GERIATRIC ONCOLOGY (TM WILDES, SECTION EDITOR)

Endometrial Cancer in the Elderly

Amy R. MacKenzie

# Springer Science+Business Media New York 2014

Abstract Endometrial cancer is a common cancer in the senioradult oncology population. Unfortunately, older patients mayfare worse than their younger counterparts for many reasons:limited evaluation beyond chronological age, scarcity of data totreat the elderly, increase in perioperative complications, and ahesitancy to offer surgical intervention in the oldest old. As thecornerstone of diagnosis and treatment is surgical, this vulnerablepopulation needs appropriate evaluation and care perioperativelyin order to derive benefit from what can be aggressive butcurative procedures. An understanding of the nature and treat-ment of the disease, as well as the approach to the senior adultoncology patient, should guide the practitioner toward a thoroughassessment and frank discussion with the patient/family/caregiv-er to establish “right-sized” care for the geriatric endometrialcancer patient.

Keywords Endometrial cancer . Preoperative assessment .

Comprehensive geriatric assessment . Geriatrics .

Gynecologic oncology

Introduction

Endometrial cancer is the most common female genital ma-lignancy and is largely a disease of the over-65 population.The projected rise in this segment of the population is signif-icant, with an estimate that by 2030, twenty percent of thepopulation will be older than 65 years [1]; by 2050, senioradults are projected to number 80 million and will carry adisproportionate number of cancer diagnoses [2]. The elderlyendometrial cancer patient presents a challenge to the treatingphysician; while treatment choices for younger patients may

be easily delineated by stage, treatment of a geriatric patient iscomplex and must take into account functional status, comor-bidities and life expectancy in the absence of the cancer [3]. Acomprehensive approach to the senior adult oncology patientwith endometrial cancer can potentially offer treatment that isindividualized and beneficial, and is in keeping with thepatient’s goals of care.

The treatment of endometrial cancer in the geriatric popula-tion is complicated for several reasons: 1) the histology of thetumors is oftenmore aggressive in older women [4]; 2) surgery isthe mainstay for staging and early stage tumors; 3) adjuvanttherapy can be difficult to tolerate, particularly after an extensivesurgery; and 4) age is an adverse prognostic factor in endometrialcancer [5, 6•]. However, elderly patients can often benefit fromtreatment and should not be overlooked because of age alone [7,8]. This review covers the epidemiology, staging and treatmentof endometrial cancer in the context of the senior adult oncologypatient. Special attention is paid to preoperative evaluation andcomprehensive geriatric assessment.

Epidemiology and Risk Factors

Endometrial cancer accounts for 6 % of all cancers diagnosedin women, and is the most common cancer in the femalegenital tract [9–12]. It is the fourth most common cancer afterbreast, lung and colorectal cancer [13], and the estimated newcases in 2014 total 52,630 [14]. Of these, an estimated 8,590women will succumb to the disease [15]. Endometrial canceris most often a disease of women who are post-menopausal;the median age at diagnosis is 62 years and 45 % of casesoccur in patients over the age of 65 [14]. One of the strongestrisk factors for the development of endometrial cancer isunopposed estrogen exposure with insufficient progesteroneto balance the mitogenic effects of estrogen [16]. This occurseither exogenously via estrogen-only post-menopausal hor-mone replacement (and, historically, the first, high-estrogenoral contraceptives), or endogenously in obese women.

A. R. MacKenzie (*)Division of Regional Cancer Care, Department of MedicalOncology, Thomas Jefferson University Hospital, 925 Chestnut St.,4th Floor, Philadelphia, PA 19017, USAe-mail: amy.mackenzie@jefferson.edu

Curr Geri RepDOI 10.1007/s13670-014-0088-3

Obesity has been estimated to account for up to 40 % ofendometrial cancer cases in Western societies [17]. Finally,excess adipose tissue leads to increased peripheral conversionof androgens to estrogens via aromatase enzymes [18]. Otherrisk factors for the development of endometrial cancer includediabetes, hypertension, tamoxifen use, increasing age andgenetic syndromes [19].

