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Adjuvant Treatmentfor Early-stageEndometrial Cancer

ISRAEL ZIGHELBOIM, MD andMATTHEW A. POWELL, MD

Division of Gynecologic Oncology, Department of Obstetricsand Gynecology, Washington University School of Medicineand Siteman Cancer Center, St Louis, Missouri

Abstract: A subgroup of endometrial cancer patientswith early-stage disease will progress or eventuallypresent with recurrent disease.Multiple risk stratifica-tion strategies have been attempted to direct adjuvanttherapeutic interventions. Radiation has been themost common form of adjuvant therapy offered tothese patients. Unfortunately, its use has not trans-lated into survival improvements. There is growingevidence supporting the use of adjuvant chemother-apy and multimodal interventions for patients withendometrial cancer. This review focuses on the role ofadjuvant therapies for patients with early-stage dis-ease with emphasis on future directions for risk stra-tification and personalized treatment.Key words: endometrial cancer, early stage, adjuvant,chemotherapy, radiotherapy, biologic therapy

IntroductionEndometrial cancer patients usually pre-sent with early symptoms which accountfor the overall good prognosis associatedwith this disease. The 5-year overall sur-

vival (OS) exceeds 95%when the tumor isconfined to the uterus.1 The understand-ing of the natural history and patterns offailure of this disease have evolved signif-icantly over the last 3 decades.Historically,patients with postmenopausal bleedingand suspected endometrial cancer under-went examination under anesthesia andfractional dilatation and curettage as themainstays of diagnosis. After this proce-dure, patients were assigned a ‘‘clinicalstage’’ and dispositioned to receive inmany cases preoperative intracavitary ra-diation followed by total hysterectomyand bilateral salpingo-oophorectomy. Sur-gery was commonly followed by wholepelvic radiotherapy with the objective ofimproving local control and increasingsurvival. It seems obvious today that such‘‘far from personalized’’ approach causedmany patients to receive unnecessary andpotentially harmful adjuvant therapy. Inaddition, the costs associated with thattreatment paradigm were not trivial.

In the 1980s, the Gynecologic Onco-logy Group’s (GOG) protocol 33 evalu-ated a systematic approach to surgical

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Correspondence: Israel Zighelboim, MD, Division ofGynecologic Oncology, Department of Obstetrics andGynecology, Washington University School of Medi-cine and Siteman Cancer Center, 4911 Barnes JewishHospital Plaza, Box 8064. St Louis, MO 63110.E-mail: [email protected]

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 2 / JUNE 2011

CLINICAL OBSTETRICS AND GYNECOLOGYVolume 54, Number 2, 245–255r 2011, Lippincott Williams & Wilkins

staging in patients with newly diagnosedendometrial cancer. This revolutionarystudy showed that clinical staging missedmetastatic disease in approximately 25%of cases.2 Given the inadequacy of clinicalstaging, the International Federation ofGynecologists and Obstetricians (FIGO)approved a surgical staging classificationfor uterine cancer in 1988 that was re-cently revised in 2009.3

Despite recent controversy with regardto direct survival benefit attributable tothe procedure, systematic surgical stagingincluding pelvic and periaortic lymphnode dissection has certainly allowed formore judicious and rational use of adju-vant treatment in patientswith endometrialcancer. Furthermore, the identification ofclinicopathologic risk features in patientswith early-stage disease has led to theconcept of risk stratification in patientswith early-stage disease. Importantly, no-vel therapeutics including chemotherapyand biologic agents have also become partof the armamentarium available to treatselected patients with early-stage disease atrisk of disease progression or recurrence.

