improved survival among elderly patients who receive surgery compared to those who do not suggests that surgery should be offered to properly selected patients regardless of age.

Elderly Head and Neck Cancer (ELAN) study: Personalized treatment according to geriatric assessment in patients age 70 or older: First prospective trials in patients with squamous cell cancer of the head and neck (SCCHN) unsuitable for surgery.

TPS6099 Background: 30% of SCCHN occur in patients (pts) >= 70y and the main challenges in these pts are to cope with the treatment benefit/risk ratio and the tumor related symptoms. However, these pts are usually not included in trials. We developed a large prospective clinical program planed to enroll 448 pts in 3 distinct trials to improve the multidisciplinary management of elderly SCCHN pts. The main objectives of this study are to demonstrate that a geriatric evaluation is feasible in daily practice for SCCHN pts and to set new standards of care in this population. Methods: To be included in one of the three trials, SCCHN pts aged 70 or over, not suitable for surgery, must first be enrolled in ELAN-ONCOVAL study where they are classified as fit or unfit, using a geriatric evaluation applicable to the daily practice. Comprehensive Geriatric Assessment is optional. In curative situation, unfit pts are proposed to be enrolled in the randomized non-inferiority ELAN-RT trial, comparing standard radiother...

The incidence and impact of comorbidity on survival and selection of initial treatment in elderly patients (pts) with head and neck cancer (HNC)

6065 Background: Comorbidity has been shown to be a determinant of survival and treatment selection in various cancers including HNC. Higher comorbidity index is associated with higher utilization of non-curative intent treatment. Methods: In this retrospective study we analyzed 182 consecutively treated HNC pts &gt;65 years (y) old at the Dallas VAMC from January 2000 through June 2007. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). Treatment was classified as curative intent versus non-curative intent. The goals were 1) to demonstrate burden of comorbidity and 2) to demonstrate the impact of comorbidity on overall survival and selection of initial treatment in elderly HNC pts. Results: Pts characteristics: 100% male; 80% white, 19.5% Black, 0.5% Hispanic; median age 72y (range 65–87); 3% stage 0, 26% stage I, 20% stage II, 18% stage III, 30% stage IV, 2% unknown; primary site - 30% oral cavity, 4% hypopharnyx, 22% oropharynx, 38% larynx, 4% other, 1% unknown; treatment - 26% radiation only, 44% surgery (S), 21% chemoradiation (CR), 9% no treatment; Median CCI -2 (range 0–11); 61% had CCI score 0–2 and 39% had CI score &gt; 3. Median overall survival was 883 days (SE 19.31 days). Rate of curative vs. non-curative intent treatment was 80% vs. 20% respectively. Pts with CCI score 0–2 had a non-significant higher rate of curative intent treatment than pts with CCI score &gt; 3 (83.8% vs. 74.6% p = 0.13). In multivariate analysis including CCI, age, race, alcohol use, primary site, treatment, and stage, only advanced clinical stage had significant prognostic importance (HR 1.66; 95% CI, 1.29 to 2.14; p &lt; 0.0005). The HR for CCI was 1.11 (95% CI, .99–1.24; p = 0.08). In separate multivariate analyses of pts treated with S and pts treated with CR, CCI was not a significant predictor of survival with HR of .88 (95% CI, .69–1.11; p = 0.29) and 1.13 (95% CI, .83–1.53; p = 0.44), respectively. Conclusions: In our population of elderly HNC pts, CCI and age had no significant impact on survival or selection of curative intent treatment. Additional study is required to better define appropriate candidates for curative intent treatment in this population. No significant financial relationships to disclose.