Because abnormal uterine bleeding is a common presenta-tion (90%), many women are diagnosed at an early stage [20].Approximately 72 % are stage I, 12 % stage II, 13 % stage IIIand 3 % stage IV [21]. Ninety percent of tumors are derivedfrom the epithelial lining of the endometrium and are classi-fied as endometrial carcinomas, either low-grade or high-grade. Less common tumor types include papillary serouscarcinoma, clear cell carcinoma, papillary endometrioid car-cinoma and mucinous carcinoma [9, 20, 22]. Endometrialcancers can also be classified by histopathology and clinicalcourse into type I and type II neoplasms [12, 22]. Type Icancers include the more common endometrioid adenocarci-nomas, which are usually low-grade, estrogen dependent andhave a better overall prognosis [9, 20]. Type II cancers aremore aggressive, derived of rarer cell types and are less welldifferentiated. Consequently, patients with this type of tumordo not tend to have as favorable a prognosis. Geriatric patientsare more likely to present with a type II tumor, further com-plicating the treatment plan for this high-risk population [4].

Diagnosis

The diagnosis of endometrial cancer has historically beenperformed by dilation and curettage (D&C). This has largelybeen replaced by hysteroscopy [20]. Biopsy can be done in theoffice and does not require anesthesia, making it a saferprocedure. Hysteroscopy with biopsy has been found to bemore sensitive in revealing uterine lesions than D&C [23];however, D&C may more accurately reflect InternationalFederation of Gynecology and Obstetrics (FIGO) grade [24].As with many malignancies, low-grade tumors carry a betterprognosis than do high-grade, more aggressive tumors. FIGOstage and tumor grade are independent predictors of disease-free and overall survival [25].

Staging and Treatment

Staging

The standard staging procedure following a positive biopsyfor endometrial cancer is total hysterectomy and bilateralsalpingo-oophorectomy. Staging of endometrial cancer isbased upon the FIGO surgical staging system. This was up-dated in 2009 to replace the previous system, last updated in

1988 [26]. The new staging system incorporates both survivaldata of more than 42,000 women who had undergone surgicalstaging [27] and prognostic information based on several largestudies [28–30]. Prior stages IA and IB have been combinedinto IA and the 1988 IC is now IB. Stage IIA and IIB havebeen consolidated into a single category (stage II) representinginvasion of the cervical stroma with endocervical glandularinvolvement downstaged to stage I.

Metastasis to regional nodes is a critical prognostic factorin endometrial cancer [12, 29]. Two studies demonstrated aclear differential in survival between patients with pelvicversus para-aortic lymph node metastases, and the stagingsystem has been updated to reflect this [21, 31].

A controversy exists regarding the extent of lymphadenec-tomy as a staging modality, in terms of both its necessity andimpact on survival. A number of retrospective studies havesuggested a benefit to lymphadenectomy in intermediate tohigh-risk patients, but no benefit in low-risk patients in termsof improving overall survival [32]. Long-term risks of lymphnode dissection include lymphocyst and lymphedema, at ap-proximately 1.3 % and 0.7 % risk, respectively [33]. In elderlypatients, similar results have been demonstrated: in low-riskpatients, there is no survival benefit to lymph node dissection.However, disease-specific survival is improved in patientswith high-grade disease [34]. Lymphadenectomy has beenassociated with a higher probability of perioperative compli-cations in women 80 years or older [8].

The fact that definitive staging is a surgical procedurehighlights important issues in the geriatric population: canthe patient tolerate the procedure and will it provide enoughbenefit to justify the risk of surgery? Geriatric patients com-prise more than a third of inpatient surgical procedures in theUS [35••], and this number will continue to rise. A thoroughconsideration of the risks and benefits of surgery is especiallywarranted when life expectancy in the absence of the cancermay be limited.

The procedure for early endometrial cancer is totalextrafascial hysterectomy with bilateral salpingo-oophrectomy with or without pelvic and para-aortic lymphnode dissection. This can be performed either by open lapa-rotomy, laparoscopy or robot-assisted laparoscopy. A compar-ison of these techniques with respect to operative and periop-erative outcomes, complications, adequacy of staging and costdemonstrated that robotic hysterectomy was comparable tolaparotomy and laparoscopy in node retrieval in the hands ofan experienced surgeon. Robotic hysterectomy took longerthan laparotomy, but offered a quicker return to preoperativeactivities and a shorter hospital stay. Additionally, robotichysterectomy has been shown, retrospectively, to lead to lowerblood loss [36, 37]. In the elderly, robotic surgery was evalu-ated versus traditional open surgery in a group of 167 patientsover 70 years of age. While operating times were slightlylonger in the robotics group, those patients had fewer minor

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adverse events, less estimated blood loss and shorter hospitalstay. Disease-free survival was not adversely affected byrobotic surgery [38]. Traditional laparoscopic staging offersmany of the same benefits to elderly patients and can beconsidered in the appropriate patient [39].