Evolving Role of AdjuvantRadiotherapy and the Conceptof Risk StratificationIn the past, the use of almost routineadjuvant radiotherapy for patients withendometrial cancer was highly prevalent.Definitive curative intent tumor-directedradiotherapy for patients with endome-trial cancer has been well described as aneffective alternative intervention and isbeyond the scope of this review. Resultsfrom 3 randomized clinical trials illustratewell the evolution toward more restrictedand rational. use of adjuvant externalbeam radiotherapy in patients with diseasethought to be confined to the uterus.4–6

Aalders et al4 from the NorwegianRadium Hospital reported in 1980 on540 patients enrolled in a randomized trial

between 1968 and 1974. In their study,women with clinical stage I endometrialcancer without obvious evidence of extrau-terine spread at the time of total abdominalhysterectomy and bilateral salpingo-oo-phorectomy received 60Gy of vaginalsurface brachytherapy followed by ran-domization to observation or externalbeam pelvic radiotherapy. One shouldnote that no specific exclusionsweremadebased on histologic grounds and thathistologic assessment comparable withtoday’s standard histotypes was not re-ported. The treatment arm received high-voltage radiation to the pelviswith prescrip-tion of 40Gy to the pelvic lymph nodesover 20 fractions with central shielding at20Gy. The treatment group had lowervaginal and pelvic recurrence rates (2%vs. 7%; P<0.01). Unfortunately, pelvicradiotherapy was also associated with ahigher distant failure rate (10% vs. 5%)and no improvement was observed in 5-yearOS. Interestingly, subset analysis suggestedthat grade 3 tumors with deep myometrialinvasion might particularly benefit from ex-ternal beam radiotherapy. In addition, thisstudy called attention to ‘‘endothelial-linedtumor cells’’ (eg, lymphovascular space in-vasion) as an important risk factor for re-currence and death.3

Twenty years after Aalders’ report,the Postoperative Radiation Therapy inEndometrial Carcinoma (PORTEC) in-vestigators published the results of theirmulti-institutional trial.5 It is importantto consider that results of GOG-33 werereported in between these two trials.Therefore, the risk stratification concepthad evolved and it was clear at the timethat even when the disease is confined tothe uterus 2 distinct subsets of patients ateither negligible or higher risk (>20% to40%) for nodal metastases (and arguablyprogression and death) could be identifiedbased on clinicopathologic risk factors.7

The PORTEC trial enrolled patients withendometrial cancer of any histologythought to be confined to the uterus and

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perceived to be at intermediate risk of recur-rence or progression (grade 1 with >50%myoinvasion, all grade 2, and grade 3 with<50% myoinvasion). Although all partici-pants underwent total abdominal hysterec-tomy and bilateral salpingo-oophorectomy,lymph node dissection was not required.Patients were randomized to observationversus 46Gyofpelvic radiotherapyadminis-tered by external beam over 23 fractions.Locoregional recurrence rates were signifi-cantly lower in the radiotherapyarm (4%vs.14%, P<0.001). There was no difference in5-year OS (81% vs. 85%, P=0.31). Thetoxicity associated with the treatment wassignificant with 25% treatment-related com-plications noted in the radiotherapy group(vs. 6%, P<0.0001). Importantly, survivalafter relapse was better in the control group(P=0.02) confirming that locoregional fail-ure canbe successfully salvagedanddoesnotnecessarily herald distant metastatic disease.Through subset analysis, this study alsoidentified age less than 60 years as a favor-able prognostic factor and defined a subsetof patients at ‘‘intermediate to high’’ risk forrecurrencewhen 2of thesemajor risk factorsare present: age 60 years or above, deep(>50%) myometrial invasion if grade 1 tograde 2, or superficially invasive grade 3histology.5 Adjuvant pelvic radiotherapy gi-ven to this ‘‘intermediate to high’’ risk groupdecreased local recurrence from 22% to8%.8