Treatment

The cornerstone of treatment for endometrial cancer is surgi-cal, usually performed as a diagnostic (staging) and therapeu-tic procedure. The elderly are at risk for perioperative compli-cations, adverse effects from hospitalization, and extendedpostoperative recovery times. Perioperativemortality has beenfound to be approximately threefold to sevenfold higher evenwith equivalent comorbidities [40]. Surgical morbidity is sig-nificantly higher in the 80 years and older population, againwith equivalent comorbid conditions [41]. Because of theheterogeneity of the elderly population and the variability offitness, a careful assessment of the patient’s functional statusas well as a discussion surrounding goals of care is crucial todevelop an appropriate treatment plan. As many elderly pa-tients can benefit from a surgical treatment for endometrialcancer, chronological age alone should not determine a pa-tient’s suitability for surgery [8].

Preoperative assessment has the potential to mitigate peri-operative complications in the elderly population by improv-ing patient selection and choice of surgical procedure. Apreoperative evaluation should begin in the office and wouldideally include a comprehensive geriatric assessment; howev-er, this can be lengthy and impractical for the busy clinician.Preoperative evaluation can also incorporate other tools, suchas the Brief Fatigue Inventory [42], performance status (eitherEastern Cooperative Oncology Group or Karnofsky) and theAmerican Society of Anesthesiologists score. These tools plusa mini-mental exam, the geriatric depression scale andSatariano’s index of comorbidities were combined by theInternational Society of Geriatric Oncology (SIOG) in a pro-spective international study, Preoperative Assessment ofCancer in the Elderly, or PACE. [43]. Outcomes in 460patients 70 years of age or older were measured after compre-hensive preoperative evaluation in terms of 30-day morbidityand mortality and length of postoperative hospital stay.Approximately 40 % had at least one complication within30 days of surgery. Of this group, 44 % suffered at least onemajor complication. Men were more likely to experiencecomplications (54.1 % vs. 29.4 %), but this may reflect thevery low numbers of complications with breast cancer pa-tients. Age was not a predictor of complications, but severityof surgery was. A low number of patients died (3.5 %) within30 days of surgery. Death was associated with male gender,advanced cancer stage and severity of surgery. Hospital staywas longer in patients dependent on activities of daily living(ADLs), instrumental activities of daily living (IADLs) and

with an abnormal performance status. Ultimately, the authorsfound that the PACE survey was reliable in measuring func-tional status and could be incorporated into presurgical assess-ment with the caveat that further research is needed to betterpredict outcomes. A recent study of preoperative and intraop-erative variables in elderly gynecologic oncology patientsdemonstrated that dependence in IADLs and poor perfor-mance status were both significantly associated with multiplecomplications.Multivariate analysis showed that high surgicalcomplexity was the single independent predictor of any, majoror multiple complications [44•].

Frailty has begun to be explored as a presurgical riskassessment tool, with the hope that identification of thosepatients who are frailer may suffer more harm than benefitfrom the proposed surgery. Several surgical studies have beenperformed using different frailty criteria that demonstrate acorrelation between frailty and increased risk for morbidity,mortality and length of stay [45].

Other medical considerations to be taken into account arethose that would be evaluated prior to any surgery, includingcardiac and pulmonary status, but expand to involve thesyndrome of frailty, delirium, and adverse events while hos-pitalized [46]. Hughes and colleagues wrote an extensive andrecent review of essential preoperative and postoperative man-agement in elderly women undergoing surgery that addresseseach organ system in detail and includes a discussion ofpostoperative issues, such as pain management, cognitivedecline and wound healing [47••].