In 2004, the GOG published the resultsof GOG-99.6 This was a phase III trial ofsurgery with or without adjuvant externalpelvic radiation therapy in patients withintermediate-risk endometrial adenocar-cinoma. Intermediate risk was defined asFIGO1988 surgical stage IB, IC, or occultstage IIA. Patients with papillary serousor clear cell tumors were excluded. Im-portantly, this studywas the first to requiresystematic surgical staging with pelvic andperiaortic lymphadenectomy. After ini-tial staging, patients were randomized toobservation or to pelvic radiotherapy byexternal beam to a total dose of 50.4Gy

divided in 28 fractions. A total of 392eligible patients were analyzed. Pelvicradiotherapy was associated with a lowerrisk of recurrence at 2 years [3% vs. 12%,hazard ratio (HR): 0.42, P=0.007]. The4-year estimated OS was not improved inthe treatment arm (86% vs. 92%, HR:0.86; P=0.56). In the midst of the studythe investigators perceived that the tar-geted population had a lower risk ofrecurrence than initially thought. There-fore, a non-preplanned regression anal-ysis of historical data from GOG-33 wasthen performed to define risk factors forrecurrence. Identified factors were (1) in-creasing age, (2) moderately to poorlydifferentiated tumor grade, (3) presenceof lymphovascular invasion, and (4) out-er-third myometrial invasion. From theresults of that analysis a new high-inter-mediate risk category was defined as (1) atleast 70 years of age with only one of theother risk factors, (2) at least 50 years ofage with any 2 of the other risk factors, or(3) any age with all 3 of the other riskfactors. All other patients were consid-ered to be at low-intermediate risk risk.The methodological strategy and timingused to define these new risk cate-gories have been harshly criticized. How-ever, inception of these strata allowedthe GOG to note a group in which thebenefit of local control at 2 years attribu-table to external beam pelvic radiother-apy was particularly significant (26% vs.6%; HR: 0.42). As expected, treatment-related toxicities were more frequent andsevere in the radiotherapy arm.6

These important studies have multiplelimitations. As discussed, the radiationequipment, prescriptions and techniquesvaried between trials. In addition, onlyGOG-99 required systematic surgical sta-ging including pelvic and periaortic lym-phadenectomy. It is therefore possiblethat a fraction of these patients perceivedto have disease localized to the uterus hadindeed undiagnosed nodal metastasis oreven distant metastatic disease. On the

Adjuvant Treatment for Early-stage Endometrial Cancer 247


basis of these studies, it is possible toconclude that pelvic radiotherapy doesnot convey an OS benefit to patients withendometrial cancer apparently confinedto the uterus. Nonetheless, these 3 land-mark trials strongly suggest that externalbeam radiotherapy improves locoregio-nal control in patients with endometrialat risk of vaginal and pelvic failures.

Interestingly, the vast majority (B75%)of recurrences in PORTEC and GOG-99occurred at the vaginal cuff, suggestingthat perhaps vaginal cuff brachytherapyalone could produce comparable resultswith less cost, morbidity and treatment-related complications. With this in mind,the PORTEC investigators conductedPORTEC-2. This randomized controlledtrial used a non-inferiority design to com-pare external beam pelvic radiotherapy(46Gy over 23 fractions) versus vaginalbrachytherapy (21Gy via high-dose rateover 3 fractions or 30Gy via low-doserate) for patients with high-intermediaterisk endometrial cancer. One should notethat this definition was different than thatproposed by GOG-99 and included pa-tients older than 60 years with FIGO 1988stage IC grade 1 or 2 or stage IB grade 3tumors or patients with stage IIA regardlessof age (excluding those with grade 3 tumorswith myoinvasion >50%). Systematicsurgical staging with routine lymphade-nectomy was not required. The primaryendpoint was vaginal recurrences. POR-TEC-2 showed non-inferiority of vaginalbrachytherapy in this patient population(1.6% recurrence rate vs. 1.8% with ex-ternal beam radiotherapy). The pelvicfailure and distant metastasis rates weresimilar. Five-year disease-free survivaland OS in the vaginal brachytherapyand external beam radiotherapy armswere comparable (OS: 85% vs. 80%,P=0.57 and disease-free survival: 83%vs. 78%, P=0.74). As expected, acutegastrointestinal toxicity was significantlylower in the vaginal brachytherapy group(13% vs. 54%).

In the absence of survival benefit de-rived from pelvic radiotherapy in patientswith intermediate-risk endometrial can-cer cost considerations could play animportant role in deciding whether ornot to recommend adjuvant radiotherapyto these patients. An incremental cost-effectiveness analysis estimated that adju-vant whole pelvic radiotherapy treatmentwould carry a cost per recurrence preventedof approximately $50,000 to $225,000 de-pending on the risk subgroup analyzed.9

Unfortunately, this study did not incor-porate quality of life data nor did it modelthe use of vaginal brachytherapy.

The role of adjuvant pelvic radiother-apy for patients with early-stage endo-metrial cancer must be individualizedand take into consideration multiple vari-ables. These include the perceived risk oflocal and distant relapse, the possibility ofunrecognized advanced regional or dis-tant metastatic disease as determined bywhether or not systematic surgical stagingwith lymphadenectomy has been per-formed as well as the potential benefits,toxicities and cost associated with radio-therapy. Analysis of this complex equa-tion in individual cases can be challengingand should always take into considerationthe patient’s preferences, comorbiditiesand goals of care. Even though moststudies of adjuvant radiotherapy haveallowed patients without comprehensivesurgical staging, we firmly believe that theindividual risk of occult nodal and distantdisease must be considered individuallybefore providing recommendations foradjuvant therapy. Table 1 summarizesadjuvant therapy recommendations forpatients with comprehensively surgicallyevaluated early-stage endometrial cancer.

The Role of AdjuvantChemotherapyThe role of adjuvant chemotherapyin patients with early-stage endometrial



cancer is yet to be defined. As previouslydiscussed, the majority of patients diag-nosed with endometrial carcinoma in thedeveloped world present with low-gradeearly-stage cancers and are usually curedwith appropriate surgical therapy. Themost appropriate management strategyfor patients determined to be at inter-mediate and high risk for recurrence re-mains unknown. Radiotherapy has notshown convincing improvements in pa-tient survival. Cytotoxic chemotherapyhad been, until recently, only used in pa-tients with advanced or recurrent endome-trial cancer not amendable to or after theuse of radiation therapy. The GOG proto-col 34 published in 1990 was traditionallycited as evidence against adjuvant chemo-therapy for these patients. In GOG-34, aftersurgery and/or radiation therapy, patientswere randomized to receive doxorubicin orobservation. The study included a heteroge-neous patient population (stages IC to IIIC)withwidely varied risk of recurrence. Radia-tion therapy was optional, left at the discre-tion of the investigator and delivered beforerandomization. The study was grossly

underpowered with only a 39% power todetect significant differences in outcomes.10

The GOG has over the past severaldecades undertaken a rational evaluationof both multiple single-agents and combi-nations of chemotherapy regimens in pa-tients with advanced stage and recurrentdisease. It is important to review theseexperiences in context as they have tai-lored most recent interventions and on-going trials for patients with early-stagedisease. After evaluating several differentsingle agents in phase II trials, the GOGimplemented GOG-177, which showedthe combination of paclitaxel, doxorubi-cin, and cisplatin (TAP) to be superior todoxorubicin and cisplatin (AP).11 Sincethen, this triplet has become the trial-sup-ported standard for patients with advanceddisease. Unfortunately, even with this mostaggressive therapy, responses are usuallyonly partial and are of a relatively shortduration with most patients ultimately dy-ing of their disease. Thus, chemotherapy inthis setting is largely palliative with amodest impact on survival. The trend intherapy development has been to focus on

TABLE 1. Adjuvant Therapy Recommendations Early-stage Endometrial Cancer AfterComprehensive Surgical Staging

FIGO 2009

Stage Tumor Characteristics Adjuvant Treatment Recommendation

IA GOG-99 HIR Vaginal brachytherapy*All others Observation

IB GOG-99HIRor PORTEC-2HIR Vaginal brachytherapy*>2/3 myoinvasion+extensiveLVSI+grade 2-3

Vaginal brachytherapy±chemotherapy

II GOG-99HIRor PORTEC-2HIR Vaginal brachytherapy±EBRT*Stromal invasion and >2/3myoinvasion+extensiveLVSI+grade 2-3

Vaginal brachytherapy±EBRT±chemotherapy

GOG-99 HIR: age >70 y+1 risk factor/age 50-70 y +2 risk factors/age <50 y +3 risk factors. Risk factors, grade 2-3,+LVSI, >2/3 myoinvasion.