Adverse effects of anesthesia are an important element toconsider when planning surgical venue and extent of surgery.A well-planned elective surgery often offers fewer risks thanan emergency surgery; however, risk is present in either caseand elderly patients often present late to treatment. A recent,in-depth review [48] found that regional anesthesia is associ-ated with reduced early mortality and morbidity, includingfewer myocardial infarctions and pulmonary emboli, but gen-eral anesthesia is notable for reduced surgery time and a lowerincidence of hypotension. Most complications were related tothe procedure and not the type of anesthesia. Risk factorsfound to be associated with a poor outcome included comor-bidities, type of surgery, and emergency surgery. Age andgender are not universally found to be predictors of outcome.Unfortunately, most surgical trials have not considered func-tional status routinely in these patients, and therefore crucialinformation may be missed. No significant differences havebeen found in outcomes with type of anesthesia [47••].

Adjuvant Therapy

Adjuvant treatment is defined as treatment that is given afterthe primary treatment, e.g., surgical, and can be in the form of

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chemotherapy, radiation, biologic and/or hormone therapy.The choice of adjuvant treatment, as with many malignancies,varies by stage and risk. Risk factors associated with endo-metrial cancer have been extensively evaluated over the last40 years and include: grade of the cancer, depth of myometrialinvasion, tumor extension into the cervix, extent of the uterinecavity involvement, lymphovascular invasion and vascularityof the tumor [22, 30]. Risk factors for advanced disease areadnexal metastases, pelvic or periaortic lymph node involve-ment, peritoneal implant metastases and distant organ metas-tases. Positive peritoneal cytology as a risk factor is contro-versial [49].

Early Stage Disease

For low-grade, stage IA endometrioid cancer, treatment con-sists of surgery alone with a very low risk for relapse over5 years, approximately 5 % [50]. In the presence of riskfactors, surgery has been traditionally followed by externalbeam radiation as was determined in the Post-OperativeRadiation Therapy in Endometrial Carcinoma (PORTEC)and GOG (Gynecologic Oncology Group) 99 trials [51].Vaginal cuff brachytherapy is equally efficacious with lesstoxicity, and can be safely substituted in intermediate riskstage I patients without a decrement in overall or relapse-free survival. An additional quality of life analysis based onthese data found a higher rate of significant gastrointestinal(GI) toxicity and thus a lower quality of life with externalbeam radiation [52]. Radiotherapy (RT) is occasionally usedas a single modality in the medically inoperable or frail patientfor early stage disease. There are no studies specific to theelderly population, but some studies have included sub-groups of patients 60 years and older [53].

Early stage, intermediate risk patients may stand to benefitfrom adjuvant treatment. The GOG 99 protocol evaluated acohort of early stage, intermediate risk women to determinethe benefit of adjuvant external beam radiation. Risk stratifi-cation identified two groups of intermediate-risk endometrialcancer patients: low risk and high risk. The intermediate-riskpatients were stage IA/IB or stage II. High intermediate-risk(HIR) patients had the following additional risk factors: grade2 or 3 pathology, lymphovascular invasion and invasion intothe outer third of the myometrium. HIR patients includedthose 70 years and older with one of the three aforementionedrisk factors, patients 50–69 years with two risks, or youngerthan 50 years with all three. HIR patients were found to have asignificantly lower risk of recurrence when treated with radia-tion, but not a significant improvement in overall survivalwhen compared to low intermediate-risk patients [54].

Studies have been conducted to determine if adding che-motherapy to radiation will improve outcomes. The RTOGconducted a prospective phase 2 trial (RTOG-9708) evaluat-ing patients with high-risk features undergoing pelvic

radiation and concomitant cisplatin, followed by vaginalbrachytherapy plus chemotherapy in the form of cisplatinand paclitaxel. Median follow-up was 4.3 years and demon-strated disease-free and overall survival of 81 % and 85 %,respectively [55]. Unfortunately, the phase-3, randomized trialwas closed due to poor accrual.