PORTEC-2 HIR: age >60 y with FIGO 1988 stage IC grade 1-2/any age with FIGO 1988 stage IIA (except deeply invasivegrade 3).

*Observation may be appropriate in certain circumstances.

EBRT indicates external beam radiotherapy; FIGO, International Federation of Gynecologists and Obstetrician; GOG,Gynecologic Oncology Group; HIR, high-intermediate risk; LVSI, lymphovascular space invasion.



less toxic regimens and importantly to directtreatment to earlier stage patients at riskfor relapse. The rationale is to intervenewith adjuvant therapy when the chancefor cure is hopefully improved.

GOG-122 was the first of several re-ported trials to challenge the long-standingrole radiation therapy held in the man-agement of patients with endometrial can-cer.12 The study evaluated abdomino-pelvicradiotherapy versus seven cycles of AP inpatients with stages III and IV (<2cmdisease). The hazard ratio for progressionwas 0.71, favoring AP (95% CI: 0.55-0.91;P<0.01). These results prompted furtherinterest in the use of chemotherapy as themain modality of adjuvant therapy forpatients with endometrial cancer.

Several studies have recently been re-ported evaluating radiation versus che-motherapy, radiation versus radiationplus chemotherapy, and radiation plusvarious combinations of chemotherapyfor patients with intermediate-risk andhigh-risk endometrial cancer.13–16 Thesestudies have included a wide variety ofpatients with variable entry criteria andhave allowed both comprehensively staged

and unstaged patients as well as a variety ofdifferent chemotherapy regimens. Someeven allowed multiple different chemother-apy regimens to be selected.15 Table 2 sum-marizes the results of these importantstudies. The Italian trial reported by Maggiet al13 involving women with ‘‘high-risk’’disease failed to showaDFSorOSbenefitfor adjuvant cisplatin-doxorubicin-cyclo-phosphamide (CDCy) comparedwith stan-dard pelvic radiotherapy. This ‘‘high-risk’’population was of lower risk than the pa-tients included in GOG-122. The JapaneseGOG has recently reported a similar trialwith CDCy versus pelvic radiotherapywith-out significant differences between arms.14

An unplanned subset analysis of the ‘‘high-intermediate risk’’ group did show an im-proved progression-free survival (84% vs.66%) and OS (90% vs. 74%) favoring theuse of CDCy chemotherapy.

Recently the Nordic Society of Gyneco-logic Oncology/European Organization forResearchandTreatmentofCancer (NSGO/EORTC-55991) combinedresults fromtheirtrial with the Italian GOG at the MarioNegri Institute (MaNGO ILIADE-III).Both trials randomly assigned women with

TABLE 2. Recent Adjuvant Disease Trials Evaluating Radiation Therapy Versus Chemo-therapy Versus the Combination of Radiation and Chemotherapy in PatientsWith Intermediate/High-risk Endometrial Cancer

Group/Protocol/PI N Stages Regimen5-y PFS(%)

5-y OS(%)

GOG-122, Randall et al12 386 III, IV DC vs. WART 50* 55*38* 42*

Italian, Maggi et al13 340 I-III CDCy vs. PXRT 63 6663 60

JGOG, Susumu et al14 385 I-III CDCy vs. PXRT 82 8584 87

NSGO/EORTC,Hogberg et al15

540 I-III Multiple+PXRTvs. PXRT

78* 82*

69* 75*GOG-184, Homesley et al16 552 III, IV PXRT+DC 62 3-y NS

PXRT+PDC 64% 3-y

* Statistically significant difference.

C indicates cisplatin; Cy, cyclophosphamide; D, doxorubicin; GOG, Gynecologic Oncology Group; JGOG, JapaneseGynecologic Oncology Group; NS, not significant; NSGO-EORTC, The Nordic Society of Gynecologic Oncology/EuropeanOrganisation for Research and Treatment of Cancer; OS, overall survival; P, paclitaxel; PFS, progression-free survival; PI,principal investigator; PXRT, pelvic radiotherapy; WART, whole abdominal radiotherapy.



intermediate/high-risk stages I to III endo-metrial cancer and no residual disease toreceive pelvic radiotherapy with or withoutchemotherapy. Several different chemother-apy regimens were allowed including APand carboplatin-paclitaxel (CP). This studyshowed a 36% reduction in the risk ofrelapse or death (HR: 0.64; 95%, CI: 0.41-0.99; P=0.04) and improved cancer-speci-fic survival (HR: 0.55; 95% CI: 0.35-0.88;P=0.01).15 GOG-184 randomized ad-vanced-stage patients (12% with stageIV) who underwent ‘‘volume-directed’’or involved field radiotherapy to eitherAP or TAP. Granulocyte colony-stimu-lating factor was used in both arms. Thestudy concluded that the addition of pa-clitaxel to cisplatin and doxorubicin aftersurgery and radiation was not associatedwith a significant improvement in recur-rence-free survival, but resulted in in-creased toxicity. It was suggested thatthe subgroup with gross residual diseaseat their initial surgery may benefit fromthe TAP regimen.16

Results of these trials suggest that thecombination of radiation plus chemother-apymay provide selected patientswith thebest chance of an improved survival. Themost appropriate regimen to combinewith radiation therapy seems to be eitherAP or CP.15,16 The use of TAP in thissetting seems to add significant toxicitywithout a tangible benefit.

The Cochrane review group recentlyreported on the role of adjuvant chemo-therapy after hysterectomy for endome-trial adenocarcinoma at the 2010 meetingof the International Gynecological Can-cer Society in Prague, Czech Republic.Seven randomized trials met inclusioncriteria; 4 trials evaluated adjuvant che-motherapy added to radiotherapy and3 compared platinum-based combinationregimens directlywith radiotherapy.Datafrom 1919 women showed an OS advan-tage from adjuvant chemotherapy [riskratio (RR)=0.85 (95% CI: 0.75-0.96)].This seemed similar regardless of random

or routine radiotherapy use. A risk ratioof 0.80 (95% CI: 0.70-0.92) was observedif the analysis was restricted to modernadjuvant platinum-based regimens (num-ber needed to treat =14; relative riskreduction of 20% with an absolute riskreduction of 7%). Chemotherapy reducedthe risk of developing a recurrence outsidethe pelvis [RR=0.73 (95% CI: 0.59-0.92)]. Chemotherapymay reduce the riskof a pelvic recurrence [RR=0.36 (95%CI: 0.13-1.03)] but only when radiother-apy was given to both groups. However,substituting radiotherapy for chemother-apy seemed to increase the risk of pelvicrecurrence [RR=1.28 (95%CI: 0.89-1.84)].The reviewers concluded that postoperativehigh-dose cyclical platinum-based chemo-therapy forhigh-risk endometrial carcinomahas a small survival advantage and re-duces the risk of metastatic disease irre-spective of radiotherapy.

In opposition to the slow evolution ofdifferent chemotherapy regimens for en-dometrial cancer, trials in patients withovarian cancer have proceeded quite ra-pidly. In the ovarian cancer literature CPhas become a standard regimen with pre-dictable and manageable toxicity. Mostrecently, this regimen has also been ex-tensively evaluated both in retrospectiveand prospective phase II studies as wellas ongoing phase III trials in endo-metrial cancer with favorable results.Use of this combination is largely basedon physicians’ vast experience with thisregimen’s tolerability and its proven effi-cacy in ovarian cancer. The CP regimen’sefficacy has been favorable in severalphase II studies with response rates ran-ging from 40% to 60%. In addition, themanageable toxicity associated with thiscombination compares favorably withthe TAP regimen. Furthermore, this regi-men seems well tolerated even when com-bined with pelvic radiotherapy. We arecurrently awaiting results from GOG-209which compared the standard TAP regi-men derived from GOG-177 with CP in



patients with advanced and recurrentdisease.