The European Organisation for Research and Treatment ofCancer (EORTC) [56], the Japan Gynecologic OncologyGroup [57], and an Italian group [57] evaluated patients withhigh-risk, early stage disease receiving radiation versus che-moradiotherapy. All three studies found an improvement inprogression-free survival with the addition of chemotherapy.In the EORTC trial, there was a 7 % absolute improvement in5-year progression-free survival (72 % v. 79 %) and a 10 %absolute improvement in cancer-specific overall survival inhigh-risk patients. The JGOG demonstrated improved overallsurvival in the high-risk group, including patients stage ICover 70 years old. Patients were eligible up to 75 years of agein this trial, but the mean age was 59 years, and improvedoverall survival was seen in a sub-group analysis. Therefore,there are limitations to these results. An additional limitation isthat patients with incompletely staged disease and stage IIIdisease were eligible for these trials. These patients represen-ted 25–40 % of all patients enrolled.

Current randomized trials examining adjuvant therapy areunderway. PORTEC 3, led by the Dutch Oncology Group,attempts to establish the overall and failure-free survival ofwomen with high-risk and advanced stage cancer when treat-ed adjuvantly with either chemoradiation followed by chemo-t h e r a py o r p e l v i c r a d i a t i o n a l on e . GOG 258(ClinicalTrials.gov identifier NCT00942357) is comparingsix cycles of standard chemotherapy with cisplatin-based che-moradiotherapy followed by chemotherapy. GOG 249(ClinicalTrials.gov identifier NCT00807768) is attempting toanswer the question of whether pelvic radiotherapy can bereplaced by vaginal cuff brachytherapy combined withchemotherapy.

Adjuvant treatment for advanced endometrial cancer in thegeneral population incorporates chemotherapy because of therisk of distant recurrence. GOG 122 evaluated whole abdom-inal irradiation (WAI) versus chemotherapy in patients withstage III and IV cancer. Over 20 % of patients were greaterthan 70 and more than 50 % were older than 60. Patientsreceiving chemotherapy alone had a hazard ratio of 0.67 forprogression-free survival and 0.69 for overall survival whencompared to WAI. Although this trial cemented the role foradjuvant therapy in node-positive endometrial cancer patients[58], the benefit was not as robust in patients over 70 years ofage in sub-group analysis.

The administration of adjuvant therapy in the elderly en-dometrial cancer patient has not been well studied [6•]. Anumber of studies have shown a tendency towardundertreatment in the senior adult oncology population among

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many malignancies. Historically, senior adult oncology pa-tients have been undertreated because of age, lack ofevidence-based guidelines, or fear of toxicity on the part ofthe physician. Several studies have demonstrated a pattern ofless aggressive care in elderly patients with breast cancer,ovarian cancer, cervical cancer, and endometrial cancer[59–64], despite comorbidities that are equivalent to youngerpersons [65]. Age and health status have been shown toinfluence treatment recommendations by both oncologistsand primary care providers in older breast cancer patients[66], and such factors have impacted treatment patterns inseveral other malignancies, including bladder, lung, headand neck, colorectal and prostate [67]. In a British study,surgeons and oncologists were asked to make treatment rec-ommendations based on hypothetical breast cancer patientprofiles. Eighty-one percent of oncologists were willing toprescribe chemotherapy to a high-risk, 68-year-old patient.Only 47%would prescribe the same treatment for an identicalpatient aged 73 [68]. Other factors influential in treatmentplanning include absence of sufficient data to treat olderpatients and physicians’ concern for increased morbidity fromtreatment [62].

Metastatic Disease

While the role of chemotherapy in metastatic disease is clearlydefined in the general endometrial cancer population [69], thebenefit of palliative chemotherapy is less easily delineated inthe elderly. Improved survival may be gained at the cost ofintolerable toxicity or decrement in life expectancy. GOG 177demonstrated that a three-drug regimen led to a significantimprovement in overall survival versus a two-drug regimenbut with increased toxicity [70]. Carboplatin and paclitaxelhas been compared to cisplatin, doxorubicin and paclitaxel,and was found to have similar response rates, progression-freesurvival, and overall survival, but with a lesser toxicity profile[71]. Treatment in the metastatic setting is palliative, andtherefore a risk-benefit and goals of care discussion is mostcrucial at this time.