Systemic Hormonal Therapyin Early-stage EndometrialCancerIn 1989, Vergote et al17 studied the role ofadjuvant systemic therapy in patientswithclinical stages I to II endometrial cancer.The investigators randomized 1148 post-hysterectomy patients to intramuscularprogesterone caproate injections for 1 yearversus observation. Patients with stage IIdisease were treated with preoperativebrachytherapy. Postoperatively, patientswith grade 3 or deeply invasive tumorswere treated with pelvic radiotherapy andvaginal brachytherapy was administeredto all other patients. There was no im-provement in survival attributable to pro-gestational therapy. However, one mustrecognize that patients were not stratifiedby receptor status and the paucity ofpatients with grade 1 tumors (B40%) sug-gest that this study was largely underpow-ered to show improvements in survival inthe group that biologically could havebenefited the most.

More recently, Decruze and Green18

reviewed hormone therapy in advancedand recurrent endometrial cancer by eval-uating 5 randomized trials and 29 phase IIstudies comprising a total of 2471 pa-tients. For the grade 1 or 2 tumors, theresponse rate for progestational agentswere in the range of 11%to 56%with a pro-gression-free survival of 2.5 to 14 months.Higher response rates are obviously seen inprogesterone receptor-positive cases. Grade3 or 4 toxicity was observed in less than 5%of participants.

The most appropriate role for hormo-nal therapy as far as combining and se-quencing with cytotoxic chemotherapyremains unknown. Hormonal therapyshould be considered at some point in themanagement of patients with low-grade

tumors requiring systemic therapy, espe-cially if progesterone-receptor positive.The large therapeutic index associatedwith hormonal therapy makes one won-der whether these agents could becomepart of the multimodal managementof receptor-positive intermediate/high-riskpatients. However, given the current data,there does not seem to be any proven rolefor adjuvant hormonal therapy in patientswith early-stage endometrial cancer.

Ongoing Clinical Trialsand a Look Into the FutureAfter much debate, the GOG has deter-mined CP to be the most appropriateregimen to be studied in 3 recently acti-vated large GOG trials (GOG 249, 258,and 86P). GOG-249, ‘‘Phase III Trialof Pelvic Radiation Therapy Versus Va-ginal Cuff Brachytherapy Followed byPaclitaxel/Carboplatin Chemotherapy inPatients with High-risk, Early-stageEndometrial Carcinoma’’ was activatedin March, 2009 with a planned samplesize of 562 which is estimated to takeapproximately 6 years for the final resultsto be known. The vaginal cuff brachyther-apy will be followed by 3 cycles of che-motherapy with carboplatin (area underthe curve 6) and paclitaxel (175mg/m2).GOG-258, ‘‘ARandomized Phase III Trialof Cisplatin and Tumor Volume DirectedIrradiation Followed by Carboplatin andPaclitaxel vs. Carboplatin and Paclitaxelfor Optimally Debulked, Advanced Endo-metrial Carcinoma’’ was activated in June,2009. Eight hundred and four patients areplanned to be enrolled in just over 4 yearswith final results being available in 5 to6 years.

As we look into the future, it seemscurrently available biologic and a newcytotoxic agent may have activity in en-dometrial carcinoma: bevacizumab, tem-sirilomus, and ixabepilone.19–21 Resultsof a phase II trial with bevacizumab



was recently reported (GOG-229E) andsingle-agent activity seemed evident witha 13.5% response rate with 40.4% of pa-tients were progression free at 6 months.TheGOG is now combining bevacizumabwith carboplatin and paclitaxel in arandomized phase II trial. GOG-86P,‘‘A three arm randomized phase II studyof paclitaxel/carboplatin/bevacizumab,paclitaxel/carboplatin/temsirilomus, andixabepilone/carboplatin/bevacizumab asinitial chemotherapy for measurablestage III or IVA, Stage IVB, or RecurrentEndometrial Cancer’’ was activated Sep-tember, 2009. The toxicity of the cytotoxicchemotherapy becomes even more rele-vant as we attempt to combine these newbiologic therapies in patients that willoften have previously received radiationtherapy. We must also realize that giventhe relatively smaller numbers of patientswith endometrial cancer at high risk forrecurrence or with recurrent disease, op-timal trial design that compares new regi-mens with the ‘‘standard’’ (TAP) from theprevious phase III trial may not always befeasible.

A New Look at RiskStratification and PotentialFuture TherapeuticImplicationsDespite complete surgical staging, manywomen with surgically confirmed or per-ceived early-stage endometrial cancer stillexperience progression or recurrences andultimately die from their disease. As pre-viously discussed, various algorithms forbetter prediction of recurrence and pro-gression have been proposed. These com-monly include prognostic clinicopathologicfeatures such as lymph-vascular space in-vasion, grade, and age. Unfortunately, the1988 FIGO surgical staging that was usedfor more than a decade for risk stratifica-tion and treatment triage proved to lack thedesired prognostic precision which in part

led to the revision of the surgical staging byFIGO in 2009.3

Although our understanding of thepathophysiology and molecular biologyof endometrial cancers has evolved tre-mendously,weare still unable to accuratelyidentify patients destined to experienceprogression or recurrence and ultimatelysuccumb to this disease. Current researchinterest is focused on the development andvalidation of novel biomarkers for riskstratification and prediction of response totherapy. A validated prognostic biomarkermay not only identify women at high riskfor recurrence and death but may alsopredict response to currently availabletreatments (chemotherapy, radiation, and/or cell cycle modulators). Further under-standing of key biologic processes in thisdisease might also facilitate the develop-ment of novel-targeted therapies for thisand other malignancies.

Multiple-acquired molecular defectshave been described in the histogenesisand progression of endometrioid endo-metrial carcinoma. It is well known thatthese tumors are characterized by a highfrequency of inactivating PTEN mutations(25%to80%), lossofDNAmismatchrepairas evidenced by microsatellite instability(25% to 30%), and to a lesser degree muta-tions in KRAS2, FGFR2, and CTNNB1.These molecular features have been inves-tigated as potential biomarkers sometimeswith conflicting results. Unfortunately, todate none of these relatively common al-terations have proven clinical value in riskstratification or for the clinical manage-ment of endometrial cancer patients.

Other less common events have alsobeen studied. Early cytogenetic studiessuggested that tumor ploidy was an in-dependent prognostic factor in womenwith endometrial cancer. Analyses ofmultiple immunohistochemical markersalso suggested that tumor expression ofmultiple antigens (HER-2/neu, CD44,urokinase plasminogen activator rece-ptor, P-cadherin, E-cadherin, syndecan-1,



versican, indoleamine 2,3-dioxygenase,BNIP3, vascular endothelial growth fac-tor, and cathepsin B, among others) couldpredict persistent or recurrent disease.Several biologic fluid biomarkers havealso been evaluated. For example, low-tissue levels of cathepsin D and increasedcirculating levels of YKL-40 have beenassociated with worse clinical outcomes.Unfortunately, these studies have severallimitations. Some have relied on rathersubjective quantitative techniques andnone of them have undergone rigorousvalidation. Unfortunately, no validatedprognostic biomarkers have been adoptedclinically.

Ideally, a biomarker for risk stratifica-tion of early-stage endometrial cancerwould be present in most patients, easilydetectable, biologically relevant, and ableto indicate molecular alterations that of-fer insight to best therapeutic approachesfor individual patients. Such developmentwould certainly change current prognos-tic and therapeutic paradigms for womenwith early-stage endometrial cancer. Wecan foresee a future in which biomarkersassist in determining the best surgicalapproach, identify patients at risk of re-currence and assist in determining the besttherapeutic interventions for individualpatients.

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