Comprehensive Geriatric Assessment

The comprehensive geriatric assessment (CGA) has beenstudied as a tool to attempt to individualize treatment in senioradults and potentially avoid some of the previously mentionedpitfalls. The CGA is a multi-dimensional tool that gives theclinician a multi-faceted understanding of the patient, includ-ing functional status, psycho-social health, nutrition, life ex-pectancy, comorbid conditions and risk for frailty. The CGAwas initially developed in the general geriatric population toidentify problems and create a care plan for frail, elderly adults

[72]. With the ongoing development of senior adult oncologyclinics [73, 74], the principles of geriatrics are being incorpo-rated into oncologic care. In this setting, the CGA is poten-tially a tool that can predict morbidity and mortality andimprove the quality of cancer care in senior adults. Studiesof CGA in the oncogeriatric setting do show that functionalstatus predicts survival, chemotherapy toxicity and postoper-ative complications [75, 76•]. A recent prospective cohortstudy evaluated 65 patients with colorectal, breast, lung canceror lymphoma to determine if CGAwas associated with com-pletion of chemotherapy, grade III/IV toxicity from chemo-therapy, or survival. Patients completed a brief geriatric as-sessment prior to treatment, which included measurement ofcognitive status, functional status, depression, medications,nutritional risk, comorbidities and renal function. The authorsfound that completion of chemotherapy was associated withcurative intent treatment, and renal function. A poor perfor-mance status (2–3) was strongly associated with failure tocomplete treatment. The presence of comorbidities caused asixfold increase in grade III/IV non-hematologic toxicity andwas the only factor significantly associated with this outcome.Falls in the month prior to chemotherapy were associated withincreased mortality, whereas curative intent treatment wasassociated with lower rates of death [77]. Data is slowlyemerging regarding the impact of the CGA on oncologicoutcomes and its potential use in affecting treatment decisions[78]. Some critical work has been done to understand riskfactors in elderly patients that may predict toxicity from che-motherapy. The Cancer and Aging Research group conducteda multi-institution study to determine the utility of a modelthat could potentially predict the risk of grade 3–5 (high grade)toxicity from chemotherapy based on several variables. Someof these included cancer type, lab tests, sociodemographicfactors and functional status. Five hundred patients wereenrolled with stage I–IV cancer and approximately 70 %received chemotherapy. Of those patients, 53 % experiencedat least one grade 3–5 toxic adverse event and 23 % werehospitalized during treatment. Two percent of patients diedsecondary to treatment. The model was found to have a betterability to identify patients at risk for severe adverse effects ofchemotherapy than the Karnofsky Performance Status (KPS),a standard scale used by oncologists to estimate function. TheKPS is limited in its ability to evaluate the complex geriatricpatient, and this model, currently being validated, has thepotential to help oncologists guide individualized treatmentdecisions [79].

A second chemotherapy toxicity model was developed bythe Senior Adult Oncology Center at theMoffit Cancer Centerin Florida. A prospective multi-center study of 518 patients≥70 beginning chemotherapy was undertaken to assess toxic-ity levels and develop predictors of hematologic (H) and non-hematologic (NH) toxicities. The Chemotherapy RiskAssessment Scale for High-Age Patients (CRASH) score

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was able to identify risk levels of toxicity based on laboratoryvalues and geriatric assessment tools (Mini-Mental Statusscore, nutritional assessment, and activities of daily living).The CRASH model is good for predicting overall toxicity aswell as split risk: H and NH. In this study, 64 % of patientsexperienced a severe adverse effect from chemotherapy andthere was a 2 % treatment-related mortality rate [80].

Conclusion

Treatment of endometrial cancer in the elderly patient requiresnot only a multi-disciplinary approach (gynecologic oncolo-gist, medical oncologist and radiation oncologist), but a com-prehensive approach to the geriatric patient [81••]. Treatmentis surgical and curative treatment is aggressive, necessitatingcareful planning prior to embarking on a course of surgery,chemotherapy and/or radiation. Senior adult oncology patientsare vulnerable because they are at risk of receiving non-standard treatment that may compromise cure, or that mayshorten life expectancy secondary to toxicity. Use of a com-prehensive geriatric assessment, or referral to a senior adultoncology clinic, can provide insight into the problems of theelderly patient that may go unnoticed, and may be associatedwith the ability or inability to tolerate treatment. Future re-search is needed to define the role of CGA in impactingtreatment decisions and oncologic outcomes, in order to indi-vidualize treatment for elderly cancer patients.

Compliance with Ethics Guidelines

Conflict of Interest Amy R. MacKenzie declares that she has noconflict of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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